The Longevity Glossary

A diabetes drug that slows the digestion of carbohydrates in the gut. In a mouse study run at three sites, it extended median lifespan by 22% in males but only 5% in females; whether it slows ageing in people is untested. Technical: Genetically heterogeneous mice at three test sites: maximum (90th percentile) lifespan increased 11% in males and 9% in females. Read: Rapamycin → Related: 17α-estradiol, Rapamycin, Metformin Source: PubMed (DOI)

Blood-pressure drugs, such as ramipril, that block the angiotensin-converting enzyme. In the HOPE trial of 9,297 high-risk people aged 55 and over without heart failure, ramipril 10 mg a day reduced heart attack, stroke or cardiovascular death from 17.8% to 14.0% over about five years. Technical: HOPE: relative risk 0.78 for the primary composite outcome. Related: Blood pressure, Polypill Source: PubMed (DOI)

A toxic metabolite of alcohol metabolism; a Group 1 carcinogen that forms DNA adducts and impairs DNA repair. Central to alcohol's cancer risk. Technical: A 2025 narrative review of alcohol and cancers of the digestive tract concludes that stopping or reducing alcohol definitely lowers cancer risk; acetaldehyde, the first breakdown product of alcohol, is a key carcinogenic mechanism. Read: Alcohol and Longevity → Related: Alcohol risk threshold Source: PubMed (DOI)

Short bouts of standing or light walking that interrupt long periods of sitting. In a meta-analysis of crossover trials, frequent short light-walking breaks lowered post-meal blood glucose and insulin compared with continuous sitting, and worked better than standing breaks. Technical: Buffey 2022, Sports Med: interrupting prolonged sitting over a single day; light-intensity walking was the superior break; neither standing nor walking breaks changed systolic blood pressure in the pooled analysis. Read: Longevity Guide for Desk Workers → Related: Sedentary behavior Source: PubMed (DOI)

Fat cells. Their number is set by early adulthood, but about a tenth are replaced each year. Technical: Adipocyte number is a major determinant of fat mass in adults; it stays constant through adulthood in lean and obese people, even after marked weight loss, so it is set during childhood and adolescence. Carbon-14 dating showed that about 10% of fat cells are renewed each year at all adult ages and body sizes. Related: Visceral Fat, Brown Adipose Tissue (BAT) Source: PubMed (DOI)

An anti-inflammatory hormone secreted by adipose tissue. Higher levels are associated with insulin sensitivity and reduced cardiovascular risk. Paradoxically, levels decrease as body fat increases. Technical: Adiponectin is encoded by apM1, the most abundant adipose-specific gene transcript. Although it is secreted only by adipose tissue, its plasma concentrations are significantly lower in people with obesity than in people without. Read: Visceral Fat → Related: Insulin Resistance Source: PubMed (DOI)

Supplements that contain hidden, unapproved drug ingredients. From 2007 to 2016 the FDA identified 776 such products, most sold for sexual enhancement, weight loss or muscle building; common hidden ingredients were sildenafil, the withdrawn weight-loss drug sibutramine, and synthetic steroids. Technical: Tucker 2018, JAMA Netw Open: 776 adulterated products from 146 companies; sexual enhancement 45.5%, weight loss 40.9%, muscle building 11.9%; 20.2% contained more than one unapproved ingredient. Read: Supplement Brand Testing and Purity → Related: Dietary supplement regulation (US), Supplement label accuracy Source: PubMed (DOI)

Proteins or fats chemically altered by sugars, linked to blood vessel damage in diabetes. Technical: AGEs are proteins or lipids that become glycated after exposure to sugars; they contribute to vascular complications by cross-linking molecules in the basement membrane of the extracellular matrix and by engaging the receptor for AGEs (RAGE). Related: HbA1c (Glycated Hemoglobin) Source: PubMed (DOI)

A keystone gut bacterium that maintains the intestinal mucus layer. Associated with metabolic health, insulin sensitivity, and reduced inflammation. Declines with age and Western diets. Technical: Reviewed as a mucus-layer bacterium that interacts with the gut immune system; as of a 2022 review, clinical studies in people with obesity and diabetes had begun, with preliminary results. Read: Gut Microbiome Optimization → Related: Microbiome Diversity, Dysbiosis Source: PubMed (DOI)

The level of drinking above which the risk of death clearly rises. In an analysis of 599,912 current drinkers in 83 studies, all-cause mortality was lowest at or below about 100 g of alcohol a week (about 12.5 UK units, or roughly 7 US standard drinks) and rose with higher intakes. Technical: Wood 2018, Lancet: individual-participant data from 19 high-income countries; the dose-response for all-cause mortality was positive and curvilinear; the study included only current drinkers, so it does not show that drinking is better than not drinking. Read: Alcohol and Longevity → Related: Dietary sodium Source: PubMed (DOI)

A bisphosphonate tablet for osteoporosis. In women with low bone density who already had a vertebral fracture, it roughly halved new vertebral fractures over about three years (8.0% versus 15.0%) and lowered hip fracture risk. Technical: Fracture Intervention Trial (vertebral fracture arm): relative risk 0.53 for new morphometric vertebral fractures; relative hazard 0.49 for hip fracture. Read: Bone Health → Related: Bisphosphonates, Denosumab, Bone mineral density (BMD) Source: PubMed (DOI)

A metabolite in the cell's energy (Krebs) cycle whose levels change with fasting, exercise and aging; in one mouse study, a calcium salt of it extended healthy life, but the NIA's multi-site Interventions Testing Program found no lifespan extension in either sex (2026). Technical: Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle whose levels change with fasting, exercise and aging. In mice, calcium AKG promoted a longer, healthier life with lower systemic inflammatory cytokines, which the authors propose works through induction of IL-10. In the multi-site Interventions Testing Program (UM-HET3 mice), alpha-ketoglutarate was among eleven compounds that did not significantly increase lifespan in male or female mice. Read: Supplements Guide → Related: Cytokines Sources: PubMed (DOI) · PubMed (DOI)

An antioxidant compound the body makes in small amounts, also sold as a supplement. In people with diabetic nerve damage, five weeks of oral ALA improved symptoms; 600 mg a day gave the best balance of benefit and side effects. Our Supplement Evidence Database rates it “Early or small trials” for diabetic nerve pain. Technical: Ziegler 2006, Diabetes Care: In people with diabetic nerve damage, five weeks of oral ALA improved symptoms; 600 mg a day gave the best balance of benefit and side effects. Other outcomes in the database: Blood sugar in type 2 diabetes: Early or small trials. Read: Alpha-lipoic acid in the Supplement Evidence Database → Source: PubMed (DOI)

A liver enzyme measured in blood; raised levels suggest liver injury. Healthy upper limits may be lower than many labs use. Technical: Using blood donors at lowest risk of liver disease, updated healthy upper limits were 30 U/L for men and 19 U/L for women, below the then-current 40 and 30 U/L, and identified hepatitis C viremia more sensitively. ALT was independently related to body mass index and to markers of abnormal lipid or carbohydrate metabolism. Ranges and units: Biomarker Reference → Related: GGT (gamma-glutamyl transferase), FIB-4 index, MASLD (Metabolic-Associated Steatotic Liver Disease) Source: PubMed (DOI)

Age-related disruption of the signalling between cells and tissues. Technical: One of the hallmarks of aging since the 2013 framework; the 2023 update kept it and listed chronic inflammation as a separate hallmark. Related: Inflammaging, SASP (Senescence-Associated Secretory Phenotype), Hallmarks of Aging Sources: PubMed (DOI) · PubMed (DOI)

A blood marker of the ovaries' remaining follicle pool; it peaks in the early 20s and declines toward menopause. Technical: AMH reflects the number of antral and pre-antral follicles, shows limited short-term variability and is used to predict ovarian response in IVF. Data on its relationship with natural fertility are very limited, and an international assay standard is still needed. Related: FSH (follicle-stimulating hormone) Source: PubMed (DOI)

A cellular energy sensor activated by low-energy states, exercise, fasting, and certain drugs (metformin, berberine). Promotes autophagy, mitochondrial biogenesis, and fat oxidation. One of the key nutrient-sensing pathways in longevity biology. Technical: AMPK is a cellular energy sensor. Activated by falling energy status, it promotes ATP production by increasing catabolic activity and conserves ATP by switching off biosynthetic pathways; it also regulates energy balance at the whole-body level. Read: AMPK → Related: mTOR (Mechanistic Target of Rapamycin), Autophagy, Metformin Source: PubMed (DOI)

A peptide that accumulates as plaques in Alzheimer's disease. In mice, its clearance from the brain increases during sleep. Whether amyloid drives the disease, rather than marking it, remains debated. Technical: Xie 2013, Science (mice): sleep or anesthesia increased brain interstitial space by 60% and the clearance rate of amyloid-beta; in people, one night of sleep deprivation raised amyloid-beta on PET (see sleep deprivation). The amyloid hypothesis remains contested even after the approval of amyloid-lowering antibodies. Read: Alzheimer's Prevention → Related: Glymphatic System, Sleep deprivation, Preclinical Alzheimer's disease Source: PubMed (DOI)

The age-related decline in the muscle's ability to build protein in response to amino acids and resistance training. Older muscle needs more protein per meal to respond fully: about 0.4 g/kg in older men versus about 0.24 g/kg in younger men. Technical: Moore 2015: myofibrillar protein synthesis requires greater relative protein intakes in healthy older than younger men (about 0.40 vs 0.24 g/kg per meal for a maximal response). Read: Muscle Protein Synthesis → Related: Muscle Protein Synthesis (MPS), Protein needs in older adults, Leucine Source: PubMed (DOI)

A low level of hemoglobin in the blood. It affects about 1 in 10 adults aged 65 and over. Technical: In US national data, 11.0% of men and 10.2% of women aged 65 and older were anemic, rising above 20% at 85 and older. About a third of cases involved nutrient deficiency, a third chronic inflammation or kidney disease, and a third had no identified cause; most were mild. Related: Ferritin, RDW (red cell distribution width), Vitamin B12 (cobalamin) Source: PubMed (DOI)

A comparison of blood pressure at the ankle with blood pressure in the arm, used to detect peripheral artery disease. In 2018 the USPSTF found the evidence insufficient to recommend ABI screening in adults without symptoms. Technical: USPSTF 2018 recommendation statement: insufficient evidence to assess the balance of benefits and harms of screening generally asymptomatic adults for peripheral artery disease and cardiovascular risk with the ABI. Read: Advanced Cardiovascular Testing → Related: Pulse wave velocity (PWV), CIMT (carotid intima-media thickness) Source: PubMed (DOI)

The idea that some genes help early in life but cause harm later in life. Technical: Developed by George Williams in 1957, after hints from Peter Medawar: animals carry genes that enhance fitness early in life but reduce it later, a genetic trade-off between early-life fitness and late-life mortality. Related: Disposable soma theory, Heritability of lifespan Source: PubMed (DOI)

Pills of antioxidants such as beta-carotene, vitamins A, C and E, and selenium. A Cochrane review of 78 trials in nearly 300,000 people found no overall effect on mortality and no evidence supporting them for prevention; beta-carotene and vitamin E seemed to increase mortality. Technical: Bjelakovic 2012, Cochrane: 78 randomised trials, 296,707 participants; beta-carotene and vitamin E (and possibly higher doses of vitamin A) associated with increased mortality; vitamin C and selenium had no significant effect. The authors argue antioxidant supplements should be evaluated like medicinal products. Read: Supplement Safety → Related: Beta-carotene supplements, Multivitamins Source: PubMed (DOI)

A protein carried by every potentially artery-clogging lipoprotein particle (LDL, VLDL, IDL and Lp(a)). Each particle carries one ApoB, so it counts those particles, and a 2019 review concluded it measures their risk more accurately than LDL cholesterol. Technical: Each VLDL, IDL, LDL, chylomicron and Lp(a) particle carries one apoB molecule. Cholesterol enters the arterial wall only within apoB particles, and the number entering depends mainly on how many circulate; with the exceptions of abnormal chylomicron remnants in type III hyperlipoproteinemia and Lp(a), apoB particles appear equally atherogenic. Read: ApoB → Ranges and units: Biomarker Reference → Related: LDL cholesterol (LDL-C), Non-HDL cholesterol, Lp(a) (Lipoprotein(a)), CAC Score (Coronary Artery Calcium Score) Source: PubMed (DOI)

The ratio of apolipoprotein B to apolipoprotein A1. In a 52-country study, it was the lipid measure most strongly linked to heart attack. Technical: In the INTERHEART case-control study across 52 countries, the non-fasting ApoB/ApoA1 ratio had the highest population-attributable risk for acute myocardial infarction (54%) and the highest odds ratio per standard deviation (1.59), outperforming the LDL/HDL cholesterol ratio (37%) and the total/HDL cholesterol ratio (32%) in every ethnic group, both sexes and all ages. Related: ApoB (Apolipoprotein B), HDL cholesterol (HDL-C), Total cholesterol Source: PubMed (DOI)

A gene with three common variants (ε2, ε3, ε4). In a large analysis of people of European ancestry, one ε4 copy raised Alzheimer's risk about 3-fold and two copies about 15-fold. Technical: Farrer 1997, JAMA: meta-analysis of APOE genotype and Alzheimer's disease stratified by ethnicity; odds ratios were highest in white participants and lower in African American and Hispanic participants. Liu 2013, Nat Rev Neurol: APOE4 also affects amyloid clearance and lipid transport in the brain. Read: Longevity Genomics → Related: Amyloid-Beta, FINGER trial Sources: PubMed (DOI) · PubMed (DOI)

Withania somnifera, a herb from Ayurvedic medicine, sold as a supplement for stress and sleep. In 64 adults with chronic stress, a root extract improved stress resistance and self-rated quality of life. Our Supplement Evidence Database rates it “Early or small trials” for stress and anxiety. Technical: Chandrasekhar 2012, Indian J Psychol Med: In 64 adults with chronic stress, a root extract improved stress resistance and self-rated quality of life. Salve 2019, Cureus: In a small trial in healthy adults, an aqueous root extract reduced stress and anxiety and improved sleep quality. Read: Ashwagandha in the Supplement Evidence Database → Sources: PubMed (DOI) · PubMed (DOI)

Daily low-dose aspirin for people who have not had a heart attack or stroke. In the ASPREE trial of 19,114 healthy adults aged 70 and older (65 and older for some US groups), 100 mg a day did not extend disability-free survival and increased major bleeding (3.8% versus 2.8%). Technical: ASPREE: hazard ratio 1.01 for the composite of death, dementia or persistent physical disability; hazard ratio 1.38 for major haemorrhage; stopped early for futility after a median of 4.7 years. Source: PubMed (DOI)

Cells that tile the entire brain and spinal cord and carry out many essential functions. Technical: Astrocytes contiguously tile the entire central nervous system and perform many essential functions in the healthy brain; they respond to all forms of injury through reactive astrogliosis, a pathological hallmark of structural lesions. Related: Microglia, Blood-brain barrier Source: PubMed (DOI)

Progressive buildup of lipid-laden plaques in arterial walls driven by ApoB-containing lipoprotein particles. The pathological process underlying heart attacks and strokes. Begins decades before clinical events. Technical: Ference 2017, Eur Heart J (EAS consensus): genetic, epidemiologic, Mendelian randomization and trial evidence together show that LDL causes atherosclerotic cardiovascular disease, with risk related to cumulative exposure over time. Read: ApoB → Related: ApoB (Apolipoprotein B), LDL cholesterol (LDL-C), CAC Score (Coronary Artery Calcium Score) Source: PubMed (DOI)

The molecule cells use as their main energy currency. Technical: ATP is the energy exchange factor that connects the building-up and breaking-down sides of metabolism, and it fuels muscle contraction, phosphorylation reactions and active transport; its role as a substrate for muscle contraction was discovered in 1929. Related: AMPK (AMP-Activated Protein Kinase), Mitochondria Source: PubMed (DOI)

A cellular recycling process that degrades damaged organelles, misfolded proteins, and intracellular pathogens. Activated by fasting, exercise, rapamycin, and AMPK signaling. One of the 12 hallmarks of aging. Declines with age. Technical: Disabled macroautophagy was added to the hallmarks of aging in the 2023 update; it was not among the nine hallmarks proposed in 2013. Read: Autophagy → Related: Mitophagy, Proteostasis, Hallmarks of Aging Sources: PubMed (DOI) · PubMed (DOI)

Bacopa monnieri, a herb from Ayurvedic medicine, sold as a supplement for memory. A trial in older adults found bacopa improved cognitive performance. Our Supplement Evidence Database rates it “Supported” for memory and attention. Technical: Calabrese 2008, J Altern Complement Med: A trial in older adults found bacopa improved cognitive performance. Morgan 2010, J Altern Complement Med: In healthy older Australians, bacopa improved memory, with digestive side effects such as cramps and nausea. Read: Bacopa in the Supplement Evidence Database → Sources: PubMed (DOI) · PubMed (DOI)

A growth factor important for neuroplasticity, memory formation and neuronal survival. Exercise raises it: a single session has a moderate effect in meta-analyses, and regular training strengthens the response. Low levels are associated with depression and cognitive decline. Technical: BDNF is a neurotrophin that may mediate the effects of exercise on cognition and mood. A meta-analysis of 29 studies with 1,111 participants examined how single exercise sessions and regular training change BDNF levels in humans. Read: BDNF → Related: Hippocampal Neurogenesis Source: PubMed (DOI)

An oral cholesterol-lowering drug studied in people who cannot tolerate statins. In 13,970 such patients, it lowered LDL cholesterol by about 21 percentage points more than placebo and reduced major cardiovascular events (11.7% versus 13.3%) over a median of 40.6 months. Technical: CLEAR Outcomes: bempedoic acid 180 mg daily versus placebo; hazard ratio 0.87 for the four-component major adverse cardiovascular events end point. Read: ApoB → Related: Statins, Ezetimibe Source: PubMed (DOI)

A plant alkaloid that activates AMPK, lowers blood glucose, reduces LDL cholesterol, and modulates the gut microbiome. Often called 'nature's metformin' due to overlapping mechanisms, though the evidence base is smaller. Technical: Yin 2008, Metabolism: In a small pilot trial in type 2 diabetes, berberine lowered blood sugar and improved blood lipids. Dong 2012, Evid Based Complement Alternat Med: A meta-analysis found berberine lowered blood sugar and blood lipids in type 2 diabetes, but the trials were small and of low quality. Our Supplement Evidence Database rates berberine “Supported” for blood sugar in type 2 diabetes. Read: Berberine → Sources: PubMed (DOI) · PubMed (DOI)

Cells in the pancreas that make insulin; people with type 2 diabetes have fewer of them. Technical: In pancreatic tissue from 124 autopsies, people with obesity and type 2 diabetes had a 63% deficit in relative beta-cell volume (40% with impaired fasting glucose) compared with non-diabetic people with obesity, and beta-cell death by apoptosis was increased 3- to 10-fold, while replication was very low in all groups. Related: Insulin, Insulin Resistance Source: PubMed (DOI)

Supplements of beta-carotene, the orange pigment in carrots that the body can turn into vitamin A. In the ATBC trial of 29,133 male smokers, beta-carotene raised lung cancer incidence by 18% and total mortality by 8%, and the US Preventive Services Task Force recommends against it for preventing heart disease or cancer. Technical: ATBC 1994, N Engl J Med: 20 mg/day beta-carotene for 5 to 8 years in Finnish male smokers aged 50 to 69. USPSTF 2022: D recommendation against beta-carotene or vitamin E supplements for preventing cardiovascular disease or cancer. Read: Supplement Safety → Related: Antioxidant supplements Sources: PubMed (DOI) · PubMed (DOI)

The process of breaking down fatty acids for energy in mitochondria. Increased by fasting, exercise and glucagon signalling, and central to metabolic flexibility. Technical: Houten 2016 reviews the biochemistry and physiology of mitochondrial fatty acid oxidation and the disorders caused when it fails. Read: GLP-1 Agonists → Related: Metabolic Flexibility, Mitochondria Source: PubMed (DOI)

The proportion of a substance that reaches the circulation after you take it. Different forms of the same nutrient or drug can differ in how well they are absorbed. Technical: Defined in US regulations (21 CFR 320.1) as the rate and extent to which the active ingredient is absorbed and becomes available at the site of action; it differs between chemical forms and formulations of the same nutrient. Read: Brand Testing → Related: Ubiquinol Source: Standard pharmacological definition (e.g., US FDA, 21 CFR 320.1)

An estimate of how old your body is functionally, as opposed to your chronological age. It is measured with epigenetic clocks (DNA methylation), blood biomarker algorithms or composite assessments, and it can differ from chronological age. Technical: Horvath 2018 reviews DNA methylation-based epigenetic clocks, which link developmental and maintenance processes to biological ageing; different clocks estimate different things, and none is validated for individual clinical decisions. Read: Biological Age Testing → Related: Chronological Age, Epigenetic Clock, PhenoAge Source: PubMed (DOI)

Osteoporosis drugs, such as zoledronic acid, that reduce bone turnover. In a three-year trial of 7,765 postmenopausal women with osteoporosis, a once-yearly zoledronic acid infusion cut new vertebral fractures by 70% and hip fractures by 41% compared with placebo. Technical: HORIZON: zoledronic acid 5 mg infused at baseline, 12 and 24 months; vertebral fracture 3.3% versus 10.9%; hip fracture hazard ratio 0.59. Related: Bone mineral density (BMD), DEXA Scan (Dual-Energy X-Ray Absorptiometry) Source: PubMed (DOI)

The force of blood against the artery walls, written as systolic over diastolic in mmHg. US categories: normal under 120/80; elevated 120-129 and under 80; stage 1 high blood pressure 130-139 or 80-89; stage 2 140 or higher or 90 or higher. Technical: Category thresholds as published by MedlinePlus (NIH): normal <120 and <80; elevated 120-129 and <80; stage 1 130-139 or 80-89; stage 2 >=140 or >=90 mmHg. Ranges and units: Biomarker Reference → Related: Pulse wave velocity (PWV), Resting heart rate Source: MedlinePlus: High Blood Pressure (medlineplus.gov, checked 2026-10-01)

The barrier formed by the brain's blood vessels that keeps blood-borne substances, microbes and cells out of the brain. Technical: The blood-brain barrier limits entry of blood-derived products, pathogens and cells into the brain, which is essential for normal neuronal function. Imaging in living people showed age-dependent breakdown of the barrier in the hippocampus that worsened with mild cognitive impairment, suggesting it is an early event in brain aging. Related: Astrocytes, White matter hyperintensities Source: PubMed (DOI)

Regions identified as having unusually many long-lived people: Okinawa (Japan), Sardinia (Italy), Nicoya (Costa Rica), Ikaria (Greece) and Loma Linda (California). Shared habits include plant-forward diets, daily movement and strong social ties. The accuracy of some of the underlying age records has been questioned. Technical: Poulain 2004 identified a mountain area of Sardinia with extreme longevity, especially among men, the origin of the Blue Zones idea. Read: Blue Zones → Related: Healthspan Source: PubMed (DOI)

The amount of mineral in bone, usually measured with a DEXA scan to diagnose osteoporosis. The USPSTF recommends osteoporosis screening for women 65 and older and for younger postmenopausal women at increased risk; the evidence for screening men is insufficient. Technical: Measured by single- or dual-energy absorptiometry, which has high specificity but lower sensitivity. USPSTF 2025: B recommendation for women aged 65 or older and for postmenopausal women younger than 65 at increased risk; insufficient evidence for men. Related: DEXA Scan (Dual-Energy X-Ray Absorptiometry), Sarcopenia Sources: PubMed (DOI) · PubMed (DOI)

Fat tissue that burns energy to make heat. In adults it is found more often in women, in younger people and in cold weather. Technical: Brown adipose tissue produces heat through uncoupling protein 1 (UCP1). In 3,640 PET-CT scans from 1,972 adults, it was detected in 7.5% of women and 3.1% of men, and detection was less likely with older age, warmer outdoor temperature, beta-blocker use and, in older patients, higher body mass index. Read: Cold Exposure → Related: Visceral Fat Source: PubMed (DOI)

A short-chain fatty acid produced when gut bacteria ferment dietary fiber. It is the main energy source for the cells lining the colon, supports the intestinal barrier and has anti-inflammatory effects. Technical: Liu 2018: a four-carbon short-chain fatty acid produced by microbial fermentation of dietary fibre in the lower intestine; its effects depend on dose and context. Read: Gut Microbiome and Longevity → Related: Fiber (Dietary), Microbiome Diversity Source: PubMed (DOI)

A fragment released in equal amounts with the body's own insulin, used to measure how much insulin the pancreas is making. Technical: C-peptide is a widely used measure of beta-cell function: it is produced in equimolar amounts to endogenous insulin but is cleared at a more constant rate over a longer time, and its level is associated with diabetes type and duration. Related: Fasting Insulin, Beta cells, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) Source: PubMed (DOI)

A CT-based measurement of calcified plaque in the coronary arteries. A score of zero indicates a low 10-year risk of cardiovascular events. It is most useful for refining risk in adults whose risk is intermediate. Technical: Budoff 2018, Eur Heart J (MESA, over 10 years of follow-up): CAC predicted atherosclerotic cardiovascular events across sex and ethnic groups; scores of zero carried low event rates. Read: CAC Scoring → Ranges and units: Biomarker Reference → Related: Atherosclerosis, MACE (Major Adverse Cardiovascular Events) Source: PubMed (DOI)

How caffeine affects sleep. In a controlled trial, 400 mg of caffeine (about four cups of coffee) taken at bedtime, 3 hours before or even 6 hours before bed significantly disturbed sleep compared with placebo, supporting a cutoff of at least 6 hours before bedtime. Technical: Drake 2013, J Clin Sleep Med: home sleep monitoring with placebo-controlled caffeine dosing at 0, 3 and 6 hours before habitual bedtime. Read: The Sleep Optimization Guide → Related: Coffee, Sleep duration Source: PubMed (DOI)

Reducing calorie intake by 10-25% below ad libitum levels without malnutrition. The most consistently demonstrated lifespan-extending intervention in animal models. The CALERIE trial showed metabolic benefits in humans at ~12% restriction. Technical: CALERIE (Kraus 2019, Lancet Diabetes Endocrinol): 218 healthy non-obese adults were randomized to a prescribed 25% restriction or ad libitum diet for 2 years; the restriction group achieved an 11.9% reduction in intake and lost 7.5 kg on average, with improvements in several cardiometabolic risk factors. Read: Caloric Restriction → Related: Intermittent Fasting, Nutrient Sensing, Autophagy Source: PubMed (DOI)

An SGLT2-inhibitor diabetes drug that, in the US Interventions Testing Program, extended median lifespan by 14% in male mice but not in female mice; whether it slows ageing in people is untested. Technical: Fed from 7 months of age at three test sites; lowered fasting glucose and improved glucose tolerance in both sexes; the authors attribute the male benefit to blunted glucose peaks, as with acarbose. Read: Rapamycin → Related: SGLT2 Inhibitors, Acarbose Source: PubMed (DOI)

Heart muscle cells; they renew, but slowly, and more slowly with age. Technical: Using carbon-14 from Cold War nuclear bomb tests to date cells, researchers found that human cardiomyocytes renew, falling from about 1% turning over each year at age 25 to 0.45% at age 75. Related: Stem Cell Exhaustion Source: PubMed (DOI)

How well your heart, lungs and muscles supply and use oxygen during sustained exercise, usually measured on a treadmill test or as VO2 max. In a Cleveland Clinic study of 122,007 patients, the least fit had about 5 times the mortality risk of the fittest, a risk comparable to or greater than smoking or diabetes. Technical: Mandsager 2018, JAMA Netw Open: risk-adjusted all-cause mortality fell steadily with higher treadmill-measured fitness with no apparent upper limit; low vs elite adjusted HR 5.04. Read: VO2 Max and Longevity → Related: VO2 Max, Heart rate recovery, METs (metabolic equivalents) Source: PubMed (DOI)

A study that compares people who have a condition (cases) with similar people who do not (controls) and looks back at their past exposures. It is efficient for rare outcomes; one such analysis compared 80,396 women with blood clots to matched controls to study hormone therapy. Technical: Vinogradova 2019, BMJ: two nested case-control studies in UK primary care databases; case-control designs estimate odds ratios and are prone to recall and selection bias. Related: Observational study, Cohort study Source: PubMed (DOI)

A structured talking and behavioral therapy for chronic insomnia that targets the habits and thoughts that keep people awake, using techniques such as sleep restriction and stimulus control. The American College of Physicians recommends it as the first treatment for all adults with chronic insomnia, before sleeping pills. Technical: Qaseem 2016, Ann Intern Med (ACP guideline): CBT-I as initial treatment for chronic insomnia disorder; medication considered only when CBT-I alone is unsuccessful, through shared decision-making. Read: The Sleep Optimization Guide → Related: Sleep duration, Orthosomnia Source: PubMed (DOI)

A CT scan with injected contrast that images the heart's arteries. In people with stable chest pain, adding it to standard care lowered five-year coronary death or heart attack from 3.9% to 2.3%, but screening people with diabetes and no symptoms did not reduce events. Technical: SCOT-HEART (n=4,146, stable chest pain): 5-year coronary death or non-fatal MI 2.3% vs 3.9%. FACTOR-64 (n=900, asymptomatic diabetes): no reduction in the composite outcome; findings do not support CCTA screening. Read: Advanced Cardiovascular Testing → Related: CAC Score (Coronary Artery Calcium Score), CIMT (carotid intima-media thickness) Sources: PubMed (DOI) · PubMed (DOI)

An enzyme that breaks down NAD+; its activity rises with age. Technical: The NAD-degrading enzyme CD38 increases in expression and activity with aging and is required for the age-related decline in NAD and mitochondrial dysfunction, acting partly through SIRT3. It is also the main enzyme that degrades the NAD precursor NMN in vivo. Related: NAD+ (Nicotinamide Adenine Dinucleotide), NMN (Nicotinamide Mononucleotide), NAMPT (Nicotinamide phosphoribosyltransferase) Source: PubMed (DOI)

The permanent arrest of cell division. Senescent cells accumulate with age and secrete inflammatory factors (the SASP) that damage neighboring tissue. Targeted removal by senolytic drugs is a major area of longevity research. Technical: Senescence arrests cell proliferation essentially permanently, which suppresses cancer, and senescent cells secrete many factors associated with inflammation and malignancy (the SASP). In progeroid mice, life-long removal of p16Ink4a-positive senescent cells delayed the onset of age-related problems in fat, muscle and the eye. Read: Cellular Senescence → Related: SASP (Senescence-Associated Secretory Phenotype), p16INK4a, Senolytics, Hayflick limit Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

A concept popularized by Peter Attia: identifying the 10 physical tasks you want to perform in the last decade of life (e.g., carrying groceries, playing with grandchildren, climbing stairs) and training for them now. Technical: A planning concept from the book Outlive (Attia and Gifford, 2023) rather than a research measure: list the physical tasks you want to manage late in life and train for them now. Read: Peter Attia's Medicine 3.0 → Related: Medicine 3.0, Muscle-strengthening activity Source: Attia P, Gifford B. Outlive: The Science and Art of Longevity. Harmony; 2023.

A widely used system for rating how confident we can be in a body of evidence, from high to very low. For example, a review of red and processed meat rated its findings as low certainty, and the Endocrine Society used GRADE for its testosterone guideline. Technical: Zeraatkar 2019, Ann Intern Med: very small associations with low-certainty evidence. Bhasin 2018, J Clin Endocrinol Metab: GRADE used to describe strength of recommendations and quality of evidence. Related: Systematic review, Umbrella review Sources: PubMed (DOI) · PubMed (DOI)

An immune sensor that detects DNA in the wrong place inside cells, including in ageing cells. Technical: cGAS recognizes chromatin fragments that leak into the cytoplasm of senescent cells, and this innate DNA sensing regulates senescence and the senescence-associated secretory phenotype (SASP). Related: SASP (Senescence-Associated Secretory Phenotype), Cellular Senescence Source: PubMed (DOI)

A wearable sensor that records glucose levels around the clock for days at a time. In healthy, non-obese people without diabetes, average sensor glucose was about 98 to 99 mg/dL. Technical: In a multicenter study of healthy children and adults without diabetes wearing a blinded Dexcom G6 sensor for up to 10 days, glucose was above 140 mg/dL for a median of 2.1% of the time and below 70 mg/dL for 1.1%, the average within-person coefficient of variation was 17%, and people over 60 averaged 104 mg/dL. Read: CGM for Non-Diabetics → Related: Time in range (TIR), Glycemic Variability, HbA1c (Glycated Hemoglobin) Source: PubMed (DOI)

Reduced kidney function or kidney damage: by the KDIGO definition, an eGFR below 60 or a urine albumin-to-creatinine ratio above 30 mg/g. Technical: A 2009 KDIGO Controversies Conference, drawing on 45 cohorts with 1,555,332 participants, kept this definition while adding albuminuria stages, splitting stage 3 and emphasizing the clinical diagnosis in classification. Related: eGFR (Estimated Glomerular Filtration Rate), UACR (urine albumin-to-creatinine ratio), Creatinine, Nephrons Source: PubMed (DOI)

The number of years since birth. Distinct from biological age: two 50-year-olds can have quite different biological ages based on epigenetic and metabolic markers. Technical: Epigenetic clocks such as Horvath's were first trained to predict chronological age; the gap between a clock estimate and chronological age is used as a marker of biological aging (Horvath 2018). Read: Biological Age Testing → Related: Biological Age, Horvath Clock Source: PubMed (DOI)

The thickness of the inner layers of the carotid (neck) artery wall, measured by ultrasound. In 45,828 people, adding it to the Framingham risk score barely improved prediction of heart attack and stroke. Technical: Individual-participant meta-analysis of 14 cohorts: net reclassification improvement 0.8% when common CIMT was added to the Framingham Risk Score; judged unlikely to be of clinical importance. Read: Advanced Cardiovascular Testing → Related: CAC Score (Coronary Artery Calcium Score), CCTA (coronary CT angiography), Pulse wave velocity (PWV) Source: PubMed (DOI)

The roughly 24-hour internal clock coordinated by the suprachiasmatic nucleus (SCN) in the brain. It regulates sleep and wake, hormone release, metabolism and gene expression. Long-term disruption, as in rotating night-shift work, is associated with higher cardiovascular risk. Technical: Vetter 2016, JAMA (Nurses' Health Studies): longer duration of rotating night shift work (3 or more night shifts a month on top of day and evening shifts) was associated with a significantly higher risk of coronary heart disease, and the risk fell with longer time since quitting shift work. Read: Circadian Rhythm and Longevity → Related: Social Jet Lag, Melatonin Source: PubMed (DOI)

The expansion, with age, of blood stem cells that carry acquired mutations, in people without a blood cancer. Technical: People whose blood carried such somatic mutations had higher risks of hematologic cancer (hazard ratio 11.1), death from any cause (1.4), coronary heart disease (2.0) and ischemic stroke (2.6). Related: Somatic mutations, Genomic Instability Source: PubMed (DOI)

One of the most studied drinks in nutrition research. An umbrella review of meta-analyses found coffee was more likely to benefit health than harm, with the largest risk reductions, including for all-cause mortality, at about three to four cups a day; in pregnancy, higher intake was linked to low birth weight and pregnancy loss. Technical: Poole 2017, BMJ (umbrella review): mostly observational evidence; apparent harms were largely removed by adjusting for smoking, except in pregnancy. Read: The Longevity Nutrition Blueprint → Related: Polyphenols Source: PubMed (DOI)

An observational study that follows a group of people over time and compares outcomes by their exposures. EPIC-Oxford, which followed meat eaters, fish eaters, vegetarians and vegans, is an example. Technical: Tong 2020, BMC Med (EPIC-Oxford): prospective cohort; cohort studies establish timing but remain vulnerable to confounding. Related: Observational study, Case-control study Source: PubMed (DOI)

An old anti-inflammatory drug, long used for gout, now studied for heart disease. In 5,522 people with chronic coronary disease, 0.5 mg a day reduced major cardiovascular events (6.8% versus 9.6%) over a median of 28.6 months, although deaths from non-cardiovascular causes were higher, a difference that was not statistically significant. Technical: LoDoCo2: hazard ratio 0.69 for the primary end point; hazard ratio 1.51 (95% CI 0.99 to 2.31) for non-cardiovascular death. Read: Advanced Cardiovascular Testing → Related: hsCRP (High-Sensitivity C-Reactive Protein) Source: PubMed (DOI)

The most abundant proteins in mammals; a family of 28 types. Technical: The collagen family comprises 28 members, each with at least one triple-helical domain. Some are restricted to particular tissues with specific functions, and four are membrane proteins that can also be shed from the cell surface in a soluble form. Related: Extracellular matrix (ECM) Source: PubMed (DOI)

The range of values within which the true effect plausibly lies, usually given as a 95% interval. A narrow interval means a precise estimate; an interval that crosses 1 for a ratio means the result is compatible with no effect. In SELECT, the hazard ratio of 0.80 came with an interval that excluded 1. Technical: Lincoff 2023, N Engl J Med (SELECT): hazard ratio 0.80 with a 95% confidence interval below 1; confidence intervals convey precision better than P values alone. Related: Hazard ratio, Statistical significance and power Source: PubMed (DOI)

When a third factor is linked to both an exposure and an outcome and creates a false or exaggerated association between them. For example, early studies suggested coffee was harmful, but an umbrella review found these apparent harms largely disappeared once smoking, which is common among heavy coffee drinkers, was properly accounted for. Technical: Poole 2017, BMJ: harmful associations of coffee were largely nullified by adequate adjustment for smoking, except in pregnancy. Randomization is the main protection against confounding. Related: Observational study, Mendelian Randomization Source: PubMed (DOI)

Rings, watches and bedside devices that estimate sleep from movement, heart rate and other signals rather than brain waves. In validation studies they detect sleep well but wake poorly, and agree with lab sleep studies on deep sleep only about half the time, so their stage numbers are rough estimates best used as trends. Technical: de Zambotti 2017, Behav Sleep Med (Oura vs polysomnography): agreement 65% light, 51% deep and 61% REM; wake specificity 48%. Chinoy 2021, Sleep (seven devices): sensitivity at least 0.93, specificity 0.18-0.54. Read: Sleep Tracking with Wearables → Related: Orthosomnia, Sleep Architecture Sources: PubMed (DOI) · PubMed (DOI)

An electron carrier in the mitochondrial energy chain. Levels fall with age and with statin use. Ubiquinol is its reduced form; whether it is meaningfully better absorbed is debated, and supplements have not been shown to relieve statin muscle symptoms. Technical: Banach 2015, Mayo Clin Proc: A 2015 meta-analysis found no significant benefit for statin-related muscle problems. Qu 2018, J Am Heart Assoc: A 2018 meta-analysis of 12 trials (575 patients) found less muscle pain, weakness, cramps and tiredness. Our Supplement Evidence Database rates CoQ10 “Mixed” for muscle symptoms on statins. Read: CoQ10 and Ubiquinol → Sources: PubMed (DOI) · PubMed (DOI)

The main stress hormone, produced by the adrenal glands. Chronically high cortisol, as in Cushing's syndrome, promotes visceral fat, muscle loss, high blood sugar and other features of metabolic syndrome. Technical: Cortisol is the main human glucocorticoid, released through the hypothalamic-pituitary-adrenal (HPA) axis. A review concluded that chronic stress, mainly through HPA axis dysregulation, promotes visceral fat accumulation, and that obesity in turn promotes low-grade inflammation that can chronically stimulate and disturb the stress system. Read: Chronic Stress → Ranges and units: Biomarker Reference → Related: Insulin Resistance Source: PubMed (DOI)

A bedside machine that blows air through a mask to keep the airway open during sleep, the standard treatment for moderate to severe sleep apnea. It reduces sleepiness and blood pressure, but in the SAVE trial of 2,717 adults with sleep apnea and existing cardiovascular disease it did not prevent cardiovascular events; average use was 3.3 hours a night. Technical: McEvoy 2016, N Engl J Med (SAVE): CPAP plus usual care vs usual care alone over a mean 3.7 years; low adherence may have limited the cardiovascular effect. Read: Sleep Apnea and Longevity → Related: Obstructive sleep apnea Source: PubMed (DOI)

An amino acid derivative that helps muscles regenerate ATP, the cell's energy currency, during short, intense effort. It is one of the best-studied supplements for muscle strength and lean mass alongside resistance training, and a 2023 meta-analysis found creatine improved memory, mainly in adults aged 66 to 76. Technical: Chilibeck 2017, Open Access J Sports Med: In older adults doing resistance training, creatine added about 1.37 kg of lean mass and improved upper- and lower-body strength. Our Supplement Evidence Database rates creatine “Supported” for muscle strength and lean mass, with strength training (older adults). Read: Creatine → Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

A blood marker filtered by the kidneys; estimates of kidney function based on serum creatinine are routinely used. Technical: The 2021 CKD-EPI creatinine equation omits race: in its validation, the earlier race-based equation overestimated measured GFR in Black participants and simply dropping the race term underestimated it, and for all equations at least 85% of estimates were within 30% of measured GFR. Read: eGFR Calculator → Related: eGFR (Estimated Glomerular Filtration Rate), Cystatin C, Chronic kidney disease (CKD) Sources: PubMed (DOI) · PubMed (DOI)

A trial in which each participant receives both the treatment and the comparison in turn, so each person serves as their own control. For example, in a time-restricted feeding study, men followed one eating schedule for 5 weeks and later crossed over to the other. Technical: Sutton 2018, Cell Metab: supervised controlled-feeding crossover trial; crossover designs need a washout and suit conditions that return to baseline. Related: Randomized controlled trial (RCT) Source: PubMed (DOI)

The main active compound in turmeric, sold as a supplement. In a 4-week trial in 367 people with knee osteoarthritis, a turmeric extract (1,500 mg a day) performed similarly to ibuprofen (1,200 mg a day) for pain and function; long-term evidence is limited. Technical: Kuptniratsaikul 2014, Clin Interv Aging: 367 patients with primary knee osteoarthritis randomised to Curcuma domestica extract or ibuprofen for 4 weeks; WOMAC scores improved similarly in both groups. Read: Supplement Safety → Related: Drug-supplement interactions Source: PubMed (DOI)

An alternative blood marker of kidney filtration. Combined with creatinine, it gives the most accurate estimate of kidney function. Technical: In validation data, the combined creatinine-cystatin C equation outperformed either marker alone and improved classification of GFR above or below 60 in people with a creatinine-based eGFR of 45 to 74, making it useful as a confirmatory test for chronic kidney disease; the 2021 race-free combined equation was also the most accurate. Read: eGFR Calculator → Related: eGFR (Estimated Glomerular Filtration Rate), Creatinine Sources: PubMed (DOI) · PubMed (DOI)

Small signaling proteins that regulate inflammation and immune responses. Pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) are elevated in inflammaging. Anti-inflammatory cytokines (IL-10) counterbalance them. Technical: Cytokines are signalling proteins that coordinate immune responses. With age, chronic, sterile, low-grade inflammation (inflammaging) develops and contributes to age-related disease; it is sustained by pathogens, cell debris, nutrients and gut microbiota, sensed by receptors that activate innate immune responses. Read: Inflammaging → Related: Inflammaging, SASP (Senescence-Associated Secretory Phenotype), hsCRP (High-Sensitivity C-Reactive Protein) Source: PubMed (DOI)

The number of steps taken in a day, a simple measure of overall activity. In a meta-analysis of 15 cohorts, more steps were linked to progressively lower mortality, with the benefit leveling off at about 6,000 to 8,000 steps a day in adults 60 and older and 8,000 to 10,000 in younger adults. Technical: Paluch 2022, Lancet Public Health: 15 studies, 47,471 adults; the widely promoted 10,000 steps target had little evidence behind it before this analysis. Read: Walking for Longevity → Related: Step cadence, Physical activity guidelines (US) Source: PubMed (DOI)

An SGLT2-inhibitor drug. In 4,304 people with chronic kidney disease, with or without type 2 diabetes, it reduced a composite of major kidney decline, kidney failure or death from kidney or cardiovascular causes (9.2% versus 14.5%). Technical: DAPA-CKD: hazard ratio 0.61 over a median of 2.4 years; the trial was stopped early for efficacy on the recommendation of its data monitoring committee. Read: Kidney Health → Related: SGLT2 Inhibitors, Empagliflozin, eGFR (Estimated Glomerular Filtration Rate) Source: PubMed (DOI)

The most-studied senolytic combination: dasatinib, a prescription cancer drug, and quercetin, a plant flavonoid. Small pilot trials in diabetic kidney disease and lung fibrosis reported fewer senescent-cell markers and showed the approach was feasible; larger trials are needed. Technical: Hickson 2019: D+Q decreased senescent cells in people with diabetic kidney disease in a preliminary report; Justice 2019: an open-label pilot in 14 people with lung fibrosis assessed feasibility. Larger controlled trials are needed. Read: Longevity Science 2025 → Related: Senolytics, Cellular Senescence Sources: PubMed (DOI) · PubMed (DOI)

Dietary Approaches to Stop Hypertension: an eating pattern rich in vegetables, fruits and low-fat dairy, developed to lower blood pressure. In the DASH-Sodium trial of 412 adults, both the DASH diet and lower sodium intake reduced blood pressure, in people with and without hypertension. Combining the DASH diet with the lowest sodium level produced the largest drops in blood pressure. Technical: Sacks 2001, N Engl J Med (DASH-Sodium): participants ate a typical US control diet or the DASH diet, each at high, intermediate and low sodium levels for 30 days in random order. Read: The Longevity Nutrition Blueprint → Related: Dietary sodium, Mediterranean Diet Source: PubMed (DOI)

An injectable osteoporosis drug given every six months. In a three-year trial in postmenopausal women with osteoporosis, it cut new vertebral fractures by 68% (2.3% versus 7.2%) and hip fractures by 40% (0.7% versus 1.2%) compared with placebo. Technical: FREEDOM trial: 60 mg subcutaneously every 6 months for 36 months; nonvertebral fractures also reduced; no cases of osteonecrosis of the jaw during the trial. Read: Bone Health → Related: Bisphosphonates, Bone mineral density (BMD) Source: PubMed (DOI)

A low-dose X-ray scan that measures bone density, lean mass and fat distribution. It is the standard test for osteoporosis and is widely used to measure muscle mass when assessing sarcopenia. Technical: The European sarcopenia consensus (EWGSOP2, Cruz-Jentoft 2019) lists DXA among methods to measure muscle quantity; USPSTF guidance sets who should have DXA bone density screening. Read: Bone Density → Related: Menopausal bone loss, Sarcopenia Source: PubMed (DOI)

A marine omega-3 fatty acid and the most abundant omega-3 in the brain, important for neuronal membranes and signalling. Found in fatty fish and algal oil. Technical: Dyall 2015 reviews omega-3 biochemistry: DHA has unique and indispensable roles in neuronal membranes. Read: Omega-3 → Related: EPA (Eicosapentaenoic Acid) Source: PubMed (DOI)

The main circulating form of the adrenal hormone DHEA; levels fall with age. Technical: In the Massachusetts Male Aging Study, DHEA, DHEA-S, cortisol and estrone declined longitudinally, while dihydrotestosterone, pituitary gonadotropins and prolactin rose. Ranges and units: Biomarker Reference → Related: Cortisol, Testosterone Source: PubMed (DOI)

Sodium in food, mostly from salt and processed foods. In the DASH-Sodium trial, cutting sodium from a high to an intermediate level lowered systolic blood pressure by 2.1 mm Hg on a typical US diet, and further reductions lowered it more. Technical: Sacks 2001, N Engl J Med: feeding trial with three sodium levels on both a control and the DASH diet; effects were seen in people with and without hypertension. Read: The Longevity Nutrition Blueprint → Related: DASH diet, Ultra-Processed Food Source: PubMed (DOI)

How supplements are overseen in the United States. The FDA regulates their quality, safety and labelling and the Federal Trade Commission monitors their marketing, but a public-health review concluded that enforcement faces vast challenges and that oversight falls short of what is needed. Technical: Starr 2015, Am J Public Health: FDA oversight of quality, safety and labelling; FTC oversight of advertising; 'vast enforcement challenges remain', which also undermines confidence that supplement research used reliable products. Read: Supplement Brand Testing and Purity → Related: Adulterated supplements, Supplement label accuracy Source: PubMed (DOI)

An evolutionary theory of aging: organisms evolved only limited investment in maintaining the body, so damage gradually builds up. Technical: Aging is attributed not to active gene programming but to evolved limitations in somatic maintenance, resulting in a build-up of damage. Related: Antagonistic pleiotropy, Genomic Instability Source: PubMed (DOI)

The addition of methyl groups to cytosine bases in DNA, which regulates gene expression without changing the DNA sequence. The basis of epigenetic clocks that measure biological age. Technical: A multi-tissue predictor built from 8,000 samples across 51 healthy tissues and cell types estimates "DNA methylation age", which is close to zero in embryonic and induced pluripotent stem cells. Read: Epigenetic Clocks → Related: Epigenetic alterations, Epigenetic Clock, Horvath Clock Source: PubMed (DOI)

An antibody that clears amyloid plaques in early symptomatic Alzheimer's disease. In 1,736 people, it slowed decline on a dementia rating scale by about 0.7 points over 76 weeks compared with placebo, with amyloid-related brain swelling or effusions (ARIA-E) in 24%. Technical: TRAILBLAZER-ALZ 2: combined-population CDR-SB difference -0.7 (95% CI -0.95 to -0.45); 23 of 24 gated outcomes statistically significant. Read: Alzheimer's Prevention → Related: Lecanemab Source: PubMed (DOI)

An enzyme that breaks down the gut hormones GLP-1 and GIP within minutes. Semaglutide was engineered to resist DPP-4 and to bind albumin, which together allow once-weekly dosing. Technical: Lau 2015 describes the design of semaglutide, a once-weekly GLP-1 analogue engineered to resist breakdown and last longer in the body. Read: GLP-1 Agonists → Related: GLP-1 (Glucagon-Like Peptide-1), Incretin, Semaglutide Source: PubMed (DOI)

When a supplement changes how a medicine works. St John's wort is the best-documented example: it changes how the body handles drugs such as cyclosporine, digoxin, tacrolimus and warfarin, and an interaction with cyclosporine caused acute organ rejection in two heart transplant patients. Technical: St John's wort interactions (review, 2019): altered pharmacokinetics of digoxin, tacrolimus, indinavir, warfarin and other drugs, largely through induction of drug-metabolising enzymes and transporters. Read: Supplement Safety → Related: Curcumin (turmeric extract) Source: PubMed (DOI)

A third-generation epigenetic clock developed by researchers at Duke and Columbia universities. Instead of estimating biological age, it estimates the current pace of biological aging from a single blood test. Technical: Belsky 2022 developed DunedinPACE, a DNA methylation biomarker of the pace of aging, from repeated measurements of physiological decline in the Dunedin cohort. Read: Epigenetic Clocks → Ranges and units: Biomarker Reference → Related: Epigenetic Clock, GrimAge, PhenoAge Source: PubMed (DOI)

An imbalance in the gut microbiome characterized by reduced diversity, decreased beneficial species, and overgrowth of pathogenic organisms. One of the 12 hallmarks of aging. Technical: Dysbiosis was added to the hallmarks of aging in the 2023 update; it was not among the nine hallmarks proposed in 2013. Read: Gut Microbiome → Related: Microbiome Diversity, Gut-Brain Axis, Hallmarks of Aging Sources: PubMed (DOI) · PubMed (DOI)

An estimate of kidney function calculated from blood creatinine (and sometimes cystatin C), age and sex; the 2021 equations no longer use race. By the KDIGO definition, an eGFR below 60 indicates chronic kidney disease, and lower eGFR is associated with higher mortality. Technical: In a meta-analysis of general-population cohorts, mortality risk was flat between eGFR 75 and 105 and rose at lower values (hazard ratios 1.18 at 60, 1.57 at 45 and 3.14 at 15, against 95). The 2021 CKD-EPI equations removed race, which the authors describe as a social rather than biologic construct, and the combined creatinine-cystatin C version was the most accurate. Read: Kidney Health → Ranges and units: Biomarker Reference → Related: Creatinine, Cystatin C, UACR (urine albumin-to-creatinine ratio), Chronic kidney disease (CKD), Nephrons Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

The share of the blood in the left ventricle that is pumped out with each heartbeat, usually measured by echocardiography. The 2026 Second Universal Definition of Heart Failure groups heart failure into reduced, preserved and improved ejection fraction instead of using rigid cut-offs. Technical: Left ventricular ejection fraction (LVEF); the 2026 AHA/ACC/ESC/WHF consensus moves away from rigid LVEF cutoffs toward reduced, preserved and improved ejection fraction categories. Read: Advanced Cardiovascular Testing → Source: PubMed (DOI)

How long top-level athletes live compared with the general population. A meta-analysis found elite athletes had lower all-cause mortality than the general population (standardized mortality ratio 0.67), meaning about a third fewer deaths than expected; lifestyle and selection effects likely contribute. Technical: Garatachea 2014, Mayo Clin Proc: pooled cohorts of elite athletes; lower mortality from cardiovascular disease and cancer than the general population. Read: Longevity Guide for Athletes → Related: Cardiorespiratory fitness, Recreational running Source: PubMed (DOI)

An SGLT2-inhibitor diabetes drug. In 7,020 people with type 2 diabetes and cardiovascular disease, it reduced cardiovascular death (3.7% versus 5.9%), heart failure hospitalisation and death from any cause (5.7% versus 8.3%) over about three years, with more genital infections. Technical: EMPA-REG OUTCOME: hazard ratio 0.86 for the composite primary outcome; no significant difference in myocardial infarction or stroke. Read: Kidney Health → Related: SGLT2 Inhibitors, Dapagliflozin Source: PubMed (DOI)

The network of membranes where most secreted and surface proteins are folded and assembled. Technical: Most proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble; the unfolded protein response adjusts the ER's folding capacity when unfolded proteins build up. Related: Unfolded protein response (UPR) Source: PubMed (DOI)

How well the endothelium, the single layer of cells lining the blood vessels, controls vessel tone and blood flow. Endothelial dysfunction is an early step in atherosclerosis and can be detected before plaques cause symptoms. Technical: Endothelial dysfunction is a systemic disorder and a key factor in atherosclerosis and its complications, and it may reflect the combined effect of all atherogenic and protective factors. Dysfunction of the coronary or peripheral endothelium independently predicts cardiovascular events, and risk-factor changes and drugs such as statins and ACE inhibitors may improve it. Read: Advanced CV Testing → Related: Atherosclerosis, Blood-brain barrier Source: PubMed (DOI)

A marine omega-3 fatty acid found in fatty fish and algal oil. A high-dose prescription form (icosapent ethyl) reduced cardiovascular events in high-risk patients on statins in the REDUCE-IT trial. With DHA, it makes up the omega-3 index. Technical: REDUCE-IT (Bhatt 2019): high-dose prescription icosapent ethyl reduced cardiovascular events in people with raised triglycerides; Harris 2004 proposed the omega-3 index as a possible risk factor, which has not become a standard clinical test. Read: Omega-3 → Related: DHA (Docosahexaenoic Acid) Sources: PubMed (DOI) · PubMed (DOI)

The gap between the age an epigenetic clock estimates and your actual age, after adjusting for chronological age. A positive value means the clock reads older than expected; GrimAge's version, AgeAccelGrim, strongly predicted time to death. Technical: Residual of a DNA methylation age estimate after adjustment for chronological age (for example AgeAccelGrim). Epigenetic clocks give accurate age estimates for any tissue across the life course. Read: Epigenetic Clocks → Related: GrimAge, Horvath Clock, Hannum clock, Biological Age Sources: PubMed (DOI) · PubMed (DOI)

Age-related changes in the chemical marks that control which genes are active, without any change to the DNA sequence itself. Technical: One of the twelve hallmarks of aging. DNA methylation patterns change so predictably with age that a predictor built from 51 tissues and cell types can estimate age from them. Related: DNA Methylation, Epigenetic Clock, Partial reprogramming Sources: PubMed (DOI) · PubMed (DOI)

An algorithm that uses DNA methylation patterns to estimate biological age or pace of aging. Major clocks include Horvath (pan-tissue), PhenoAge (disease risk), GrimAge (mortality), and DunedinPACE (pace of aging). Technical: Horvath 2018, Nat Rev Genet: DNA methylation-based clocks link developmental and maintenance processes to biological ageing. Clocks differ in what they were trained to predict (chronological age, disease risk, mortality or pace of aging), consumer tests vary between laboratories, and lowering a clock score has not been shown to change health outcomes. Read: Epigenetic Clocks → Related: Partial reprogramming, Chronological Age Source: PubMed (DOI)

A research method for measuring insulin sensitivity: insulin is infused at a fixed level while glucose is infused to hold blood sugar steady, and the glucose needed shows how well the body responds to insulin. Technical: Described in 1979, the euglycemic insulin clamp raises plasma insulin to about 100 µU/mL with a continuous infusion while a variable glucose infusion holds glucose at its basal level; because glucose is held constant, the glucose infusion rate indexes glucose metabolism. A related hyperglycemic clamp measures beta-cell sensitivity to glucose. Related: Insulin Resistance, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), TyG index (triglyceride-glucose index) Source: PubMed (DOI)

The effect of physical activity on thinking and memory. A meta-analysis of 39 randomized trials in adults over 50 found that exercise improved cognitive function regardless of participants' starting cognitive status, with benefits from sessions of 45 to 60 minutes at moderate intensity or higher. Technical: Northey 2018, Br J Sports Med: aerobic exercise, resistance training, multicomponent training and tai chi all had significant point estimates. Read: Exercise and the Brain → Related: Myokines, Physical activity guidelines (US) Source: PubMed (DOI)

Exercise programs designed to reduce falls in older adults, usually built around balance and functional movements. In a Cochrane review, exercise reduced the rate of falls by 23% overall, balance and functional exercise by 24%, and programs combining several types of exercise by about 34%. Technical: Sherrington 2019, Cochrane (community-dwelling adults 60+): rate ratio 0.77 for exercise vs control; multiple exercise types (commonly balance and functional plus resistance exercise) probably reduce falls by 34%. Read: Longevity Guide for Retirees → Related: Physical activity guidelines (US), Frailty, Sarcopenia Source: PubMed (DOI)

The network of proteins outside cells that gives tissues structure and sends signals to cells. Technical: The ECM does far more than provide structural support: its proteins bind adhesion receptors such as integrins, which anchor cells and transmit signals into them, and they bind growth factors and control their distribution, activation and presentation. It matters in development, stem-cell niches, cancer and genetic diseases. Related: Collagen Source: PubMed (DOI)

A non-statin drug that lowers LDL cholesterol by reducing cholesterol absorption from the gut. Added to a statin in 18,144 people recently hospitalised with an acute coronary syndrome, it lowered average LDL from about 70 to 54 mg/dL and modestly reduced cardiovascular events (32.7% versus 34.7% over seven years). Technical: IMPROVE-IT: simvastatin 40 mg plus ezetimibe 10 mg versus simvastatin alone; hazard ratio 0.936 for the composite primary end point; similar rates of muscle, gallbladder and liver adverse effects. Read: ApoB → Related: Statins, LDL cholesterol (LDL-C) Source: PubMed (DOI)

An inherited condition that causes high LDL cholesterol and greatly raises heart disease risk. It affects about 1 in 200 to 1 in 500 people and is often undiagnosed. Technical: A 2013 European Atherosclerosis Society consensus estimated that 14 to 34 million people worldwide have FH (prevalence between 1 in 500 and 1 in 200; direct screening in a Northern European population found about 1 in 200 with the heterozygous form), reported up to 13-fold higher coronary heart disease risk, and called for screening and early treatment because of severe underdiagnosis. Related: LDL cholesterol (LDL-C), Lp(a) (Lipoprotein(a)), ApoB (Apolipoprotein B) Source: PubMed (DOI)

The level of insulin in the blood after an overnight fast. A raised level can signal insulin resistance; in one large cohort, insulin sensitivity was already falling steeply in the five years before diabetes was diagnosed. Reference ranges vary by lab and assay. Technical: In the Whitehall II study of 6,538 British civil servants, HOMA insulin sensitivity declined steeply in the 5 years before type 2 diabetes was diagnosed, while fasting glucose rose sharply only in the final 3 years (from 5.79 to 7.40 mmol/L). Insulin assays are not standardized, which is one reason reference ranges differ. Read: Fasting Insulin → Ranges and units: Biomarker Reference → Related: HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), Insulin Resistance, Prediabetes Sources: PubMed (DOI) · PubMed (DOI)

Blood glucose measured after an overnight fast: 99 mg/dL or below is normal, 100 to 125 mg/dL indicates prediabetes and 126 mg/dL or above indicates diabetes. Technical: Fasting plasma glucose is one of the standard tests used to diagnose diabetes and prediabetes (NIDDK). In the Whitehall II study, fasting glucose rose steeply only in the 3 years before diabetes was diagnosed, from 5.79 to 7.40 mmol/L. Read: Lab Unit Converter → Ranges and units: Biomarker Reference → Related: HbA1c (Glycated Hemoglobin), OGTT (oral glucose tolerance test), Prediabetes, Fasting Insulin Sources: NIDDK: Diabetes Tests & Diagnosis (niddk.nih.gov, checked 2026-10-01) · PubMed (DOI)

A five-day, low-calorie, plant-based eating plan designed to mimic some effects of fasting, developed in Valter Longo's lab. In a randomized trial, three monthly cycles lowered body weight, blood pressure and IGF-1. Technical: Wei 2017, Sci Transl Med: 100 generally healthy US adults; three monthly 5-day cycles of a diet low in calories, sugars and protein but high in unsaturated fats reduced body weight, trunk and total body fat, blood pressure and IGF-1; 71 participants completed three cycles. Long-term outcome data are lacking. Read: Prolonged Fasting and FMD → Related: Intermittent Fasting, IGF-1 (Insulin-Like Growth Factor 1) Source: PubMed (DOI)

Foods made with live microbes, such as yogurt, kefir, kimchi and sauerkraut. In a 17-week randomized study of 36 healthy adults, a diet high in fermented foods steadily increased gut microbiome diversity and lowered inflammatory markers, while a high-fiber diet left diversity unchanged. Technical: Wastyk 2021, Cell: randomized trial comparing high-fermented-food and high-fiber diets; the trial's primary outcome (a cytokine response score) did not change. Read: The Gut-Brain Axis → Related: Probiotics, Fiber (Dietary) Source: PubMed (DOI)

A protein that stores iron; its blood level is used as a marker of the body's iron stores and is central to diagnosing both iron deficiency and iron overload. Technical: Ferritin is predominantly used as a serum marker of total body iron stores. Elevated serum and tissue ferritin have also been linked to coronary artery disease, malignancy and poor outcomes after stem cell transplantation, and most people with two copies of the HFE C282Y hemochromatosis variant have raised ferritin and transferrin saturation. Read: Iron Status → Ranges and units: Biomarker Reference → Related: Transferrin saturation, Anemia Sources: PubMed (DOI) · PubMed (DOI)

A hormone the liver releases during fasting; raising it extended lifespan in mice. Technical: FGF21 is secreted by the liver during fasting and drives parts of the starvation response: it induces fat oxidation and ketone production in the liver, increases insulin sensitivity, blocks growth and causes bone loss. Transgenic overexpression extended lifespan in mice without reducing food intake. Related: Ketones (Beta-Hydroxybutyrate), Insulin Resistance Source: PubMed (DOI)

A score for liver scarring calculated from age, AST, ALT and platelet count; low values help rule out advanced fibrosis. Technical: FIB-4 equals age times AST divided by platelet count times the square root of ALT. In the HIV and hepatitis C cohort that developed it, a value below 1.45 had a 90% negative predictive value for advanced fibrosis and a value above 3.25 a 65% positive predictive value. For people aged 65 and over, a cut-off of 2.0 improved specificity to 70% without reducing sensitivity. Read: FIB-4 Calculator → Related: ALT (alanine aminotransferase), MASLD (Metabolic-Associated Steatotic Liver Disease) Sources: PubMed (DOI) · PubMed (DOI)

Carbohydrates that the body cannot digest; gut bacteria ferment some of them into short-chain fatty acids such as butyrate. In a large analysis of cohort studies and trials, people eating 25 to 29 grams a day or more had lower mortality and heart disease risk than those eating less. Technical: Reynolds 2019, Lancet: systematic reviews and meta-analyses of cohort studies and trials; observational data suggest 15-30% lower all-cause and cardiovascular mortality and lower incidence of heart disease, stroke, type 2 diabetes and colorectal cancer with the highest versus lowest fibre intakes; risk reduction was greatest at 25-29 g/day. Read: Gut Optimization → Related: Mediterranean Diet, Probiotics Source: PubMed (DOI)

A clotting protein in the blood. Higher levels are associated with heart disease and stroke, but whether fibrinogen causes them is unknown. Technical: In an individual-participant meta-analysis of prospective studies, the age- and sex-adjusted hazard ratio for coronary heart disease was 2.42 per 1 g/L higher usual fibrinogen, falling to about 1.8 after adjustment for established risk factors. Associations were approximately log-linear with no threshold, and their causal relevance needs further research. Related: hsCRP (High-Sensitivity C-Reactive Protein), IL-6 (Interleukin-6) Source: PubMed (DOI)

A non-steroidal drug that blocks the mineralocorticoid receptor, used in chronic kidney disease with type 2 diabetes. In a trial of 5,674 such patients, it reduced kidney failure, major loss of kidney function or kidney death (17.8% versus 21.1%) and cardiovascular events over 2.6 years; stopping because of high potassium was more common. Technical: FIDELIO-DKD: hazard ratio 0.82 for the primary kidney composite and 0.86 for the key cardiovascular composite. Read: Kidney Health → Related: eGFR (Estimated Glomerular Filtration Rate), SGLT2 Inhibitors Source: PubMed (DOI)

A Finnish randomized trial testing whether a combined lifestyle program can protect thinking in at-risk older adults. Among 1,260 people aged 60 to 77, two years of diet advice, exercise, cognitive training and vascular risk management produced a modest improvement in cognitive test scores compared with general health advice. Technical: Ngandu 2015, Lancet: estimated mean change in the composite neuropsychological test battery score at 2 years was 0.20 with the intervention vs 0.16 with control; the World-Wide FINGERS network is testing adapted versions. Read: The Brain Longevity Blueprint → Related: Exercise and cognition, APOE (Apolipoprotein E) Source: PubMed (DOI)

A flavonoid found in strawberries and other fruits, studied as a senolytic (a compound that clears senescent cells). No human trial has yet tested whether it improves health; in mice, giving it late in life reduced age-related damage and extended median and maximum lifespan. Our Supplement Evidence Database rates it “No human trials” for clearing senescent cells and health in people. Technical: Yousefzadeh 2018, EBioMedicine: No human trial has yet tested whether it improves health; in mice, giving it late in life reduced age-related damage and extended median and maximum lifespan. Read: Fisetin in the Supplement Evidence Database → Related: Senolytics, Cellular Senescence Source: PubMed (DOI)

A B vitamin needed to convert homocysteine back to methionine; blood homocysteine is used as a functional marker of folate status. Technical: Homocysteine rises when the body cannot convert it to methionine for lack of 5-MTHF. The most commonly used cut-off for elevated homocysteine is 16 µmol/L, with 12 to 14 µmol/L also used (NIH Office of Dietary Supplements). Ranges and units: Biomarker Reference → Related: Homocysteine, Methylfolate (5-MTHF), MTHFR (Methylenetetrahydrofolate Reductase), Vitamin B12 (cobalamin) Source: NIH Office of Dietary Supplements: Folate fact sheet (ods.od.nih.gov, checked 2026-10-01)

A gene encoding a transcription factor involved in stress resistance, DNA repair and autophagy. Certain FOXO3 variants were strongly associated with longevity in long-lived Japanese-American men in Hawaii, and the link has since been found in other populations. Technical: FOXO3 (FOXO3A) encodes a transcription factor in the insulin/IGF-1 signalling pathway, an evolutionarily conserved pathway that influences aging in animal models. In a long-lived population of men, genetic variation within FOXO3A was strongly associated with longevity, and the GG genotype went with markers of greater insulin sensitivity. Read: Longevity Genomics → Related: IGF-1 (Insulin-Like Growth Factor 1) Source: PubMed (DOI)

A clinical syndrome in older adults marked by weakness, exhaustion, slow walking, low activity and unintended weight loss. Technical: In the widely used phenotype definition, frailty is present when three or more of five criteria are met: unintentional weight loss, self-reported exhaustion, weakness measured by grip strength, slow walking speed and low physical activity. In the original community-dwelling cohort, 6.9% were frail. Related: Sarcopenia, Grip Strength Source: PubMed (DOI)

A score equal to the proportion of possible health deficits, such as symptoms, signs, functional impairments and abnormal lab results, that a person has. In elderly Canadians, deficits accumulated at about 3% per year, and the index reflected severity of illness and proximity to death. Technical: Deficit-accumulation index (Mitnitski and colleagues, 2001): an individual state variable whose slope was insensitive to the particular deficits counted and which served as a prognostic factor for life expectancy. Related: Frailty, Fried frailty phenotype, Biological Age Source: PubMed (DOI)

Reactive oxygen species are produced mainly by mitochondria. At low levels they act as signalling molecules; in excess they damage DNA, proteins and lipids. The older idea that their accumulation drives aging has not held up as a complete explanation. Technical: An umbrella term for derivatives of molecular oxygen. Elevated levels cause molecular damage ("oxidative distress"), while physiological levels act as redox signals ("oxidative eustress"); hydrogen peroxide and superoxide, the key signalling species, are made by more than 40 enzymes, including NADPH oxidases and the mitochondrial electron transport chain. Read: Mitochondria → Related: Mitochondrial dysfunction, Hormesis Source: PubMed (DOI)

The fraction of testosterone not bound to proteins, which reflects the hormone available to tissues better than total testosterone; it is usually calculated from total testosterone and SHBG. Technical: Free testosterone calculated from total testosterone and immunoassayed SHBG was a rapid, simple and reliable index of bioavailable testosterone, comparable to equilibrium dialysis, except in pregnancy; direct analog immunoassays and the free androgen index were not reliable. Related: Testosterone, SHBG (sex hormone-binding globulin) Sources: PubMed (DOI) · PubMed (DOI)

A definition of frailty as three or more of five signs: unintentional weight loss, exhaustion, weak grip, slow walking and low physical activity. In 5,317 adults aged 65 and older, 6.9% met the definition. Technical: Operationalised in the Cardiovascular Health Study; weight loss criterion of 10 lb in the past year. Frailty is considered to confer high risk for falls, disability, hospitalisation and mortality. Related: Frailty, Frailty index, Grip Strength, Gait speed Source: PubMed (DOI)

A blood test that, like glycated albumin, reflects average glucose over the previous 2 to 4 weeks, a shorter window than HbA1c. Technical: In the Atherosclerosis Risk in Communities study of 11,348 adults without diabetes, fructosamine above the 95th percentile was associated with a nearly fivefold risk of incident diabetes (hazard ratio 4.96). Fructosamine and glycated albumin predicted kidney disease almost as well as HbA1c, though HbA1c better predicted incident diabetes. Related: HbA1c (Glycated Hemoglobin), Prediabetes Source: PubMed (DOI)

A hormone that rises across the menopause transition, beginning about 6 years before the final menstrual period. Technical: In SWAN, FSH began to rise 6.10 years before the final menstrual period, accelerated 2.05 years before it and stabilized about 2 years after; obesity blunted the rise. These patterns were not related to age at the final period or smoking. Related: AMH (anti-Müllerian hormone) Source: PubMed (DOI)

How fast you walk at your usual pace, usually measured in metres per second. In 34,485 adults aged 65 and older, each 0.1 m/s faster was linked to about 12% lower risk of death, across the full range of speeds. Technical: Usual gait speed; pooled individual data from 9 cohorts (n=34,485, age 65+, follow-up 6-21 years): hazard ratio per 0.1 m/s 0.88 (95% CI 0.87-0.90). Related: SPPB (Short Physical Performance Battery), Frailty, Sarcopenia, Timed Up and Go (TUG) Source: PubMed (DOI)

A circulating protein, linked to weight loss in people, that reduces food intake in mice. Technical: GDF15 is a distant member of the TGF-β family that circulates as a dimer. Elevated GDF15 correlates with weight loss in people, and in mice with obesity it reduces body weight partly by decreasing food intake; GFRAL is its receptor. Source: PubMed (DOI)

The accumulation of DNA damage over time from endogenous (replication errors, ROS) and exogenous (UV, pollution) sources. The first hallmark of aging. Partially addressed by DNA repair enzymes (PARPs), which require NAD+. Technical: The accumulation of DNA damage and mutations, first on the 2023 list of twelve hallmarks of aging. In adult stem cells from several human tissues, mutations accumulated steadily at about 40 new mutations a year. Read: Hallmarks of Aging → Related: Somatic mutations, Clonal hematopoiesis (CHIP), Hallmarks of Aging Sources: PubMed (DOI) · PubMed (DOI)

The field that studies how the biology of aging drives chronic disease, aiming to delay many diseases at once. Technical: Its premise is that aging is the greatest risk factor for most of the chronic diseases that drive illness and death, and that mammalian aging can be delayed with genetic, dietary and drug approaches. Related: Gerotherapeutic, Hallmarks of Aging, Healthspan Source: PubMed (DOI)

A drug or intervention that targets the biology of aging itself rather than one disease. None is approved for aging; the proposed TAME trial of metformin was designed to test whether a drug can delay several age-related diseases at once. Technical: Barzilai 2016 proposed testing metformin in the TAME trial as a first step toward drugs that target aging itself; no gerotherapeutic is approved. Read: Longevity Science 2025 → Related: Metformin, TAME Trial (Targeting Aging with Metformin), Rapamycin Source: PubMed (DOI)

A liver enzyme. Higher levels are associated with higher all-cause mortality in general populations. Technical: In a meta-analysis of 19 cohorts with over 9.24 million participants, the top third of GGT carried 60% higher all-cause mortality than the bottom third, and risk rose 7% per 5 U/L. Alkaline phosphatase was also associated (relative risk 1.38), AST showed no strong association, and the association for ALT differed by region. Related: ALT (alanine aminotransferase), MASLD (Metabolic-Associated Steatotic Liver Disease) Source: PubMed (DOI)

An incretin hormone that enhances insulin secretion, promotes lipid metabolism, and has direct effects on adipose tissue and bone. Targeted by tirzepatide and retatrutide alongside GLP-1. Technical: GIP is one of the two main incretin hormones alongside GLP-1. Jastreboff 2023, N Engl J Med: retatrutide, an agonist of the GIP, GLP-1 and glucagon receptors, produced substantial weight loss in a phase 2 obesity trial. Read: GLP-1 Agonists → Related: GLP-1 (Glucagon-Like Peptide-1), Tirzepatide Source: PubMed (DOI)

A gut hormone released after eating that stimulates insulin, suppresses glucagon, slows stomach emptying and reduces appetite. Drugs that mimic it (GLP-1 receptor agonists such as semaglutide) are used for diabetes and obesity. Technical: Drucker 2018, Cell Metab: GLP-1 from gut enteroendocrine cells controls meal-related glucose excursions by increasing insulin and inhibiting glucagon secretion, and also slows gastric emptying and food intake. Read: GLP-1 Agonists → Related: Semaglutide, Tirzepatide, GIP (Glucose-Dependent Insulinotropic Polypeptide) Source: PubMed (DOI)

An antioxidant the body makes from building blocks including cysteine and glycine; older people may make less of it. Technical: In a study of 8 older and 8 younger adults, the older adults had markedly lower red-blood-cell glycine and lower glutathione synthesis, a deficit linked to oxidative stress that dietary cysteine and glycine supplementation corrected. Related: Free Radicals (ROS), Nrf2 Source: PubMed (DOI)

A blood marker of inflammation measured by NMR spectroscopy, reflecting sugar groups on several acute-phase proteins. Technical: GlycA comes from N-acetylglucosamine residues on glycosylated acute-phase proteins, chiefly alpha-1-acid glycoprotein, haptoglobin, alpha-1-antitrypsin, alpha-1-antichymotrypsin and transferrin. In 5,537 MESA participants it correlated with hsCRP (r = 0.56), fibrinogen (0.46) and IL-6 (0.35), and its week-to-week variability in healthy volunteers (4.3%) was far lower than that of hsCRP (29.2%). Related: hsCRP (High-Sensitivity C-Reactive Protein), Fibrinogen, IL-6 (Interleukin-6) Source: PubMed (DOI)

A ranking of carbohydrate foods by how much they raise blood glucose compared with pure glucose. In the multinational PURE cohort, a diet with a high glycemic index was linked to a higher risk of major cardiovascular events or death, in people with and without existing heart disease. Technical: Jenkins 2021, N Engl J Med (PURE): glycemic index and load estimated from country-specific food-frequency questionnaires across low-, middle- and high-income countries; comparison of highest vs lowest quintiles. Read: Continuous Glucose Monitoring → Related: Glycemic Variability, Fiber (Dietary) Source: PubMed (DOI)

How much blood glucose swings up and down over the day. In people with type 2 diabetes, large swings activated oxidative stress more than steady high glucose did; whether variability matters in people without diabetes is uncertain. Technical: In type 2 diabetes, the mean amplitude of glycemic excursions (MAGE), measured with continuous glucose monitoring, was strongly associated with a marker of oxidative stress (standardized coefficient 0.830), and glucose swings showed a more specific triggering effect on oxidative stress than sustained high glucose. Read: CGM → Related: CGM (Continuous Glucose Monitor), HbA1c (Glycated Hemoglobin) Source: PubMed (DOI)

The brain's waste-clearance system, in which cerebrospinal fluid flows along channels around blood vessels. In mice it is most active during sleep and clears amyloid-beta; impaired clearance is implicated in Alzheimer's disease. Technical: Xie 2013, Science: in mice, natural sleep or anesthesia increased the interstitial space by 60%, increasing convective exchange of cerebrospinal and interstitial fluid and the clearance of amyloid-beta. How closely this applies to humans, and how much depends on deep sleep, is still debated. Read: Brain Longevity Blueprint → Related: Amyloid-Beta, Slow-Wave Sleep (SWS), Sleep deprivation Source: PubMed (DOI)

The observation that adult death rates rise exponentially with age. Technical: In 1825 the actuary Benjamin Gompertz showed that over much of the adult human lifespan, age-specific mortality rates increase exponentially. Related: Lifespan Source: PubMed (DOI)

Concentrated green tea catechins, chiefly epigallocatechin gallate (EGCG), sold as an extract. A meta-analysis found green tea drinks or extracts modestly lowered total and LDL cholesterol, with no effect on HDL. Our Supplement Evidence Database rates it “Supported” for cholesterol. Technical: Zheng 2011, Am J Clin Nutr: A meta-analysis found green tea drinks or extracts modestly lowered total and LDL cholesterol, with no effect on HDL. Hartley 2013, Cochrane Database Syst Rev: A Cochrane review found favourable effects on cardiovascular risk factors but very few long-term trials. Read: Green tea extract (EGCG) in the Supplement Evidence Database → Related: Polyphenols Sources: PubMed (DOI) · PubMed (DOI)

A second-generation epigenetic clock built to predict time to death, using DNA methylation stand-ins for smoking history and several blood proteins. In its developers' validation cohorts it strongly predicted lifespan and healthspan. Technical: Lu 2019 built GrimAge from DNA methylation surrogates of plasma proteins and smoking pack-years; it strongly predicted lifespan and healthspan in the original cohorts. Read: Epigenetic Clocks → Ranges and units: Biomarker Reference → Related: PhenoAge, DunedinPACE, Epigenetic Clock Source: PubMed (DOI)

The maximum force of your hand grip. In a 17-country study, each 5 kg lower grip strength was linked to 16 percent higher mortality, and grip strength predicted death better than systolic blood pressure. Technical: Leong 2015 (PURE, 17 countries): grip strength was a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure; its link with cancer varied by country income. Read: Grip Strength → Ranges and units: Biomarker Reference → Related: Sarcopenia, Muscle-strengthening activity Source: PubMed (DOI)

A pituitary hormone released mostly during deep sleep; its secretion falls with age. Growth hormone treatment for aging remains controversial, because raising IGF-1 may carry long-term risks despite short-term effects on body composition. Technical: Growth hormone is secreted by the pituitary in bursts. In 21 healthy men aged 21 to 71, sampled every 10 minutes for 24 hours, age and relative adiposity were specific negative determinants of the frequency and amplitude of these bursts. Read: Hormones → Related: IGF-1 (Insulin-Like Growth Factor 1) Source: PubMed (DOI)

The use of growth hormone injections in healthy older adults to counter aging. A systematic review found only small changes in body composition and frequent side effects, including swelling, joint pain, carpal tunnel syndrome and breast enlargement in men, and concluded it cannot be recommended as an anti-aging therapy. Technical: Liu 2007, Ann Intern Med: systematic review of randomized trials in healthy elderly people; treated participants were also somewhat more likely to develop diabetes. Related: Growth Hormone (GH), IGF-1 (Insulin-Like Growth Factor 1) Source: PubMed (DOI)

The bidirectional communication network between the gastrointestinal tract and the central nervous system, mediated by the vagus nerve, immune signaling, neurotransmitter production, and microbial metabolites. Technical: Cryan 2019, Physiol Rev: the microbiota and brain communicate through the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids; much of the causal evidence comes from animal studies. Read: Gut-Brain Axis → Related: Fermented foods, Probiotics Source: PubMed (DOI)

The 12 interconnected biological processes identified as the fundamental drivers of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled autophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, inflammaging, and dysbiosis. Technical: A framework first proposing nine hallmarks, common denominators of aging across organisms, in 2013, expanded to twelve in 2023: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation and dysbiosis. Read: Hallmarks of Aging → Related: Genomic Instability, Telomeres, Epigenetic alterations, Proteostasis, Autophagy, Nutrient Sensing, Mitochondrial dysfunction, Cellular Senescence, Stem Cell Exhaustion, Altered intercellular communication, Inflammaging, Dysbiosis Sources: PubMed (DOI) · PubMed (DOI)

An epigenetic clock published in 2013 that estimates how fast a person's DNA methylation pattern is ageing, built from more than 450,000 sites measured in the blood of 656 people aged 19 to 101. Technical: Quantitative model of methylome ageing rate from whole-blood DNA methylation at >450,000 CpG markers (n=656, ages 19-101); ageing rates were influenced by gender and genetic variants, and the model showed an advanced ageing rate in tumour tissue. Read: Epigenetic Clocks → Related: Horvath Clock, GrimAge, PhenoAge, DNA Methylation, Epigenetic age acceleration Source: PubMed (DOI)

An autoimmune condition in which the immune system attacks the thyroid gland; it is the most common cause of subclinical hypothyroidism. Technical: Now considered the most common autoimmune disease, Hashimoto thyroiditis is diagnosed from circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on ultrasound in a patient with matching clinical features; treatment is thyroid hormone replacement to correct hypothyroidism as needed. Read: Thyroid Function → Related: TPO antibodies (thyroid peroxidase antibodies), Thyroid (TSH, T4, T3), Subclinical Hypothyroidism Sources: PubMed (DOI) · PubMed (DOI)

The limited number of times normal human cells can divide in culture before they stop. Technical: Discovered by Leonard Hayflick: cultured normal human cells have a limited capacity to divide, after which they become senescent. Related: Telomeres, Telomerase, Cellular Senescence Source: PubMed (DOI)

A measure comparing how often an event happens over time in one group versus another. A hazard ratio of 0.80 means the event rate was 20% lower in the treated group, as in the SELECT trial of semaglutide; a value of 1 means no difference. Technical: Lincoff 2023, N Engl J Med (SELECT): hazard ratio 0.80 for major adverse cardiovascular events; hazard ratios are relative measures and say nothing about absolute risk on their own. Related: Relative vs absolute risk, Confidence interval Source: PubMed (DOI)

A blood test that reflects average blood glucose over recent months. An HbA1c below 5.7% is normal, 5.7 to 6.4% indicates prediabetes, and 6.5% or higher indicates diabetes. Technical: Health care professionals can use the A1C test alone or with other tests to diagnose type 2 diabetes and prediabetes (NIDDK). Prediabetes, glucose above normal but below the diabetes threshold, progresses to diabetes in 5 to 10% of people a year. Read: Bloodwork Guide → Ranges and units: Biomarker Reference → Related: Prediabetes, OGTT (oral glucose tolerance test), CGM (Continuous Glucose Monitor) Sources: NIDDK: The A1C Test & Diabetes (niddk.nih.gov, checked 2026-10-01) · PubMed (DOI)

Enzymes that remove acetyl tags from proteins, including the histones that package DNA. Technical: HDACs catalyse the removal of acetyl groups from lysine residues of histone and non-histone proteins. Humans have 18, which use zinc- or NAD+-dependent mechanisms; removing histone acetylation regulates chromatin structure and transcription. Related: Sirtuins, Ketones (Beta-Hydroxybutyrate), Epigenetic alterations Source: PubMed (DOI)

The cholesterol carried in high-density lipoprotein particles. Higher HDL cholesterol is linked to lower heart attack risk, but genetic studies suggest that raising it does not by itself lower risk. Technical: In a Mendelian randomization study, a variant that raised HDL cholesterol (LIPG 396Ser) was not associated with myocardial infarction (odds ratio 0.99), nor was a genetic score of 14 HDL-raising variants, although observationally each standard deviation of HDL went with 38% lower risk. The authors concluded that raising HDL cholesterol will not uniformly reduce risk. Ranges and units: Biomarker Reference → Related: LDL cholesterol (LDL-C), Non-HDL cholesterol, Triglycerides Source: PubMed (DOI)

The period of life spent in good health, free from chronic disease, disability, and significant functional decline. Distinct from lifespan (total years alive). The primary goal of longevity medicine. Technical: Kaeberlein 2018 ('How healthy is the healthspan concept?') discusses how healthspan is defined and measured; there is no single agreed measure. Related: Biological Age, Gerotherapeutic Source: PubMed (DOI)

A clinical syndrome in which a structural or functional heart abnormality causes symptoms or signs, backed up by raised natriuretic peptide levels or evidence of congestion. It is staged from at risk (A) and pre-heart failure (B) to heart failure (C) and advanced heart failure (D); a 2026 update groups it by reduced, preserved or improved ejection fraction. Technical: 2021 universal definition (HFSA/HFA/JHFS) with stages A-D; the 2026 Second Universal Definition replaces rigid ejection fraction cut-offs with reduced, preserved and improved categories. Read: Advanced Cardiovascular Testing → Related: Ejection fraction Sources: PubMed (DOI) · PubMed (DOI)

How much your heart rate falls in the first minute after stopping hard exercise. In a six-year study of 2,428 adults, a fall of 12 beats per minute or less was defined as abnormal and predicted overall mortality. Technical: Peak exercise heart rate minus heart rate one minute after stopping; reflects vagal reactivation. Abnormal defined as 12 beats per minute or less after symptom-limited exercise testing. Read: VO2 Max and Longevity → Related: HRV (Heart Rate Variability), VO2 Max, Resting heart rate Source: PubMed (DOI)

Protective proteins switched on by the heat-shock response; in worms, they help extend lifespan. Technical: The heat-shock response is controlled by the transcription factor HSF-1. In C. elegans, reducing HSF-1 activity accelerated tissue aging and shortened lifespan, overexpressing it extended lifespan, and HSF-1 with DAF-16 switched on genes for small heat-shock proteins that promote longevity. Related: Insulin/IGF-1 signalling (IIS), Unfolded protein response (UPR) Source: PubMed (DOI)

Bone-marrow stem cells that produce blood cells; with age they become more numerous but biased toward certain cell types. Technical: Aging of the blood system brings lower bone-marrow cellularity, weaker adaptive immunity and more anaemia, blood disorders and blood cancers. In healthy people, aged hematopoietic stem cells were more frequent, less quiescent and biased toward producing myeloid cells compared with young ones. Related: Clonal hematopoiesis (CHIP), Stem Cell Exhaustion, Immunosenescence Source: PubMed (DOI)

The master regulator of iron metabolism. Produced by the liver. Elevated hepcidin blocks iron absorption and traps iron in cells; low hepcidin permits excessive iron absorption. Technical: Nemeth and Ganz 2021: hepcidin controls systemic iron by blocking ferroportin; iron restriction or deficiency can result from genetic or inflammatory overproduction of hepcidin. Read: Iron Status → Source: PubMed (DOI)

The share of differences in lifespan between people that is explained by genetic differences. Technical: A study of 2,872 Danish twin pairs estimated it at 0.26 in men and 0.23 in women. An analysis of family trees covering hundreds of millions of people found that much of the resemblance between relatives was also seen between in-laws, a sign that assortative mating inflates the estimates. Related: FOXO3, APOE (Apolipoprotein E), Antagonistic pleiotropy Sources: PubMed (DOI) · PubMed (DOI)

An experiment that joins the circulations of a young and an old animal to test how factors in the blood affect aging. Technical: Pairing young and old mice exposed the old mice to factors in young serum and restored the activation, proliferation and regenerative capacity of their aged muscle satellite cells. Related: Stem Cell Exhaustion Source: PubMed (DOI)

Exercise protocol alternating short bursts of high-intensity effort (85-95% max heart rate) with recovery periods. The Norwegian 4x4 protocol is the most studied HIIT format for VO2 max improvement. Technical: Helgerud 2007: aerobic high-intensity intervals improved VO2 max more than moderate training in healthy young men; in older adults, the Generation 100 trial found no mortality difference versus recommended activity. Read: HIIT vs Steady-State → Related: 4x4 interval training, VO2 Max Source: PubMed (DOI)

The formation of new neurons in the hippocampus, a brain region central to memory. Whether, and how much, it continues in adult humans is debated: one 2018 study found it drops to undetectable levels after childhood, while another found it persists into old age. Technical: In adult mammals, new neurons form in the subgranular zone of the dentate gyrus. In humans, one 2018 study found that neurogenesis drops sharply in childhood to undetectable levels in adults, while another found similar numbers of neural progenitors and thousands of immature neurons in people aged 14 to 79. Read: Exercise and the Brain → Related: BDNF (Brain-Derived Neurotrophic Factor) Sources: PubMed (DOI) · PubMed (DOI)

A brain region central to memory that shrinks in late adulthood. Technical: The hippocampus shrinks in late adulthood, impairing memory and raising dementia risk; in a randomized trial of 120 older adults, aerobic exercise enlarged its anterior part by 2%. London taxi drivers had larger posterior hippocampi than controls, with volume tracking their years of driving. Related: Hippocampal Neurogenesis, Synapses Sources: PubMed (DOI) · PubMed (DOI)

An estimate of insulin resistance calculated from fasting insulin and fasting glucose. There is no universal cut-off: thresholds vary with age, sex and population. Technical: Introduced in 1985, the homeostasis model compares fasting glucose and insulin with a model of their feedback loop. Its insulin-resistance estimate correlated with the euglycemic clamp (Rs = 0.88), but its precision is low (coefficient of variation 31%). In a Spanish population study, optimal cut-offs depended on age and sex and fell between the 70th and 75th percentiles. Read: Fasting Insulin and HOMA-IR → Ranges and units: Biomarker Reference → Related: Fasting Insulin, Insulin Resistance, TyG index (triglyceride-glucose index) Sources: PubMed (DOI) · PubMed (DOI)

An amino acid made in the methionine cycle. Raised levels have been proposed as a cardiovascular risk factor, but B-vitamin supplements that lower homocysteine did not prevent heart attacks or deaths in trials, though they slightly reduced stroke. Technical: A 2017 Cochrane review of randomized trials found no effect of homocysteine-lowering vitamin B6, B9 (folate) or B12 supplements on myocardial infarction (7.1% vs 6.0%; risk ratio 1.02) or death from any cause (risk ratio 1.01), but a small reduction in stroke (4.3% vs 5.1%; risk ratio 0.90), with the stroke evidence coming mainly from one very large trial. Read: Homocysteine → Ranges and units: Biomarker Reference → Related: hsCRP (High-Sensitivity C-Reactive Protein) Source: PubMed (DOI)

A dose-response pattern in which a low dose of a stressor (exercise, fasting, cold, heat, some plant compounds) triggers protective adaptations, while higher doses cause harm. Proposed as the basis of several longevity interventions. Technical: In toxicology, a biphasic dose-response with a low-dose stimulatory or beneficial effect and a high-dose inhibitory or toxic effect. In biology and medicine, an adaptive response to moderate, usually intermittent stress, such as ischemic preconditioning, exercise, dietary energy restriction or low doses of some phytochemicals. Related: Caloric Restriction, Free Radicals (ROS) Source: PubMed (DOI)

The link between menopausal hormone therapy and breast cancer. A pooled analysis of worldwide studies found that every type except vaginal estrogen increased risk, more so for estrogen plus progestagen than estrogen alone; the excess was present even in the first 4 years and grew with longer use. Technical: Collaborative Group on Hormonal Factors in Breast Cancer 2019, Lancet: among current users in years 1-4, relative risk 1.60 for oestrogen-progestagen and 1.17 for oestrogen-only, roughly doubling in years 5-14. Related: HRT (Hormone Replacement Therapy), Women's Health Initiative (WHI) Source: PubMed (DOI)

The first epigenetic clock to work across almost all tissues (2013). It uses 353 DNA methylation sites to estimate age and became the benchmark for later clocks. Technical: Horvath 2013 built a multi-tissue DNA methylation age predictor that works across most tissues and cell types; it was trained on chronological age. Read: Epigenetic Clocks → Related: Epigenetic Clock, PhenoAge, Chronological Age Source: PubMed (DOI)

Replacement of declining sex hormones. For women under 60 or within 10 years of menopause without contraindications, guidelines support hormone therapy for hot flashes and to prevent bone loss; it is not recommended to prevent heart disease or other chronic conditions. Transdermal estradiol carries a lower risk of blood clots than oral forms. Technical: NAMS 2022 position statement: for women younger than 60 or within 10 years of menopause onset without contraindications, the benefit-risk ratio is favorable for bothersome vasomotor symptoms and prevention of bone loss, and less favorable when started later. USPSTF 2022 recommends against combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons. Vinogradova 2019, BMJ (nested case-control studies, 80,396 women with VTE): transdermal preparations were not associated with increased venous thromboembolism risk, unlike oral therapy. Read: HRT for Women → Related: Women's Health Initiative (WHI), Timing hypothesis (hormone therapy), Hormone therapy and breast cancer, Transdermal estrogen, Vasomotor symptoms (hot flashes), Menopausal bone loss Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

The variation in time between successive heartbeats. Higher HRV generally reflects stronger parasympathetic (rest-and-digest) activity, and it is used to track stress, fitness and recovery. Technical: Shaffer 2017, Front Public Health: HRV is measured over 24 hours, short-term (~5 minutes) or ultra-short-term (<5 minutes) recordings using time-domain (such as RMSSD), frequency-domain and non-linear metrics; values depend heavily on recording length and conditions, so trends within one person are more useful than comparisons between people. Read: HRV → Ranges and units: Biomarker Reference → Related: Resting heart rate, Consumer sleep trackers Source: PubMed (DOI)

A sensitive blood test for C-reactive protein, a marker of inflammation. Higher levels are linked to heart disease and stroke, but the link depends heavily on other risk factors. Technical: In individual data on 160,309 people from 54 prospective studies, each threefold higher CRP was associated with 37% higher coronary heart disease risk after adjustment for conventional risk factors and 23% after further adjustment for fibrinogen. CRP showed continuous associations of similar size with coronary disease, ischemic stroke, vascular mortality and death from several cancers and lung disease, whose relevance is unclear. Read: Bloodwork Guide → Ranges and units: Biomarker Reference → Related: IL-6 (Interleukin-6), Inflammaging, Fibrinogen Source: PubMed (DOI)

A rare genetic disorder with features resembling marked premature aging. Technical: Caused by mutations in the lamin A gene (LMNA): 18 of 20 classical cases carried the same new, non-inherited single-base change. Related: Werner syndrome, Genomic Instability Source: PubMed (DOI)

A high level of uric acid in the blood. It causes gout and is linked to high blood pressure and heart disease in observational studies, but a Mendelian randomization study found no evidence that uric acid itself causes heart disease or high blood pressure, and in the ALL-HEART trial, lowering it with allopurinol did not reduce cardiovascular events. Technical: Palmer 2013, BMJ: genetic instrument SLC2A9; observational associations were confirmed but causal associations were not. Mackenzie 2022, Lancet (ALL-HEART): allopurinol vs usual care in people aged 60 or older with ischaemic heart disease and no gout. Read: Uric Acid → Related: Blood pressure, Metabolic syndrome Sources: PubMed (DOI) · PubMed (DOI)

A prescription drug made of highly purified EPA, an omega-3 fat. At 4 g a day in 8,179 statin-treated patients with raised triglycerides and cardiovascular disease or diabetes, it reduced major cardiovascular events from 22.0% to 17.2% over a median of 4.9 years. It is not the same as fish-oil supplements. Technical: REDUCE-IT: 2 g twice daily versus placebo; hazard ratio 0.75 for the composite primary end point. Read: Omega-3 Fatty Acids → Related: EPA (Eicosapentaenoic Acid), Omega-3 Index, Triglycerides Source: PubMed (DOI)

A growth factor driven by growth hormone. It supports growth, but lower IGF-1 signalling is linked to longer life in animals, and in a study of people in their nineties, women with lower IGF-1 lived longer. Technical: IGF-1 and growth hormone form the GH/IGF-1 signalling axis. Attenuated GH/IGF-1 signalling is associated with extended lifespan in several animal models; among 184 nonagenarians, women with IGF-1 levels below the median survived significantly longer. Read: Centenarian Biology → Ranges and units: Biomarker Reference → Related: Growth Hormone (GH), FOXO3 Source: PubMed (DOI)

An inflammatory signalling protein. Blocking it lowered the rate of repeat cardiovascular events in a large trial, independently of cholesterol. Technical: In the CANTOS trial of 10,061 people with a previous heart attack and raised hsCRP, canakinumab, an antibody against IL-1β, given at 150 mg every 3 months lowered recurrent cardiovascular events (hazard ratio 0.85) independently of lipid lowering, with no significant difference in all-cause mortality. Related: IL-6 (Interleukin-6), hsCRP (High-Sensitivity C-Reactive Protein), Inflammaging, TNF (Tumor necrosis factor) Source: PubMed (DOI)

An inflammatory signalling protein; higher blood levels in older people go with a higher risk of death. Technical: IL-6 is a pro-inflammatory cytokine. In nondisabled older people, those with the highest plasma IL-6 levels had about twice the risk of death of those with the lowest (relative risk 1.9, top versus bottom quartile). Ranges and units: Biomarker Reference → Related: Cytokines, hsCRP (High-Sensitivity C-Reactive Protein), Inflammaging Source: PubMed (DOI)

The gradual decline of immune function with age, marked by a shrinking thymus, fewer new (naive) T cells, more senescent immune cells and weaker responses to vaccines. Technical: Its hallmarks are a fall in naive T cells in the blood with a relative rise in memory cells, together with inflammaging. The result is greater vulnerability to infection and weaker responses to vaccination. Read: Zinc and Immune Aging → Related: Inflammaging, Altered intercellular communication Source: PubMed (DOI)

An injection, given at the start, at three months and then every six months, that blocks the liver's production of PCSK9. In two trials of people with cardiovascular disease or high risk despite statins, it lowered LDL cholesterol by about 50%, with more injection-site reactions than placebo. These trials measured cholesterol, not heart events. Technical: ORION-10 and ORION-11: placebo-corrected LDL reductions of 52.3% and 49.9% at day 510; small interfering RNA targeting hepatic PCSK9 synthesis. Read: ApoB → Related: PCSK9 inhibitors, Statins Source: PubMed (DOI)

A gut hormone that stimulates insulin secretion in a glucose-dependent manner after eating. The two major incretins are GLP-1 and GIP. Pharmaceutical analogs of these hormones form the GLP-1 agonist drug class. Technical: Drucker 2018: GLP-1 controls meal-related glucose excursions by augmenting insulin and inhibiting glucagon secretion; GIP is the other main incretin. Read: GLP-1 Agonists → Related: GLP-1 (Glucagon-Like Peptide-1), GIP (Glucose-Dependent Insulinotropic Polypeptide) Source: PubMed (DOI)

Chronic, low-grade inflammation that rises with age, fed by senescent cells, visceral fat, changes in the gut and immune aging. It is thought to contribute to many age-related diseases. Technical: Chronic, sterile, low-grade inflammation that develops during ageing and contributes to age-related diseases. It is sustained by pathogens, by endogenous cell debris and misplaced molecules, and by nutrients and gut microbiota. Read: Inflammaging → Related: SASP (Senescence-Associated Secretory Phenotype), Immunosenescence, Altered intercellular communication Source: PubMed (DOI)

A hormone that regulates how the body uses and stores glucose and fat; in type 2 diabetes, muscle, fat and liver respond to it less. Technical: Insulin acts through its receptor, which activates a network of signalling pathways regulating intermediary metabolism. In type 2 diabetes and impaired glucose tolerance, muscle, fat and liver become less responsive or resistant to insulin, a state linked to obesity, hyperlipidaemia, hypertension and atherosclerosis. Related: Insulin Resistance, Fasting Insulin, Insulin/IGF-1 signalling (IIS) Source: PubMed (DOI)

A state in which cells respond less to insulin, so the body needs more insulin to keep blood glucose normal. It can be present years before type 2 diabetes is diagnosed: in one large cohort, insulin sensitivity was already falling steeply in the five years before diagnosis. Technical: Insulin resistance is more common in overweight people and is linked to higher risk of type 2 diabetes and cardiovascular disease. In overweight adults, triglycerides, the triglyceride-to-HDL ratio and fasting insulin identified insulin-resistant people about as well as the metabolic syndrome criteria; research studies measure insulin action directly with clamp or insulin-suppression tests. Read: Fasting Insulin → Related: Fasting Insulin, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), Metabolic syndrome, Prediabetes, TyG index (triglyceride-glucose index) Sources: PubMed (DOI) · PubMed (DOI)

A signalling pathway triggered by insulin and IGF-1; turning it down extends lifespan in worms and other animals. Technical: The insulin/IGF-1 signalling pathway is an evolutionarily conserved pathway that influences aging in animal models. In C. elegans, mutations in daf-2, the insulin/IGF-1 receptor gene, made adult worms live more than twice as long as normal, an effect that required the transcription factors DAF-16 and HSF-1. Related: IGF-1 (Insulin-Like Growth Factor 1), FOXO3, Klotho, Insulin Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

Analyzing everyone in the group they were assigned to, whether or not they stuck with the treatment. It keeps the benefits of randomization and gives a realistic estimate of effect; the Virta Health study reported intention-to-treat results. Technical: Hallberg 2018, Diabetes Ther: intention-to-treat analysis of the intervention group; per-protocol analyses of only adherent participants tend to overstate benefits. Related: Randomized controlled trial (RCT) Source: PubMed (DOI)

Eating patterns that cycle between eating and fasting, such as 16:8 (eating within an 8-hour window) or 5:2 (two very-low-calorie days a week). In a year-long trial, adding time-restricted eating to calorie restriction did not increase weight loss. Technical: Umbrella term covering time-restricted eating, alternate-day fasting and 5:2 patterns. In Liu 2022 (N Engl J Med; 139 adults, 12 months), adding an 8-hour eating window to calorie restriction did not change weight loss significantly, suggesting most benefits come through eating less. Read: Fasting Myths → Related: Time-Restricted Eating (TRE), Caloric Restriction, Fasting-Mimicking Diet (FMD) Source: PubMed (DOI)

A US National Institute on Aging program that tests possible anti-aging compounds in genetically diverse mice at three sites, to make results more reliable. Its best-known finding is that rapamycin extended lifespan even when started late in life (by 14% in females and 9% in males, measured at 90% mortality). Technical: Harrison 2009, Nature: genetically heterogeneous mice; rapamycin started at 600 days of age; disease patterns did not differ from controls. Related: Rapamycin Source: PubMed (DOI)

The lining that controls what passes from the gut into the body; popular "leaky gut" claims often outrun the evidence. Technical: The intestinal barrier includes surface mucus, the epithelial layer and immune defences, and permeability rises through paracellular transport, cell death or transcellular routes. A clinical review cautioned that public claims about a "leaky gut" need confirmation before dietary exclusions or supplements to repair it are endorsed. Related: Microbiome Diversity, Gut-Brain Axis Source: PubMed (DOI)

A very low-carbohydrate, high-fat diet that shifts the body toward burning fat and making ketones. In a 24-week randomized trial of 84 adults with obesity and type 2 diabetes, diabetes medications were reduced or eliminated in 95.2% of people on a ketogenic diet; long-term effects on cholesterol and the gut microbiome vary between people. Technical: Westman 2008, Nutr Metab (Lond): low-carbohydrate ketogenic diet (<20 g carbohydrate/day) versus a low-glycemic, reduced-calorie diet; both improved glycemic control, with greater medication reduction on the ketogenic diet. Read: The Ketogenic Diet and Longevity → Related: Ketones (Beta-Hydroxybutyrate), Insulin Resistance, Intermittent Fasting Source: PubMed (DOI)

Fuel molecules made by the liver during fasting or carbohydrate restriction. Beta-hydroxybutyrate (BHB) is also a signalling molecule: in mice it inhibits histone deacetylases and protects against oxidative stress. Technical: Beta-hydroxybutyrate (BHB) is a ketone body that specifically inhibits class I histone deacetylases. In mice, giving BHB, fasting and calorie restriction all increased histone acetylation, with changes in genes for oxidative-stress resistance such as FOXO3A and MT2. Read: Ketogenic Diet → Related: FOXO3, Free Radicals (ROS) Source: PubMed (DOI)

A protein whose loss causes an ageing-like syndrome in mice and whose excess extends their lifespan. Technical: Mice lacking klotho develop a syndrome resembling human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema, while overexpressing it extended lifespan. Klotho acts as a circulating hormone that represses insulin and IGF-1 signalling. Related: Insulin/IGF-1 signalling (IIS), IGF-1 (Insulin-Like Growth Factor 1) Sources: PubMed (DOI) · PubMed (DOI)

The exercise intensity at which lactate starts to build up in the blood. Zone 2 training is usually set just below the first lactate threshold, an intensity at which fat burning is near its peak. Technical: San-Millán 2018: across groups from athletes to people with metabolic syndrome, fat oxidation and blood lactate during exercise were inversely correlated (r = -0.76). Read: Zone 2 Training → Related: Zone 2 Training, Metabolic Flexibility Source: PubMed (DOI)

The cholesterol carried in low-density lipoprotein particles, the usual way LDL is measured. Genetic studies, cohorts and trials together show that LDL causes atherosclerotic cardiovascular disease. Technical: A 2017 European Atherosclerosis Society consensus, drawing on more than 200 cohort studies, Mendelian randomization studies and randomized trials with over 2 million participants, concluded that LDL causes atherosclerotic cardiovascular disease, that the effect grows with longer exposure, and that lowering LDL particle concentration by any mechanism should reduce risk in proportion to the reduction. Ranges and units: Biomarker Reference → Related: ApoB (Apolipoprotein B), Non-HDL cholesterol, Familial hypercholesterolemia (FH), HDL cholesterol (HDL-C) Source: PubMed (DOI)

The number of LDL particles in the blood. Because the cholesterol carried per particle varies, LDL particle number and LDL cholesterol can disagree. Technical: Measured by nuclear magnetic resonance in the Multi-Ethnic Study of Atherosclerosis, LDL particle number and LDL cholesterol were discordant in many people, partly because smaller particles carry less cholesterol. Among people with discordant values, only particle number was associated with incident cardiovascular disease (hazard ratio 1.45, against 1.07 for LDL cholesterol), and carotid wall thickness tracked particle number. Related: ApoB (Apolipoprotein B), LDL cholesterol (LDL-C), Small dense LDL (sdLDL) Source: PubMed (DOI)

An antibody that removes amyloid from the brain in early Alzheimer's disease. In 1,795 people, it slowed decline on a dementia rating scale by 0.45 points over 18 months (1.21 versus 1.66), with infusion reactions in 26.4% and amyloid-related brain swelling or effusions (ARIA-E) in 12.6%. Technical: CLARITY AD: change in CDR-SB from a baseline of about 3.2; amyloid reduced by 59.1 centiloids versus placebo in a substudy; described as moderately less decline with adverse events. Read: Alzheimer's Prevention → Related: Donanemab Source: PubMed (DOI)

A hormone made by fat tissue that signals how large the body's fat stores are. Technical: Leptin is the product of the obese (ob) gene, identified in mice by positional cloning along with its human counterpart; it may act in a signalling pathway from adipose tissue that regulates the size of the body fat depot. Related: Adiponectin Source: PubMed (DOI)

An essential amino acid that switches on mTORC1 and muscle protein synthesis. Leucine-rich proteins such as whey stimulate muscle protein synthesis more than lower-leucine proteins at the same dose. Technical: Tang 2009: in young men, whey hydrolysate and soy stimulated muscle protein synthesis more than casein at rest and after resistance exercise, consistent with faster digestion and higher leucine content. Read: Muscle Protein Synthesis → Related: Muscle Protein Synthesis (MPS), Anabolic Resistance Source: PubMed (DOI)

Synthetic thyroid hormone (T4), used to treat an underactive thyroid. In a trial of 737 adults aged 65 and older with mild (subclinical) hypothyroidism, it provided no apparent benefit. Technical: TRUST trial: persisting subclinical hypothyroidism (thyrotropin 4.60-19.99 mIU/L); no benefit on symptoms or secondary outcomes. Read: Thyroid Function → Related: Subclinical Hypothyroidism, Thyroid (TSH, T4, T3) Source: PubMed (DOI)

The total number of years an individual lives. Distinct from healthspan. The goal of longevity medicine is to extend both lifespan and healthspan, ideally compressing the period of decline (morbidity compression). Technical: In 1980, Fries noted that average life expectancy had risen from 47 to 73 years during the century while maximum life span had not increased, so survival curves had become more rectangular. Related: Healthspan, Morbidity Compression, Gompertz law Source: PubMed (DOI)

An edible mushroom (Hericium erinaceus) sold as a supplement for memory and thinking. In a small trial in older adults with mild cognitive impairment, lion's mane improved cognitive scores. Our Supplement Evidence Database rates it “Early or small trials” for memory and thinking. Technical: Mori 2009, Phytother Res: In a small trial in older adults with mild cognitive impairment, lion's mane improved cognitive scores. Saitsu 2019, Biomed Res: A small trial reported improved cognitive function with lion's mane. Read: Lion's mane in the Supplement Evidence Database → Sources: PubMed (DOI) · PubMed (DOI)

A cholesterol-carrying particle whose level is partly set by inherited variation in the LPA gene. Large genetic and epidemiological studies support a causal, continuous link between Lp(a) and cardiovascular disease, even when LDL cholesterol is very low. Technical: A 2022 European Atherosclerosis Society consensus concluded that epidemiologic and genetic studies of hundreds of thousands of people strongly support a causal and continuous association between Lp(a) and cardiovascular outcomes, and that current findings do not support Lp(a) as a risk factor for venous thrombosis. In two Danish studies, the number of KIV-2 repeats in the LPA gene explained 21% and 27% of the variation in Lp(a), and genetically elevated Lp(a) raised myocardial infarction risk by 22% per doubling. Read: Lp(a) → Ranges and units: Biomarker Reference → Related: ApoB (Apolipoprotein B), LDL cholesterol (LDL-C), Familial hypercholesterolemia (FH) Sources: PubMed (DOI) · PubMed (DOI)

Organelles that break down and recycle cellular material and act as signalling hubs for metabolism. Technical: Once seen as static waste-disposal organelles, lysosomes are now known to be dynamic structures that help cells adapt their metabolism; lysosome-based signalling senses metabolic status and controls the switch between building up and breaking down, partly by regulating autophagy. Related: Autophagy, Mitophagy Source: PubMed (DOI)

A composite endpoint that typically combines cardiovascular death, nonfatal heart attack and nonfatal stroke. It is the usual primary endpoint in cardiovascular outcome trials, although definitions vary between studies. Technical: Bosco 2021, BMC Med Res Methodol: MACE is increasingly used as a composite outcome in trials and observational studies, but its components are defined inconsistently, which complicates comparisons between studies. Read: GLP-1 Agonists → Related: SELECT Trial, TRAVERSE trial Source: PubMed (DOI)

Versatile immune cells that help resolve inflammation and repair tissue. Technical: Macrophages are mononuclear phagocytes with marked plasticity: in an M2 or M2-like activation state they help resolve inflammation and repair and remodel tissue, roles seen in wound healing, allergy, parasite infection and cancer. Related: Inflammaging, Cytokines Source: PubMed (DOI)

An essential mineral that is a cofactor in more than 300 enzyme systems, including those for protein synthesis, muscle and nerve function, blood glucose control and blood pressure. Almost half of Americans get less than the required amount from food. Technical: Low magnesium intakes and blood levels have been associated with type 2 diabetes, metabolic syndrome, raised CRP, hypertension, atherosclerotic disease, sudden cardiac death, osteoporosis and migraine; these are associations, and a 2012 review argued that requirements set by balance studies may be misleading. Read: Magnesium → Ranges and units: Biomarker Reference → Related: Vitamin D (25-OH) Sources: NIH Office of Dietary Supplements: Magnesium fact sheet (ods.od.nih.gov, checked 2026-10-01) · PubMed (DOI)

Low testosterone production with symptoms. The Endocrine Society recommends diagnosing it only in men who have symptoms and signs of deficiency and consistently low testosterone, measured on fasting morning blood tests with an accurate assay. Technical: Bhasin 2018, J Clin Endocrinol Metab (Endocrine Society guideline): GRADE-based recommendations; testosterone falls modestly with age, and low levels without symptoms do not warrant treatment. Read: Longevity for Men → Related: Testosterone, Free testosterone, Testosterone therapy Source: PubMed (DOI)

The name adopted in 2023 for fatty liver disease linked to metabolic risk factors (formerly NAFLD). It affects about 30% of adults worldwide. Technical: A multisociety Delphi consensus replaced NAFLD with metabolic dysfunction-associated steatotic liver disease and created a separate category, MetALD, for metabolic dysfunction combined with higher alcohol intake. A meta-analysis put global prevalence at 30%, rising from 25% in 1990 to 2006 to 38% in 2016 to 2019. Read: Liver Health → Related: ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase), FIB-4 index Sources: PubMed (DOI) · PubMed (DOI)

A conceptual framework popularized by Peter Attia describing a proactive, preventive approach to medicine — in contrast to Medicine 2.0's reactive disease treatment. Emphasizes early detection, aggressive risk factor management, and interventions targeting the four leading causes of death. Technical: A framework from the book Outlive (Attia and Gifford, 2023), not a clinical guideline; its preventive emphasis overlaps with standard prevention, while some recommended tests go beyond guidelines. Read: Peter Attia's Medicine 3.0 → Related: Centenarian Decathlon Source: Attia P, Gifford B. Outlive: The Science and Art of Longevity. Harmony; 2023.

A dietary pattern built on olive oil, vegetables, legumes, fruit, whole grains, fish and nuts. In the PREDIMED trial (republished in 2018 after problems with randomization were found), Mediterranean diets supplemented with olive oil or nuts lowered major cardiovascular events by about 30%. Technical: PREDIMED (Estruch 2018, N Engl J Med, republished): 7,447 Spanish adults aged 55 to 80 at high cardiovascular risk; 96 primary events with extra-virgin olive oil and 83 with nuts versus the reduced-fat control diet. The primary end point combined heart attack, stroke and cardiovascular death. Read: Mediterranean Diet → Related: MIND Diet, Polyphenols, Fiber (Dietary) Source: PubMed (DOI)

A hormone made by the pineal gland in darkness that helps time sleep. In adults over 50 with insomnia, a low 0.3 mg dose restored sleep efficiency. Technical: Older people typically have poor sleep efficiency and low night-time plasma melatonin. In a randomized, placebo-controlled trial in people over 50 with insomnia, a physiological 0.3 mg dose restored sleep efficiency, mainly in the middle third of the night; a pharmacological 3.0 mg dose also improved sleep. Read: Melatonin → Source: PubMed (DOI)

A method that uses genetic variants as natural experiments to test whether an exposure causes an outcome, which reduces confounding. In a large Chinese study, genetic evidence showed that moderate drinking does not protect against stroke, and genetic studies support Lp(a) as a cause of heart attacks. Technical: Genetic variants are assigned at conception, so they are largely free of the lifestyle confounding that affects observational studies. Kamstrup 2009, JAMA: genetically elevated lipoprotein(a) was associated with heart attack risk, consistent with causation. Millwood 2019, Lancet (China Kadoorie Biobank): genetic analysis indicated that the apparent protection from moderate drinking against stroke was largely non-causal. Palmer 2013, BMJ: no evidence that uric acid causally raises heart disease or blood pressure. Results depend on valid genetic instruments. Read: Alcohol and Longevity → Related: Confounding, Observational study, Hyperuricemia, Lp(a) (Lipoprotein(a)) Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

The rapid loss of bone density around the final menstrual period. In the SWAN study, women lost 10.6% of lumbar spine bone density over 10 years spanning menopause, much of it during the transition itself. Technical: Greendale 2012, J Bone Miner Res (SWAN): rate and timing of BMD loss relative to the final menstrual period; hormone therapy is approved for preventing this loss. Read: Perimenopause Longevity Guide → Related: DEXA Scan (Dual-Energy X-Ray Absorptiometry), Menopause staging (STRAW+10) Source: PubMed (DOI)

A standard system for describing where a woman is in reproductive aging, from the late reproductive years through the menopause transition to postmenopause, based mainly on changes in menstrual bleeding patterns with supporting hormone markers. Technical: Harlow 2012 (STRAW+10 executive summary): updated the 2001 criteria, simplified bleeding criteria for the early and late menopausal transition, and revised the late reproductive and early postmenopause stages. Read: Perimenopause Longevity Guide → Related: FSH (follicle-stimulating hormone), AMH (anti-Müllerian hormone), Vasomotor symptoms (hot flashes) Source: PubMed (DOI)

A statistical method that pools the results of several studies to get a more precise overall estimate. For example, a meta-analysis of cohort studies found muscle-strengthening activity was linked to a 10 to 17% lower risk of death; the result is only as reliable as the studies pooled. Technical: Momma 2022, Br J Sports Med: systematic review and meta-analysis of prospective cohorts; pooling observational studies increases precision but does not remove their shared biases. Related: Systematic review, Umbrella review Source: PubMed (DOI)

The ability to switch between burning glucose and fat as fuel supply and demand change. Reduced flexibility accompanies insulin resistance and obesity. Technical: Goodpaster 2017, Cell Metab: metabolic flexibility describes adaptation to changing metabolic demand, including the switch between glucose and fatty acid oxidation; obesity and type 2 diabetes are characterized by metabolic inflexibility. Read: Metabolic Flexibility → Related: Insulin Resistance, Zone 2 Training Source: PubMed (DOI)

A cluster of risk factors for heart disease and type 2 diabetes that occur together more often than by chance: raised blood pressure, raised triglycerides, low HDL cholesterol, raised fasting glucose and central obesity. Technical: A 2009 joint statement by several major organizations harmonized the definition: no single component is obligatory, one set of cut points applies to every component except waist circumference, and national or regional waist cut points can be used in the interim. Related: Insulin Resistance, Triglycerides, HDL cholesterol (HDL-C), Prediabetes, Visceral Fat Source: PubMed (DOI)

A diabetes drug that lowers glucose production by the liver. Observational and animal studies prompted interest in it as an anti-aging drug, and the proposed TAME trial would test whether it delays several age-related diseases at once. Technical: Barzilai 2016 notes protective associations with several age-related diseases and proposes the TAME trial; there is no trial evidence yet that metformin slows aging in people without diabetes. Read: Metformin → Related: Gerotherapeutic, TAME Trial (Targeting Aging with Metformin) Source: PubMed (DOI)

The main circulating, active form of folate (vitamin B9). Supplements are marketed to people with MTHFR variants, but medical genetics guidelines find MTHFR testing has minimal clinical utility. Technical: MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulating form of folate and the carbon donor for converting homocysteine back to methionine; when 5-MTHF is lacking, homocysteine rises. Read: Folate vs Folic Acid → Related: MTHFR (Methylenetetrahydrofolate Reductase), Folate (vitamin B9), Homocysteine Sources: PubMed (DOI) · PubMed (DOI) · NIH Office of Dietary Supplements: Folate fact sheet (ods.od.nih.gov, checked 2026-10-01)

A way of expressing exercise intensity or capacity as multiples of resting energy use. In 6,213 men referred for treadmill testing, peak exercise capacity in METs was the strongest predictor of the risk of death. Technical: Peak exercise capacity in METs was the strongest age-adjusted predictor of mortality among men with and without cardiovascular disease referred for clinical treadmill testing. Read: VO2 Max and Longevity → Related: VO2 Max, Zone 2 Training Source: PubMed (DOI)

The variety of microbial species in the gut. Higher diversity is generally associated with better health; in one large study, a gut microbiome that became more distinctive with age predicted better survival in older adults. Technical: Wilmanns 2021: in older adults, retaining high Bacteroides dominance or having a low gut microbiome uniqueness measure predicted decreased survival over 4 years. Read: Gut Microbiome → Related: Fermented foods, Fiber (Dietary), Dysbiosis Source: PubMed (DOI)

Cells of the brain and spinal cord that are central players in brain disease and help shape neural circuits. Technical: Microglia are involved in many central nervous system disorders; in the healthy brain they help sculpt developing neuronal circuits and guide learning-associated plasticity. Related: Astrocytes, Inflammaging Source: PubMed (DOI)

A hybrid of the Mediterranean and DASH diets designed for brain health, emphasizing berries, leafy greens, nuts, olive oil, fish and whole grains. In a three-year trial, it did not slow cognitive decline more than a control diet when both groups lost similar weight. Technical: Barnes 2023, N Engl J Med: 604 cognitively unimpaired older adults with a family history of dementia were randomized to the MIND diet or a control diet, both with mild calorie restriction; over 3 years, changes in cognition and brain MRI did not differ significantly. Earlier support came from observational studies. Read: Mediterranean Diet → Related: Mediterranean Diet, Caloric Restriction Source: PubMed (DOI)

Organelles that produce most of the cell's energy (ATP). Mitochondrial dysfunction is one of the 12 hallmarks of aging. Endurance exercise increases mitochondrial content in muscle. Technical: Mitochondria are dynamic organelles. In muscle they form a functional network that is maintained by biogenesis and fusion and balanced by fission and mitophagy, and they can adjust their volume, structure and capacity in response to exercise. Mitochondrial dysfunction is one of the twelve hallmarks of aging. Read: Mitochondria and Aging → Related: Mitochondrial dysfunction, Mitophagy, PGC-1α, ATP (Adenosine triphosphate) Sources: PubMed (DOI) · PubMed (DOI)

The small genome inside mitochondria, passed down through the mother. Technical: Mitochondrial diseases, defined by defects in oxidative phosphorylation, can be caused by mutations in nuclear or mitochondrial DNA; harmful mtDNA mutations are strictly maternally inherited. Related: Mitochondria, Mitochondrial dysfunction Source: PubMed (DOI)

The age-related decline in the quality and activity of mitochondria, the structures that produce most of a cell's energy. Technical: One of the twelve hallmarks of aging. Declining mitochondrial quality and activity is associated with normal aging and many age-related diseases, and mitochondria contribute to cellular senescence, chronic inflammation and the age-related decline in stem cell activity. Related: Mitochondria, Mitophagy, Free Radicals (ROS) Sources: PubMed (DOI) · PubMed (DOI)

The selective recycling of damaged mitochondria, part of the cell's quality control for these organelles. Technical: Mitophagy works with fission to balance the biogenesis and fusion that maintain mitochondrial networks in muscle. Urolithin A stimulates mitophagy in old animals; in a first human trial in sedentary older adults, 4 weeks at 500 or 1,000 mg modulated plasma acylcarnitines and muscle mitochondrial gene expression. Read: Mitochondria and Aging → Related: Mitochondria, Autophagy, Urolithin A Sources: PubMed (DOI) · PubMed (DOI)

A 10-minute screening test for mild cognitive impairment. In its 2005 validation, with a cut-off score of 26, it detected 90% of people with mild cognitive impairment, compared with 18% for the older MMSE test. Technical: Validation in 94 patients with MCI, 93 with mild Alzheimer disease and 90 controls: MoCA sensitivity 90% (MCI) and 100% (mild AD); specificity 87% versus 100% for the MMSE. Read: Alzheimer Prevention → Source: PubMed (DOI)

People with a normal BMI who have metabolic abnormalities such as insulin resistance, high blood pressure or abnormal lipids. In US national data, about 1 in 4 normal-weight adults had two or more such abnormalities. Technical: Wildman 2008, Arch Intern Med (NHANES 1999-2004): normal-weight adults were classed as metabolically abnormal if they had two or more cardiometabolic abnormalities, which applied to 23.5% of them. Read: Visceral Fat → Related: Visceral Fat, Metabolic syndrome Source: PubMed (DOI)

The concept of delaying the onset of disease and disability to the latest possible point in life, compressing the period of decline into the shortest possible timeframe before death. The practical goal of healthspan extension. Technical: Fries argued that if chronic illness can be postponed while maximum life span stays fixed, the average age at first infirmity can rise, compressing illness into a shorter period before death; he calculated an ideal average life span of about 85 years. Related: Lifespan, Healthspan Source: PubMed (DOI)

An enzyme that converts folate into its main circulating form. A common variant, C677T, makes the enzyme heat-unstable and raises homocysteine in people who carry two copies. Medical genetics guidelines say MTHFR testing should not be part of routine thrombophilia evaluation. Technical: The C677T substitution occurred in about 38% of unselected chromosomes, and homozygotes had significantly higher homocysteine. The American College of Medical Genetics and Genomics notes that meta-analyses have disproven an association between raised homocysteine and coronary heart disease, and concludes that MTHFR testing has minimal clinical utility. Read: Folate vs Folic Acid → Related: Methylfolate (5-MTHF), Homocysteine, Folate (vitamin B9) Sources: PubMed (DOI) · PubMed (DOI)

A nutrient-sensing kinase that drives growth and protein synthesis when nutrients are plentiful. Inhibiting it with rapamycin extends lifespan in mice, even when started late in life; whether intermittent inhibition benefits people is not yet known. Technical: mTOR is a kinase that coordinates cell growth and metabolism with nutrients and growth factors, regulating processes from protein synthesis to autophagy. Inhibiting it with rapamycin extended median and maximal lifespan in male and female mice even when started at 600 days of age. Read: mTOR → Related: AMPK (AMP-Activated Protein Kinase), Rapamycin, Autophagy Sources: PubMed (DOI) · PubMed (DOI)

Blood tests that look for signals from many types of cancer at once, using DNA fragments shed into the bloodstream. In the PATHFINDER study of 6,621 people, a cancer signal was detected in 92 (1.4%); whether these tests reduce cancer deaths has not been shown. Technical: Schrag 2023, Lancet (PATHFINDER): prospective cohort; a methylation signature predicted the cancer signal origin to guide diagnostic workup. As of October 2026, no randomized trial had shown that MCED screening reduces cancer mortality. Related: Cohort study Source: PubMed (DOI)

Supplements combining many vitamins and minerals. In the Physicians' Health Study II, a daily multivitamin taken for a median of 11 years by 14,641 men did not reduce major cardiovascular events, and the US Preventive Services Task Force judges the evidence insufficient to recommend them for preventing heart disease or cancer. Technical: PHS II 2012, JAMA: hazard ratio 1.01 for major cardiovascular events; no effect on heart attack, stroke or cardiovascular death. USPSTF 2022: I statement (insufficient evidence) for multivitamins. Read: Supplement Evidence Database → Related: Antioxidant supplements, Vitamin D supplements Sources: PubMed (DOI) · PubMed (DOI)

The slow-twitch (type 1) and fast-twitch (type 2) fibers that make up skeletal muscle. Technical: In whole vastus lateralis muscles from 43 healthy men aged 15 to 83, age-related atrophy began around age 25 and then accelerated, driven mainly by a loss of fibers of both types and, to a lesser extent, by shrinking fibers, mostly type 2. Related: Sarcopenia, Satellite cells Source: PubMed (DOI)

The process by which muscles build new protein in response to eating protein (especially leucine-rich protein) and to resistance training; its balance against muscle breakdown decides whether muscle is gained or lost. Older muscle needs more protein per meal to respond fully: in pooled studies, older men needed about 0.4 g of protein per kg of body weight per meal, about two-thirds more than the 0.24 g/kg younger men needed. Technical: Moore 2015, J Gerontol A Biol Sci Med Sci: retrospective analysis of dose-response studies of myofibrillar protein synthesis; the relative protein dose for a maximal response was higher in older than younger men. Read: Muscle Protein Synthesis → Related: Anabolic Resistance, Sarcopenia, Muscle-strengthening activity Source: PubMed (DOI)

Exercise that works the muscles against resistance, such as weights, bands or body-weight moves. In a meta-analysis, it was linked to a 10 to 17% lower risk of death, heart disease, cancer and diabetes independent of aerobic activity, with the largest benefit at about 30 to 60 minutes a week. Technical: Momma 2022, Br J Sports Med: J-shaped associations, maximum risk reduction of about 10-20% at roughly 30-60 min/week for all-cause mortality, CVD and total cancer; the benefit of higher volumes was unclear. Read: Strength Training for Longevity → Related: Physical activity guidelines (US), Sarcopenia, Grip Strength Source: PubMed (DOI)

Signalling proteins, such as IL-6, made and released by muscle fibres; they let muscle communicate with other organs such as fat tissue. Technical: Skeletal muscle has been identified as a secretory organ: cytokines and other peptides produced and released by muscle fibres that act locally or on distant organs are classified as myokines. The muscle secretome includes several hundred peptides; myostatin, LIF, IL-6 and IL-7 are involved in muscle growth, and BDNF and IL-6 in AMPK-mediated fat oxidation. Read: Strength Training → Related: IL-6 (Interleukin-6), BDNF (Brain-Derived Neurotrophic Factor), Sarcopenia Source: PubMed (DOI)

A coenzyme essential for energy metabolism and for enzymes such as PARPs and sirtuins. NAD+ levels fall with age in several tissues; NMN and NR are precursors being studied as ways to restore it. Technical: NAD+ is a coenzyme for redox reactions, central to energy metabolism, and an essential cofactor for non-redox enzymes including sirtuins, CD38 and poly(ADP-ribose) polymerases. It influences metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. Read: NAD+ and Sirtuins → Related: Sirtuins, NMN (Nicotinamide Mononucleotide), NR (Nicotinamide Riboside) Source: PubMed (DOI)

T cells that have not yet met the target they recognise; their numbers fall with age. Technical: With age, the number of naive T cells in the blood falls, with a relative increase in memory cells, part of the immune ageing that brings greater vulnerability to infection and weaker responses to vaccination. Related: Thymic involution, Immunosenescence Source: PubMed (DOI)

An enzyme that sets the pace of NAD+ production in mammalian cells. Technical: NAMPT was the rate-limiting component of the mammalian NAD biosynthesis pathway it shares with NMNAT. Because sirtuins require NAD for their deacetylase activity, this pathway regulates their activity. Related: NAD+ (Nicotinamide Adenine Dinucleotide), Sirtuins, CD38 Source: PubMed (DOI)

Innate immune cells that help control tumours and infections. Technical: NK cells are effector lymphocytes of the innate immune system that control several types of tumours and microbial infections; they also regulate immune responses through interactions with dendritic cells, macrophages, T cells and endothelial cells. Related: Macrophages, Immunosenescence Source: PubMed (DOI)

The kidney's filtering units, which are gradually lost with age. Technical: Kidneys age through a steady loss of nephrons and a matching fall in glomerular filtration rate starting around age 30. A modest, persistent reduction in GFR (about 45 to 59 ml/min/1.73 m2) without abnormal protein in the urine does not seem to carry much added risk of death in older adults. Related: eGFR (Estimated Glomerular Filtration Rate) Source: PubMed (DOI)

The brain's ability to reorganize itself by forming new neural connections throughout life. Driven by BDNF, exercise, learning, and adequate sleep. Not limited to youth — adults retain meaningful plasticity, though the rate declines. Technical: Voss 2013, Trends Cogn Sci: converging animal and human evidence suggests exercise benefits hippocampal structure, neurotrophic factors and cognition across the lifespan, which may translate into reduced Alzheimer's risk. Read: Neuroplasticity → Related: BDNF (Brain-Derived Neurotrophic Factor), Exercise and cognition, Hippocampal Neurogenesis Source: PubMed (DOI)

A transcription factor switched on by many different signals that controls a large number of genes. Technical: NF-κB has served as the standard example of an inducible transcription factor for more than 20 years; numerous stimuli activate it, and it regulates a large number of genes. Related: Cytokines, Inflammaging Source: PubMed (DOI)

Vitamin B3. In its nicotinic acid form it was long used at high doses as a cholesterol drug. In 3,414 patients with cardiovascular disease and low LDL on statins, adding niacin gave no additional benefit (AIM-HIGH). Our Supplement Evidence Database rates it “Not supported in trials” for heart attacks and strokes, added to statins. Technical: Boden 2011, N Engl J Med: In 3,414 patients with cardiovascular disease and low LDL on statins, adding niacin gave no additional benefit (AIM-HIGH). Landray 2014, N Engl J Med: In 25,673 adults with vascular disease, extended-release niacin with laropiprant did not reduce major vascular events and increased serious adverse events (HPS2-THRIVE). Read: Niacin (vitamin B3) in the Supplement Evidence Database → Related: Statins Sources: PubMed (DOI) · PubMed (DOI)

The ratio of neutrophils to lymphocytes in a routine blood count, an easily obtained marker of inflammation. Technical: Across 60,087 participants in five randomized trials, a higher neutrophil-lymphocyte ratio independently predicted major cardiovascular events and all-cause mortality (in CANTOS, risk rose 20% per quartile). It correlated modestly with IL-6, CRP and fibrinogen but minimally with lipids, and canakinumab lowered it while lipid-lowering drugs did not. Related: hsCRP (High-Sensitivity C-Reactive Protein), IL-6 (Interleukin-6), IL-1β (interleukin-1 beta) Source: PubMed (DOI)

A direct precursor of NAD+. Human trials are small and short: in women with prediabetes it improved muscle insulin sensitivity, and trials have tested doses of up to 900 mg a day. Technical: NMN availability is a rate-limiting factor in mammalian NAD+ biosynthesis. In a 10-week trial in women with prediabetes, NMN increased muscle insulin sensitivity; a 60-day trial in 80 healthy middle-aged adults compared blood NAD levels across doses. Read: NMN vs NR → Related: NAD+ (Nicotinamide Adenine Dinucleotide), NR (Nicotinamide Riboside) Sources: PubMed (DOI) · PubMed (DOI)

Total cholesterol minus HDL cholesterol: the cholesterol carried in all potentially artery-clogging particles. Higher levels are strongly linked to long-term cardiovascular risk. Technical: In data from 398,846 people in 38 cohorts from 19 countries, 30-year cardiovascular event rates rose steadily with non-HDL cholesterol (in women, from 7.7% below 2.6 mmol/L to 33.7% at 5.7 mmol/L or more), and the modelled benefit of halving non-HDL cholesterol was greater the earlier it was lowered. Related: LDL cholesterol (LDL-C), ApoB (Apolipoprotein B), HDL cholesterol (HDL-C) Source: PubMed (DOI)

A trial designed to show that a treatment is not meaningfully worse than a comparison on a key outcome, within a pre-set margin, rather than that it is better. TRAVERSE used this design to test whether testosterone increases cardiovascular events in 5,246 men. Technical: Lincoff 2023, N Engl J Med (TRAVERSE): testosterone met the noninferiority margin for major cardiovascular events; noninferiority does not rule out other harms, and TRAVERSE found more atrial fibrillation, kidney injury and pulmonary embolism. Related: Randomized controlled trial (RCT), TRAVERSE trial Source: PubMed (DOI)

An NAD+ precursor that enters the salvage pathway through NRK enzymes. In a trial in healthy middle-aged and older adults, NR was well tolerated and raised NAD+ levels. Technical: NR is an NAD+ precursor vitamin. In a 2 x 6-week randomized, double-blind, placebo-controlled crossover trial in healthy middle-aged and older adults, chronic NR supplementation was well tolerated and raised NAD+ levels. Read: NMN vs NR → Related: NAD+ (Nicotinamide Adenine Dinucleotide), NMN (Nicotinamide Mononucleotide) Source: PubMed (DOI)

A transcription factor that switches on cell defences against stresses from inside and outside the body. Technical: Nrf2 works with its regulator Keap1 through antioxidant response elements (ARE) in DNA. Keap1-Nrf2-ARE signalling protects cells from internal and external stresses, and Nrf2 knockout mice are more sensitive to toxic exposures, inflammatory stresses and chronic cigarette smoke. Related: Free Radicals (ROS), Glutathione Source: PubMed (DOI)

How many people need to receive a treatment for one person to benefit. In a Cochrane review, about 42 people needed to take probiotics during antibiotic treatment to prevent one case of C. difficile diarrhea. Technical: Goldenberg 2017, Cochrane: NNTB 42 overall, falling to about 12 when baseline risk exceeded 5%; NNT depends heavily on how common the outcome is. Related: Relative vs absolute risk Source: PubMed (DOI)

Cellular pathways that detect nutrient availability and adjust growth and metabolism accordingly. The four major nutrient-sensing pathways in longevity biology are mTOR, AMPK, sirtuins, and insulin/IGF-1 signaling. Technical: Deregulated nutrient-sensing is one of the twelve hallmarks of aging, covering pathways such as mTOR, AMPK, sirtuins and insulin/IGF-1 signaling. Read: Hallmarks of Aging → Related: mTOR (Mechanistic Target of Rapamycin), AMPK (AMP-Activated Protein Kinase), Sirtuins, IGF-1 (Insulin-Like Growth Factor 1), Caloric Restriction Source: PubMed (DOI)

Tree nuts and peanuts, rich in unsaturated fats, fiber and minerals. In a meta-analysis of cohort studies, each 28 g a day (about a handful) was linked to a 29% lower risk of coronary heart disease. Technical: Aune 2016, BMC Med: summary relative risk 0.71 per 28 g/day for coronary heart disease; observational data, consistent with the PREDIMED nuts arm. Read: The Mediterranean Diet for Longevity → Related: Mediterranean Diet, Olive oil Source: PubMed (DOI)

A study that measures people's habits or exposures and follows what happens to them, without assigning any treatment. It can reveal associations but cannot by itself prove cause and effect. For example, a meta-analysis of 1.4 million people linked short sleep to higher mortality, but could not show that sleeping more would lower risk. Technical: Cappuccio 2010, Sleep: prospective cohort data; such associations can reflect confounding or reverse causation (for example, illness causing long sleep). Related: Confounding, Cohort study, Randomized controlled trial (RCT) Source: PubMed (DOI)

Repeated collapse of the upper airway during sleep, causing breathing pauses, drops in oxygen and fragmented sleep. An estimated 936 million adults aged 30 to 69 worldwide have it, 425 million of them moderate to severe, and untreated severe sleep apnea has been linked to about 2.9 times the odds of fatal cardiovascular events. Technical: Benjafield 2019, Lancet Respir Med: global prevalence estimate using AHI thresholds of 5 and 15 events per hour. Marin 2005, Lancet: men with untreated severe OSA had an odds ratio of 2.87 for fatal cardiovascular events. Read: Sleep Apnea and Longevity → Related: CPAP (continuous positive airway pressure), STOP-Bang questionnaire Sources: PubMed (DOI) · PubMed (DOI)

A test that measures blood glucose two hours after drinking a standard glucose solution, used to diagnose diabetes and prediabetes. Technical: In the Whitehall II study, 49.1% of 505 new diabetes cases were diagnosed by oral glucose tolerance test, and 2-hour post-load glucose rose sharply over the 3 years before diagnosis, from 7.60 to 11.90 mmol/L. Related: Prediabetes, HbA1c (Glycated Hemoglobin), Fasting Insulin Source: PubMed (DOI)

The main fat of the Mediterranean diet. In US cohorts of 92,383 adults, people consuming more than half a tablespoon a day had 19% lower cardiovascular mortality than those who rarely used it, and replacing 10 g a day of butter, margarine, mayonnaise or dairy fat with olive oil was linked to 8 to 34% lower mortality. Technical: Guasch-Ferre 2022, J Am Coll Cardiol: Nurses' Health Study (60,582 women) and Health Professionals Follow-up Study (31,801 men); observational substitution analyses. In PREDIMED, extra-virgin olive oil was part of the intervention arm that reduced cardiovascular events. Read: The Mediterranean Diet for Longevity → Related: Mediterranean Diet, Polyphenols Source: PubMed (DOI)

An experimental small interfering RNA drug that lowers Lp(a). In 281 people with cardiovascular disease and high Lp(a), injections every 12 or 24 weeks cut Lp(a) by 70% to over 95% compared with placebo at 36 weeks; whether it prevents heart events depends on its own outcome trials; the first such trial for a different Lp(a)-lowering drug, pelacarsen, did not reduce events (September 2026). Technical: OCEAN(a)-DOSE: placebo-adjusted mean changes of -70.5% (10 mg) to -101.1% (225 mg every 12 weeks); injection-site reactions were the most common drug-related adverse events. Read: Lp(a) → Related: Lp(a) (Lipoprotein(a)), Pelacarsen (AKCEA-APO(a)-LRx) Sources: PubMed (DOI) · Ionis Pharmaceuticals Form 8-K, Exhibit 99.1: Novartis announces Lp(a)HORIZON Phase 3 topline results for pelacarsen (September 4, 2026; sec.gov, checked 2026-10-03)

EPA and DHA, long-chain omega-3 fats found in oily fish and fish-oil supplements. In 15,480 people with diabetes but no cardiovascular disease, 1 g of fish oil a day did not reduce serious vascular events (ASCEND). Our Supplement Evidence Database rates it “Mixed” for heart attacks and cardiovascular events (fish-oil supplements). Technical: Bowman 2018, N Engl J Med: In 15,480 people with diabetes but no cardiovascular disease, 1 g of fish oil a day did not reduce serious vascular events (ASCEND). Manson 2019, N Engl J Med: In 25,871 generally healthy adults, fish oil did not reduce major cardiovascular events or cancer (VITAL). Other outcomes in the database: Cardiovascular events with prescription EPA (high-risk patients): Supported. Read: Omega-3 (fish oil) in the Supplement Evidence Database → Related: Omega-3 Index, Icosapent ethyl Sources: PubMed (DOI) · PubMed (DOI)

The percentage of EPA plus DHA in red blood cell membranes. In the paper that proposed it, an index of 8% or more was associated with the lowest risk of death from coronary heart disease and 4% or less with the highest. Technical: Red blood cell fatty acid composition reflects long-term intake of EPA and DHA. The authors who proposed the index noted that, in secondary prevention trials, fish or fish oil reduced total and coronary mortality at intakes of about 1 g a day. Read: Omega-3 → Ranges and units: Biomarker Reference → Related: Vitamin D (25-OH) Source: PubMed (DOI)

Studies in which participants and researchers know who receives which treatment (open-label), and people are not assigned by chance (non-randomized). Their results are more prone to bias. The Virta Health diabetes study was both open-label and non-randomized. Technical: Hallberg 2018, Diabetes Ther: open-label, non-randomized, controlled before-and-after 1-year study of a continuous care intervention. Related: Randomized controlled trial (RCT), Placebo-controlled and double-blind trials Source: PubMed (DOI)

A once-daily tablet GLP-1 drug that, unlike semaglutide, is not a peptide. In a 72-week trial of 3,127 adults with obesity but not diabetes, the highest dose (36 mg) reduced body weight by 11.2%, versus 2.1% with placebo. Technical: Phase 3 trial (doses 6, 12 and 36 mg) as an adjunct to diet and physical activity; mean weight change -7.5%, -8.4% and -11.2% versus -2.1%. Read: GLP-1 Agonists and Longevity → Related: GLP-1 (Glucagon-Like Peptide-1), Semaglutide, Tirzepatide Source: PubMed (DOI)

A term coined in 2017 for sleep problems driven by a preoccupation with perfecting sleep-tracker data. Technical: Baron 2017, J Clin Sleep Med: case series of patients seeking treatment for self-diagnosed sleep problems based on tracker data; the inferred link between tracker data and daytime fatigue can become a perfectionistic quest for ideal sleep, and patients may trust tracker data over validated measures. Read: Sleep Tracking → Related: Consumer sleep trackers, CBT-I (cognitive behavioral therapy for insomnia) Source: PubMed (DOI)

The main bone-forming cells. Technical: Osteoblasts are the main bone-forming cells of the skeleton. Their differentiation is regulated by major developmental signals, including WNT and Notch, and by transcription factors such as RUNX2 and osterix, and they may also influence the behaviour of other cell types. Related: Osteoclasts Source: PubMed (DOI)

Bone cells that break down (resorb) bone. Technical: Bone resorption is the unique function of the osteoclast, a specialized multinucleated cell of the macrophage family whose formation is regulated mainly by M-CSF, RANK ligand and osteoprotegerin. Osteoporosis typically reflects resorption outpacing formation, and anti-osteoporosis drugs have targeted this cell. Related: Macrophages Source: PubMed (DOI)

A protein made by many senescent cells and used to identify them in research. Technical: In progeroid mice, drug-triggered removal of p16Ink4a-positive senescent cells delayed the onset of age-related problems in fat, skeletal muscle and the eye, and clearance late in life slowed disorders already present. Related: Cellular Senescence, Senolytics Source: PubMed (DOI)

A tumour-suppressor protein that works mainly by switching genes on. Technical: p53's tumour-suppressor functions have long been recognized, and it also contributes to many other aspects of disease and normal life. Activating transcription remains key to how it works, and control of that activity determines which p53 response occurs. Related: Cellular Senescence Source: PubMed (DOI)

DNA repair enzymes that consume NAD+ as they fix DNA breaks. Rising DNA damage with age increases their demand for NAD+, which may contribute to falling NAD+ levels. Technical: Braidy 2011: age-related oxidative damage activates PARP, and the resulting NAD+ depletion may play a major role in aging; Covarrubias 2021 reviews NAD+ metabolism in aging, mostly from animal studies. Read: NAD+ → Sources: PubMed (DOI) · PubMed (DOI)

Brief, repeated activation of the Yamanaka factors, aimed at making cells behave more youthfully without fully reprogramming them. Technical: Short-term cyclic expression of Oct4, Sox2, Klf4 and c-Myc improved cellular and physiological hallmarks of aging and extended lifespan in a mouse model of premature aging, and improved recovery from metabolic disease and muscle injury in older normal mice. It has not been tested for aging in people. Related: Yamanaka Factors, Epigenetic alterations Source: PubMed (DOI)

A common hormonal condition marked by irregular periods, signs of excess androgens and polycystic ovaries, linked to insulin resistance and higher cardiometabolic risk. The 2023 international guideline simplified diagnosis and allows anti-Mullerian hormone testing as an alternative to ultrasound in adults, while noting the evidence base is of low quality. Technical: Teede 2023 (international evidence-based PCOS guideline): refined diagnostic criteria and a simplified algorithm; diagnosis is still often delayed. Read: Longevity Protocol with PCOS → Related: AMH (anti-Müllerian hormone), Insulin Resistance Source: PubMed (DOI)

Injectable drugs, such as the antibody evolocumab, that block PCSK9 and so lower LDL cholesterol sharply. In 27,564 people with cardiovascular disease already taking statins, evolocumab cut LDL by 59% (median 92 to 30 mg/dL) and reduced cardiovascular events (9.8% versus 11.3%) over a median of 2.2 years. Technical: FOURIER: evolocumab 140 mg every 2 weeks or 420 mg monthly versus placebo; hazard ratio 0.85 for the primary composite end point. Read: ApoB → Related: Inclisiran, Statins, LDL cholesterol (LDL-C) Source: PubMed (DOI)

A 48-week double-blind, placebo-controlled trial of intermittent low-dose rapamycin in healthy middle-aged and older adults, designed mainly to assess safety. Its primary outcome, visceral fat measured by DXA, did not change significantly. Technical: Moel 2025, Aging (NCT04488601): decentralized trial; secondary outcomes included blood biomarkers, lean tissue and bone mineral content; it was not designed to test effects on aging or lifespan. Related: Rapamycin Source: PubMed (DOI)

An experimental antisense drug that lowers Lp(a). In a 2020 phase 2 trial of 286 people with cardiovascular disease and high Lp(a), it lowered Lp(a) in a dose-dependent way, by up to 80%. In September 2026, its phase 3 outcome trial (Lp(a)HORIZON, 8,323 people with cardiovascular disease) was reported not to reduce cardiovascular events despite lowering Lp(a). Technical: Hepatocyte-directed antisense oligonucleotide given subcutaneously; mean Lp(a) reductions of 35% at 20 mg every 4 weeks up to 80% at 20 mg weekly. Read: Lp(a) → Related: Lp(a) (Lipoprotein(a)) Sources: PubMed (DOI) · Ionis Pharmaceuticals Form 8-K, Exhibit 99.1: Novartis announces Lp(a)HORIZON Phase 3 topline results for pelacarsen (September 4, 2026; sec.gov, checked 2026-10-03)

Cells associated with the blood-brain barrier; their injury tracks barrier breakdown in the aging brain. Technical: In living people, breakdown of the blood-brain barrier in the hippocampus worsened with mild cognitive impairment, and this correlated with injury to barrier-associated pericytes measured in cerebrospinal fluid. Related: Blood-brain barrier Source: PubMed (DOI)

A protein that switches on the genes cells need to build new mitochondria. Technical: PGC-1α, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells, partly by strongly inducing NRF-1 and NRF-2 and coactivating NRF-1 on the gene for mitochondrial transcription factor A. Related: Mitochondria, AMPK (AMP-Activated Protein Kinase) Source: PubMed (DOI)

A second-generation epigenetic clock (2018) trained on a blood-test-based measure of physiological age rather than on chronological age. It outperformed earlier clocks at predicting mortality and age-related disease. Technical: Levine 2018 built PhenoAge in two steps from clinical markers of phenotypic age; higher epigenetic age relative to chronological age was associated with activation of pro-inflammatory and interferon pathways. Read: Epigenetic Clocks → Ranges and units: Biomarker Reference → Related: GrimAge, DunedinPACE, Horvath Clock Source: PubMed (DOI)

Skin aging caused by sun exposure; daily sunscreen slowed it in a randomized trial. Technical: In a randomized trial of 903 adults younger than 55, the group assigned daily broad-spectrum sunscreen showed no detectable increase in skin aging over 4.5 years, and their skin aged 24% less than that of people using sunscreen at their own discretion. Source: PubMed (DOI)

How health benefits change as the amount of exercise rises. In a pooled analysis of 661,137 adults, meeting the minimum guideline was linked to substantially lower mortality, the benefit leveled off at about 3 to 5 times the minimum, and there was no evidence of harm even at 10 times the minimum. Technical: Arem 2015, JAMA Intern Med: pooled analysis of 6 cohorts; benefits were largest when moving from no activity to some activity. Read: The Longevity Exercise Blueprint → Related: Physical activity guidelines (US), METs (metabolic equivalents) Source: PubMed (DOI)

The official US recommendations for how much exercise adults need: at least 150 to 300 minutes a week of moderate-intensity activity, or 75 to 150 minutes of vigorous activity, plus muscle-strengthening activities on 2 or more days a week. Older adults should also include balance training. Technical: Piercy 2018, JAMA (Physical Activity Guidelines for Americans, 2nd edition): equivalent combinations of moderate and vigorous activity count; older adults should do multicomponent activity combining balance, aerobic and muscle-strengthening work. Read: The Longevity Exercise Blueprint → Related: Muscle-strengthening activity, METs (metabolic equivalents), Zone 2 Training Source: PubMed (DOI)

The finding that leisure-time physical activity is linked to better health while heavy work-related physical activity may not be. In a meta-analysis, men with high occupational physical activity had an 18% higher risk of early death than men with low occupational activity; no such link was found in women. Technical: Coenen 2018, Br J Sports Med: first quantitative systematic review of occupational physical activity and all-cause mortality; 17 studies, 193,696 participants; no such association was found in women. Leisure-time activity remains clearly beneficial. Read: Longevity Guide for Outdoor and Manual Workers → Related: Physical activity guidelines (US), Sedentary behavior Source: PubMed (DOI)

Trials in which the comparison group receives an inactive look-alike (placebo) and neither participants nor researchers know who gets which (double-blind). This prevents expectations from shaping results. The TRUST trial of thyroid hormone in 737 older adults used this design and found no apparent benefit. Technical: Stott 2017, N Engl J Med (TRUST): double-blind, randomized, placebo-controlled, parallel-group trial of levothyroxine for subclinical hypothyroidism. Related: Randomized controlled trial (RCT), Open-label and non-randomized studies Source: PubMed (DOI)

Whether protein comes from plants or animals. In large US cohorts, replacing protein from processed red meat with plant protein was linked to lower mortality, but only in people with at least one unhealthy lifestyle factor such as smoking, heavy drinking, excess weight or inactivity. Technical: Song 2016, JAMA Intern Med: Nurses' Health Study and Health Professionals Follow-up Study; observational associations. Read: Protein Sources for Longevity → Related: Protein needs in older adults, Mediterranean Diet Source: PubMed (DOI)

A large family of plant compounds (flavonoids, stilbenes, phenolic acids) found in berries, tea, cocoa, olive oil, coffee and vegetables. Their health effects are thought to come partly from triggering stress-response pathways rather than only from direct antioxidant activity. Technical: Del Rio 2013 (Antioxid Redox Signal) reviews polyphenol structures, absorption and metabolism. Mattson 2008 describes hormesis, an adaptive response of cells to moderate, usually intermittent stress, including exposure to low doses of certain phytochemicals, as a proposed mechanism for their benefits. Human outcome evidence for specific polyphenols is limited. Read: Polyphenols → Related: Mediterranean Diet, Heat shock proteins Sources: PubMed (DOI) · PubMed (DOI)

A single pill combining several heart-protective drugs. In 5,713 people without cardiovascular disease, a polypill containing a statin and blood-pressure drugs lowered LDL by about 19 mg/dL and systolic pressure by about 5.8 mm Hg; with aspirin, it reduced cardiovascular death, heart attack or stroke (4.1% versus 5.8%). Technical: TIPS-3: polypill alone hazard ratio 0.79 (95% CI 0.63 to 1.00); polypill plus aspirin hazard ratio 0.69; hypotension or dizziness more common with the polypill. Related: Statins, ACE inhibitors, Aspirin (low-dose, for people without heart disease) Source: PubMed (DOI)

The long, symptom-free stage of Alzheimer's disease when brain changes are already under way. In people with an inherited form of the disease, amyloid changes in spinal fluid were detectable about 25 years before the expected onset of symptoms. Technical: Bateman 2012, N Engl J Med (DIAN): cross-sectional analysis by estimated years from expected symptom onset in autosomal dominant Alzheimer's disease; the timeline in common late-onset disease may differ. Read: The Brain Longevity Blueprint → Related: Amyloid-Beta, APOE (Apolipoprotein E) Source: PubMed (DOI)

Blood sugar that is higher than normal but below the diabetes threshold. About 5 to 10% of people with prediabetes progress to diabetes each year, and about as many return to normal. Technical: Prediabetes (intermediate hyperglycemia) is defined by glycemic values above normal but below diabetes thresholds. Observational evidence links it to early kidney disease, small fibre neuropathy, retinopathy and macrovascular disease, and lifestyle change reduces progression to diabetes by 40 to 70%. Related: HbA1c (Glycated Hemoglobin), OGTT (oral glucose tolerance test), Insulin Resistance, Metabolic syndrome Source: PubMed (DOI)

A Spanish randomized trial of 7,447 people at high cardiovascular risk. Mediterranean diets supplemented with extra-virgin olive oil or nuts reduced major cardiovascular events by about 30% compared with advice to follow a reduced-fat diet. The results were republished in 2018 after problems with randomization at some sites were corrected for. Technical: Estruch 2018 (republished): 7,447 adults aged 55 to 80 at high cardiovascular risk; Mediterranean diets with extra-virgin olive oil or nuts reduced major cardiovascular events versus a reduced-fat diet. Read: Mediterranean Diet → Related: Mediterranean Diet, Olive oil, Nuts Source: PubMed (DOI)

Live microorganisms that, taken in adequate amounts, may benefit health. Their best-supported use is preventing Clostridioides difficile diarrhea during antibiotic treatment: in a Cochrane review of 31 trials, about 42 people needed to take probiotics to prevent one case, with most of the benefit in people at higher risk. Technical: Goldenberg 2017, Cochrane: 31 RCTs, 8,672 patients; moderate-certainty evidence; NNTB 42 overall and 12 where baseline risk exceeded 5%, with no clear benefit below that. Short-term use appeared safe in people who are not immunocompromised or severely debilitated. Read: Gut Microbiome Guide → Source: PubMed (DOI)

The cell's protein shredder, which destroys proteins tagged with ubiquitin. Technical: Degradation through the ubiquitin-proteasome pathway takes two steps: several ubiquitin molecules are attached to the target protein, and the tagged protein is then degraded by the 26S proteasome. Related: Ubiquitin system, Heat shock proteins Source: PubMed (DOI)

How much protein people over 65 need. The RDA is 0.8 g per kg of body weight a day, but the PROT-AGE expert group recommends at least 1.0 to 1.2 g/kg a day for healthy older adults, and more for those who are active or ill. Technical: Bauer 2013, J Am Med Dir Assoc (PROT-AGE study group): recommendations aimed at maintaining muscle and function with age; higher intakes are advised for people with acute or chronic illness, with exceptions for severe kidney disease. Read: Protein and Longevity → Related: Muscle Protein Synthesis (MPS), Sarcopenia, Anabolic Resistance Source: PubMed (DOI)

Adding protein (food or supplements) to a resistance-training program. A meta-analysis found it modestly increased gains in muscle mass and strength, and gains in lean mass leveled off at a total protein intake of about 1.62 g per kg of body weight per day. Technical: Morton 2018, Br J Sports Med (49 randomized trials): protein supplementation augmented resistance-training-induced gains in strength and fat-free mass; the effect was smaller with training experience and age. Read: Protein and Longevity → Related: Muscle Protein Synthesis (MPS), Muscle-strengthening activity, Anabolic Resistance Source: PubMed (DOI)

An estimate of biological age from blood proteins. A 2024 clock built in 45,441 UK Biobank participants used 204 proteins that predicted chronological age closely, and faster proteomic aging was linked to 18 major chronic diseases and to death. Technical: Clock trained on 2,897 plasma proteins; 204 proteins predicted chronological age (r = 0.94). Proteomic age gap associated with incidence of 18 chronic diseases, multimorbidity and all-cause mortality. Related: Biological Age, Epigenetic age acceleration Source: PubMed (DOI)

The maintenance of proper protein folding, function, and degradation. Loss of proteostasis — the accumulation of misfolded or aggregated proteins — is one of the 12 hallmarks of aging and underlies neurodegenerative diseases. Technical: Loss of proteostasis is one of the twelve hallmarks of aging. In the endoplasmic reticulum, where most secreted and surface proteins fold, cells match protein-folding capacity to need, and a burden of unfolded proteins activates the unfolded protein response. Read: Hallmarks of Aging → Related: Unfolded protein response (UPR), Autophagy, Hallmarks of Aging Sources: PubMed (DOI) · PubMed (DOI)

A blood test whose level correlates with prostate cancer risk and aggressiveness but has limited specificity. Technical: Refinements such as free PSA, PSA density and PSA velocity have emerged as adjuncts to screening. The USPSTF advises an individual decision about PSA screening for men aged 55 to 69 and recommends against it from age 70. Ranges and units: Biomarker Reference → Related: Testosterone Sources: PubMed (DOI) · USPSTF: Prostate Cancer Screening recommendation (uspreventiveservicestaskforce.org, checked 2026-10-01)

The speed at which the pressure wave from each heartbeat travels along the aorta; stiffer arteries carry it faster. In 17,635 people, higher aortic PWV improved prediction of heart disease and stroke beyond standard risk factors, with weaker associations at older ages. Technical: Individual-participant meta-analysis of 16 studies: hazard ratios per 1-SD change in log aortic PWV of 1.35 for coronary heart disease, 1.54 for stroke and 1.45 for cardiovascular disease. Read: Advanced Cardiovascular Testing → Related: Blood pressure, CIMT (carotid intima-media thickness) Source: PubMed (DOI)

A study in which participants are assigned by chance to a treatment or a comparison group, so that other differences between the groups even out. It is the strongest design for showing cause and effect. For example, SPRINT randomly assigned 9,361 adults to intensive or standard blood pressure targets. Technical: SPRINT Research Group 2015, N Engl J Med: random assignment balances known and unknown confounders on average, which observational studies cannot guarantee. Related: Observational study, Placebo-controlled and double-blind trials, Intention-to-treat analysis Source: PubMed (DOI)

Drugs related to rapamycin that inhibit the mTORC1 complex. In a phase 2a trial of 264 older adults, six weeks of a low-dose combination (BEZ235 plus RAD001, also known as everolimus) was safe and was followed by fewer reported infections over the next year and better responses to flu vaccination. Technical: Selective TORC1 inhibition with a catalytic plus an allosteric mTOR inhibitor; antiviral gene expression was up-regulated. Read: Rapamycin → Related: Rapamycin, mTOR (Mechanistic Target of Rapamycin) Source: PubMed (DOI)

An mTOR inhibitor used to prevent organ-transplant rejection. It has extended lifespan in yeast, worms, flies and mice, including when started late in life in mice. Intermittent low-dose regimens are being studied in people, but there is no proof yet that it slows human aging. Technical: Harrison 2009, Nature (Interventions Testing Program): started late in life in genetically heterogeneous mice, rapamycin increased age at 90% mortality by 14% in females and 9% in males. In people, the PEARL trial of intermittent low-dose rapamycin reported safety data over 48 weeks but no change in its primary outcome. Read: Rapamycin and mTOR → Related: mTOR (Mechanistic Target of Rapamycin), Interventions Testing Program (ITP), PEARL trial Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

How much red blood cells vary in size, reported on a standard blood count; higher values predict higher mortality. Technical: In US adults aged 45 and older, each 1% higher RDW was associated with 22% higher all-cause mortality, and the association held in people without anemia and in those within the reference range (11% to 15%) without iron, folate or B12 deficiency. Related: Anemia Source: PubMed (DOI)

The daily intake of a nutrient that meets the needs of nearly all healthy people. For vitamin D, the Institute of Medicine set RDAs of 600 IU a day up to age 70 and 800 IU after, enough to meet the requirements of at least 97.5% of the population. Technical: Institute of Medicine 2011 dietary reference intakes for calcium and vitamin D: the RDA is set to cover at least 97.5% of the population; for vitamin D it corresponds to a blood 25-hydroxyvitamin D level of at least 20 ng/mL. Read: Vitamin D and Longevity → Related: Vitamin D supplements, Vitamin D (25-OH) Source: PubMed (DOI)

Running for health or leisure. In a study of 55,137 adults, runners had 30% lower all-cause and 45% lower cardiovascular mortality than non-runners, and running less than 51 minutes a week was enough to see a benefit. Technical: Lee 2014, J Am Coll Cardiol: benefits were similar across running doses and speeds; persistent runners had the largest reductions in risk. Read: Top 10 Exercise Myths → Related: Cardiorespiratory fitness, Physical activity guidelines (US) Source: PubMed (DOI)

Beef, pork and lamb, and meats preserved by curing, salting or smoking such as bacon and sausages. A 2019 systematic review found low-certainty evidence that eating 3 fewer servings a week was linked to very small reductions in the risk of death, heart disease, stroke and type 2 diabetes. Technical: Zeraatkar 2019, Ann Intern Med: cohort studies; the magnitude of association was very small and the evidence of low certainty. Other bodies, including the WHO's cancer agency, classify processed meat as a cause of colorectal cancer. Read: Protein Sources for Longevity → Related: Plant vs animal protein, Ultra-Processed Food Source: PubMed (DOI)

Relative risk tells you how much a factor changes risk in proportion (for example, doubling it); absolute risk tells you how many extra cases occur. In the EPIC-Oxford study, vegans had 2.31 times the hip fracture risk of meat eaters, which translated into about 15 extra cases per 1,000 people over 10 years. Technical: Tong 2020, BMC Med: hazard ratio 2.31 and rate difference 14.9 per 1,000 over 10 years. Rossouw 2007, JAMA: hormone therapy started within 10 years of menopause carried an absolute CHD excess of -6 per 10,000 person-years. Related: Hazard ratio, Number needed to treat (NNT) Sources: PubMed (DOI) · PubMed (DOI)

The sleep stage with rapid eye movements, vivid dreams and near-total muscle paralysis. It is thought to support emotional processing and some kinds of memory; heavy drinking suppresses it early in the night, and moderate to heavy drinking reduces it across the night. Technical: Ohayon 2004, Sleep (65 studies, 3,577 people aged 5 to 102): age-related changes in sleep stages. Ebrahim 2013, Alcohol Clin Exp Res: at high doses alcohol suppresses REM in the first half of the night, while low and moderate doses show no clear trend there; total-night REM is reduced at moderate and high doses, and all doses disrupt the second half of sleep. Read: Sleep Stages → Related: Sleep Architecture, Slow-Wave Sleep (SWS) Sources: PubMed (DOI) · PubMed (DOI)

The cholesterol carried in triglyceride-rich lipoproteins. Genetic studies suggest that high levels cause ischemic heart disease. Technical: Using genetic variants, a 1 mmol/L (39 mg/dL) genetic increase in nonfasting remnant cholesterol carried a 2.8-fold causal risk of ischemic heart disease, independent of HDL cholesterol, against an observational hazard ratio of 1.4; the authors note that pleiotropy cannot be fully excluded and confirmation is needed. Related: Triglycerides, ApoB (Apolipoprotein B), HDL cholesterol (HDL-C) Source: PubMed (DOI)

Your heart rate at rest, in beats per minute. For adults, 60 to 100 is normal (40 to 60 in well-trained athletes). In a meta-analysis of prospective studies, each 10 beats per minute higher was linked to 17% higher all-cause mortality. Technical: Summary relative risk per 10 bpm higher resting heart rate: 1.17 (95% CI 1.14-1.19) for all-cause mortality and 1.15 for cardiovascular disease (87 studies). Read: Heart Rate Variability → Ranges and units: Biomarker Reference → Related: HRV (Heart Rate Variability), Heart rate recovery, Blood pressure Sources: MedlinePlus: Pulse (medlineplus.gov, checked 2026-10-01) · PubMed (DOI)

A polyphenol found in grapes and red wine, once promoted as a sirtuin activator. Later research showed that some early test-tube results depended on the assay used, and in older Italian adults, dietary resveratrol levels were not associated with longer life. Current evidence does not support supplements for longevity. Technical: Gliemann 2013, J Physiol: In older men doing exercise training, resveratrol blunted the cardiovascular benefits of exercise. Our Supplement Evidence Database rates resveratrol “Possible harm in trials” for exercise benefits (older men). Read: Sirtuins → Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

A triple receptor agonist (GLP-1, GIP and glucagon) that is not yet approved. It produced 24.2% weight loss at 48 weeks in a phase 2 trial; in the phase 3 TRIUMPH-1 trial, Lilly's topline results reported 28.3% average weight loss at 80 weeks on 12 mg (25.0% counting everyone who started). The glucagon component is thought to add effects on energy expenditure and liver fat. Technical: Jastreboff 2023 (phase 2 obesity trial) and Sanyal 2024 (liver fat substudy) reported large reductions in weight and liver fat; phase 3 TRIUMPH topline results were announced by the manufacturer in May 2026. Read: GLP-1 Agonists → Related: Tirzepatide, Semaglutide, GIP (Glucose-Dependent Insulinotropic Polypeptide) Sources: PubMed (DOI) · Eli Lilly press release, May 21, 2026: TRIUMPH-1 topline results (investor.lilly.com) · PubMed (DOI)

Age-related loss of muscle mass, strength and function. It is associated with falls, frailty, disability and higher mortality. Resistance training is the main countermeasure, alongside adequate protein. Technical: The 2018 European consensus (EWGSOP2) defines sarcopenia as a muscle disease, or muscle failure, rooted in adverse muscle changes that accrue across a lifetime. It uses low muscle strength as the key characteristic and low muscle quantity or quality to confirm the diagnosis. Read: Strength Training → Related: Satellite cells, Muscle fiber types, Muscle Protein Synthesis (MPS) Source: PubMed (DOI)

The cocktail of inflammatory cytokines, chemokines, proteases, and growth factors secreted by senescent cells. The SASP drives local and systemic inflammation, damages neighboring tissue, and promotes further senescence in a paracrine fashion. Technical: In human cells pushed into senescence by DNA damage, the SASP developed slowly over several days and only after damage severe enough to induce senescence, with remarkably similar profiles in normal fibroblasts, normal epithelial cells and tumor cells. Read: Cellular Senescence → Related: Cellular Senescence, Inflammaging Source: PubMed (DOI)

Muscle stem cells that repair damaged muscle. Technical: Satellite cells sit between a muscle fibre's membrane and its basement membrane. Pax7-positive satellite cells repaired damaged muscle repeatedly after injury in transplantation and lineage-tracing studies, and they are required for injury-induced muscle regeneration. Related: Sarcopenia, Stem Cell Exhaustion Source: PubMed (DOI)

Time spent sitting or lying down while awake with very little energy use, such as sitting at a desk or watching TV. Long sitting time is linked to worse health even in people who exercise, but about 60 to 75 minutes of moderate activity a day appeared to eliminate the extra risk of death linked to high sitting time. Technical: Biswas 2015, Ann Intern Med: prolonged sedentary time independently associated with deleterious outcomes regardless of physical activity. Ekelund 2016, Lancet: 60-75 min/day of moderate activity eliminated the mortality risk of high sitting time but only attenuated that of high TV viewing. Read: Longevity Guide for Desk Workers → Related: Activity breaks (breaking up sitting), Daily step count Sources: PubMed (DOI) · PubMed (DOI)

A cardiovascular outcome trial of 17,604 people with established cardiovascular disease and overweight or obesity but no diabetes. Semaglutide 2.4 mg reduced major adverse cardiovascular events by 20% (hazard ratio 0.80). Published in the New England Journal of Medicine in 2023. Technical: Lincoff 2023, N Engl J Med: semaglutide 2.4 mg weekly vs placebo in 17,604 adults aged 45 or older with established cardiovascular disease and BMI of 27 or more without diabetes; primary composite of cardiovascular death, nonfatal heart attack or nonfatal stroke, hazard ratio 0.80. Read: GLP-1 Agonists → Related: Semaglutide, MACE (Major Adverse Cardiovascular Events) Source: PubMed (DOI)

A GLP-1 receptor agonist sold as Ozempic (diabetes) and Wegovy (weight management). In the SELECT trial it reduced major cardiovascular events by 20% in people with heart disease and overweight or obesity without diabetes, and in the FLOW trial it reduced serious kidney outcomes in people with diabetes and kidney disease by 24%. Technical: SELECT (Lincoff 2023, N Engl J Med): hazard ratio 0.80 for major cardiovascular events in people with cardiovascular disease and overweight or obesity without diabetes. FLOW (Perkovic 2024, N Engl J Med): reduced major kidney disease events in people with type 2 diabetes and chronic kidney disease. Read: GLP-1 Agonists → Related: SELECT Trial, GLP-1 (Glucagon-Like Peptide-1), Tirzepatide Sources: PubMed (DOI) · PubMed (DOI)

Drugs that selectively kill senescent cells. The most studied combination is dasatinib plus quercetin. Human trials are small and early. Technical: Kirkland 2017, J Am Geriatr Soc: senescent cells accumulate in many tissues with age and at sites of chronic disease; senolytics such as dasatinib plus quercetin and fisetin clear them in animal models, and human trials so far are small and early. Read: Longevity Science 2025 → Related: Rapamycin, Stem Cell Exhaustion Source: PubMed (DOI)

A protein measured in routine blood tests. Lower levels, even within the normal range, are associated with higher mortality. Technical: Across many populations, serum albumin was inversely related to mortality in a graded manner over its entire range, with the odds of death 24% to 56% higher for each 2.5 g/L lower; the authors suggest it is a sensitive indicator of preclinical disease and of disease severity. Related: hsCRP (High-Sensitivity C-Reactive Protein), eGFR (Estimated Glomerular Filtration Rate) Source: PubMed (DOI)

Diabetes drugs (such as empagliflozin and dapagliflozin) that make the kidneys excrete glucose. In large trials they reduced hospitalization for heart failure and the progression of kidney disease. Technical: Zelniker 2019 meta-analysis: SGLT2 inhibitors had moderate benefits on atherosclerotic major cardiovascular events, seemingly confined to people with established atherosclerotic disease. Read: Kidney Health → Related: MACE (Major Adverse Cardiovascular Events) Source: PubMed (DOI)

A blood protein that binds sex hormones, including testosterone. In men it rises with age, while free and bioavailable testosterone fall faster than total testosterone. Technical: In the Massachusetts Male Aging Study, SHBG rose about 1.6% a year cross-sectionally while bioavailable testosterone fell faster than total testosterone. The Endocrine Society recommends measuring free testosterone when total testosterone is near the lower limit or when a condition alters SHBG. Ranges and units: Biomarker Reference → Related: Testosterone, Free testosterone Sources: PubMed (DOI) · PubMed (DOI)

A family of NAD+-dependent enzymes (SIRT1 to SIRT7) involved in DNA repair, metabolism and stress responses. Their activity depends on NAD+ levels, which fall with age; whether boosting them extends human life is unknown. Technical: Sirtuins are NAD+-consuming enzymes, like PARPs and the CD38/157 ectoenzymes. NAD+ biosynthesis through the enzyme NAMPT and SIRT1 together regulate metabolism and circadian rhythm, and NAD+ levels decline during aging. Read: Sirtuins → Related: NAD+ (Nicotinamide Adenine Dinucleotide) Source: PubMed (DOI)

A test of sitting down on the floor and getting back up using as little support from hands or knees as possible, scored 0 to 10. In 2,002 adults aged 51 to 80, each extra point was linked to 21% better survival. Technical: Each of sitting and rising is scored 0-5, subtracting a point per support used (hand/knee); in a retrospective cohort (median follow-up 6.3 years), lower scores were associated with higher all-cause mortality. Related: Grip Strength, Gait speed Source: PubMed (DOI)

How far you can walk in six minutes, used to measure functional exercise capacity. Because results shift with small changes in how the test is run, and people improve with practice, two tests are recommended when tracking change. Technical: ERS/ATS 2014 technical standard: valid, reliable and responsive to change with some interventions; encouragement, supplemental oxygen, track layout and walking aids should be held constant, and the best of two tests recorded. Read: VO2 Max and Longevity → Related: VO2 Max, Gait speed, METs (metabolic equivalents) Sources: PubMed (DOI) · PubMed (DOI)

The structure of sleep across the night, cycling through non-REM stages (N1, N2, N3) and REM sleep roughly every 90 minutes. Deep (slow-wave) sleep is concentrated in the first half of the night and REM sleep in the second half. Technical: Patel 2024, StatPearls (Physiology, Sleep Stages): non-REM stages N1-N3 and REM alternate in cycles of roughly 90 minutes; deep N3 sleep dominates early cycles and REM lengthens in later cycles. Read: Sleep Stages → Related: Slow-Wave Sleep (SWS), REM Sleep, Consumer sleep trackers Source: NCBI Bookshelf NBK526132 (StatPearls: Physiology, Sleep Stages)

Getting less sleep than the body needs, either acutely (a night without sleep) or chronically (repeated short nights). In a PET imaging study, a single night without sleep increased amyloid-beta in the hippocampus and thalamus of healthy adults, though whether repeated short sleep causes Alzheimer's disease is not known. Technical: Shokri-Kojori 2018, Proc Natl Acad Sci: one night of sleep deprivation increased amyloid-beta burden on PET in the right hippocampus and thalamus. Read: Sleep and Longevity → Related: Amyloid-Beta, Glymphatic System, Sleep duration Source: PubMed (DOI)

How long you sleep in a typical night; most adults are advised to get 7 to 9 hours. In a meta-analysis of 1.4 million people, habitually short sleep was linked to a 12% higher risk of death, although long sleep may partly reflect existing illness. Technical: Cappuccio 2010, Sleep: meta-analysis of prospective studies (1,382,999 participants); both ends of the duration curve were associated with mortality, which does not establish that changing sleep length changes risk. Read: Sleep and Longevity → Related: Sleep Architecture, Circadian Rhythm Source: PubMed (DOI)

The deepest stage of non-REM sleep, marked by slow, high-amplitude delta waves. It declines markedly from early adulthood to midlife, in step with a fall in growth hormone secretion. Technical: Van Cauter 2000, JAMA: in 149 healthy men aged 16 to 83, slow-wave sleep fell steeply from early adulthood (16 to 25) to midlife, in parallel with a decline in growth hormone secretion. Read: Sleep Stages → Related: Sleep Architecture, Glymphatic System Source: PubMed (DOI)

Small, dense LDL particles. In a long-term US study, small dense LDL cholesterol was the lipid measure most strongly linked to future cardiovascular disease. Technical: In the Framingham Offspring Study, 20.2% of participants developed atherosclerotic cardiovascular disease over 16 years. Small dense LDL cholesterol, direct LDL cholesterol and Lp(a) remained significant after adjustment for standard risk factors, and no other lipoprotein measure added information to the pooled cohort equations once small dense LDL cholesterol was included. Related: LDL cholesterol (LDL-C), LDL particle number (LDL-P), ApoB (Apolipoprotein B), Lp(a) (Lipoprotein(a)) Source: PubMed (DOI)

The mismatch between the sleep timing that work or social schedules impose and the timing your body clock prefers, often seen as sleeping much later on weekends. In a large population study, more social jetlag was associated with a higher BMI. Technical: Roenneberg 2012, Curr Biol: in a large epidemiological study, social jetlag was associated with higher BMI beyond the effect of sleep duration, consistent with circadian disruption affecting energy balance. Read: Circadian Rhythm → Related: Circadian Rhythm, Sleep duration Source: PubMed (DOI)

Changes in DNA that arise in the body's cells during life, rather than being inherited. Technical: In adult stem cells from several human tissues, mutations accumulated steadily at about 40 new mutations a year, despite large differences in cancer incidence between the tissues. Related: Genomic Instability, Clonal hematopoiesis (CHIP) Source: PubMed (DOI)

A natural polyamine whose levels fall with age; it extends lifespan in yeast, flies and worms. Technical: Spermidine, whose intracellular concentration declines during human ageing, extended the lifespan of yeast, flies, worms and human immune cells, partly by inducing autophagy, and inhibited oxidative stress in ageing mice. In a 12-month randomized trial in older adults with subjective cognitive decline, spermidine did not improve memory compared with placebo. Related: Autophagy Sources: PubMed (DOI) · PubMed (DOI)

A short test of leg function that scores standing balance, an 8-foot walk and five chair rises. Lower scores predicted death and nursing home admission, even among people who reported almost no disability. Technical: Summary score (0-12) from side-by-side, semi-tandem and tandem stands, 8-foot walk time and time for five chair rises; commonly grouped as 0-3, 4-6, 7-9 and 10-12. Related: Gait speed, Frailty, 30-second chair stand Sources: PubMed (DOI) · PubMed (DOI)

The brain-health part of the SPRINT blood pressure trial. Among 9,361 adults, intensive blood pressure control (systolic below 120 mm Hg) did not significantly reduce probable dementia (149 vs 176 cases), but it significantly reduced mild cognitive impairment. Technical: SPRINT MIND Investigators 2019, JAMA: adjudicated probable dementia was the primary cognitive outcome; the trial ended early, so dementia cases were fewer than planned. Read: Longevity Protocol by Age → Related: SPRINT trial, Blood pressure, FINGER trial Source: PubMed (DOI)

A US trial testing how low to push blood pressure in 9,361 adults at high cardiovascular risk without diabetes. Aiming for a systolic pressure below 120 mm Hg, rather than below 140, led to lower rates of major cardiovascular events and death, with more side effects such as low blood pressure and kidney problems. Technical: SPRINT Research Group 2015, N Engl J Med: intensive vs standard systolic targets; the trial was stopped early for benefit. Read: Longevity Protocol by Age → Related: Blood pressure, SPRINT MIND, MACE (Major Adverse Cardiovascular Events) Source: PubMed (DOI)

Cholesterol-lowering drugs that block the liver enzyme HMG-CoA reductase. In a meta-analysis of 26 trials with about 170,000 people, each 1 mmol/L (about 39 mg/dL) reduction in LDL cholesterol cut major vascular events by about a fifth and all-cause mortality by 10%. Technical: Cholesterol Treatment Trialists' individual-participant meta-analysis: rate ratio 0.78 for major vascular events and 0.90 for all-cause mortality per 1.0 mmol/L LDL reduction; more versus less intensive regimens gave a further 15% reduction in major vascular events. Read: ApoB → Related: LDL cholesterol (LDL-C), ApoB (Apolipoprotein B), Ezetimibe, PCSK9 inhibitors Source: PubMed (DOI)

Statistical significance indicates a result unlikely to be due to chance alone; power is a study's ability to detect a real effect. A non-significant result is not proof of no effect: in SPRINT MIND, intensive blood pressure control produced 149 vs 176 dementia cases, a difference that was not significant, partly because the trial ended early with fewer cases than expected. Technical: SPRINT MIND Investigators 2019, JAMA: underpowered for the primary dementia outcome; the secondary outcome of mild cognitive impairment was significantly reduced. Related: Confidence interval, Randomized controlled trial (RCT) Source: PubMed (DOI)

The age-related decline in stem cell number and regenerative capacity. One of the 12 hallmarks of aging. Reduces the body's ability to repair tissue, maintain immune function, and replace damaged cells. Technical: One of the twelve hallmarks of aging. In heterochronic parabiosis experiments, exposing old mice to factors in young blood restored the activation, proliferation and regenerative capacity of aged muscle stem (satellite) cells. Read: Hallmarks of Aging → Related: Heterochronic parabiosis, Hallmarks of Aging Sources: PubMed (DOI) · PubMed (DOI)

How fast you walk, measured in steps per minute; about 100 steps per minute is roughly moderate intensity. In a large meta-analysis, after accounting for total steps, time spent at 100 or more steps per minute was not significantly linked to mortality, although a faster peak 30-minute cadence was. Technical: Paluch 2022, Lancet Public Health: adjusting for steps per day, peak 30-minute and 60-minute cadence remained significantly associated with lower mortality; minutes at 40+ or 100+ steps/min did not. Read: Walking for Longevity → Related: Daily step count Source: PubMed (DOI)

An eight-question screening tool for obstructive sleep apnea: Snoring, Tiredness, Observed apnea, high blood Pressure, BMI over 35, Age over 50, Neck circumference over 40 cm and male Gender. A score of 0 to 2 suggests low risk and 5 to 8 high risk; a score of 3 or more picks up 93% of people with moderate to severe sleep apnea. Technical: Chung 2016, Chest: a score of 3 or more had 93% sensitivity for moderate to severe OSA (AHI above 15) and 100% for severe OSA (AHI above 30); intermediate scores can be refined using BMI and other items. Read: Sleep Apnea and Longevity → Related: Obstructive sleep apnea Source: PubMed (DOI)

A raised TSH with normal free T4. It is common, and in a trial of adults aged 65 and over, levothyroxine did not improve symptoms or tiredness, so monitoring is often preferred to treatment. Technical: In the TRUST trial, 737 adults aged 65 or older with persistent subclinical hypothyroidism (TSH 4.60 to 19.99 mIU/L) were randomized to levothyroxine or placebo; after 1 year there was no apparent benefit on symptoms, tiredness or secondary outcomes. A review notes treatment might be indicated at TSH 10 mU/L or higher and that levothyroxine can cause overtreatment, especially in elderly patients. Read: Thyroid Function → Related: Thyroid (TSH, T4, T3), Hashimoto's Thyroiditis, TPO antibodies (thyroid peroxidase antibodies) Sources: PubMed (DOI) · PubMed (DOI)

Drinks with added sugar, such as soda, sweetened juice drinks and energy drinks. In a meta-analysis of 11 cohort studies with 310,819 people, those drinking the most (usually 1 to 2 servings a day) had a 26% greater risk of developing type 2 diabetes than those drinking the least. Technical: Malik 2010, Diabetes Care: highest vs lowest quantile; 15,043 cases of type 2 diabetes; the studies also linked higher intake to metabolic syndrome. Read: The Longevity Nutrition Blueprint → Related: Ultra-Processed Food, Insulin Resistance Source: PubMed (DOI)

A stable blood protein that reflects low-grade inflammation and predicts disease and death. Technical: In a general-population cohort, higher baseline suPAR was associated with greater risk of cancer, cardiovascular disease, type 2 diabetes and death, independently of C-reactive protein, with stronger associations in men and in younger people. Related: hsCRP (High-Sensitivity C-Reactive Protein), Inflammaging Source: PubMed (DOI)

Whether a supplement contains what its label says. In a study of melatonin products, actual content ranged from 83% less to 478% more than labelled, and varied by as much as 465% between batches of the same product. Technical: Erland 2017, J Clin Sleep Med: 31 supplements analysed (30 commercial products); variability was not explained by manufacturer or product type, and some products contained serotonin. Read: Supplement Brand Testing and Purity → Related: Adulterated supplements, Dietary supplement regulation (US) Source: PubMed (DOI)

Liver damage caused by herbal or dietary supplements. These products now account for about 20% of drug-induced liver injury cases in the United States, with anabolic steroids, green tea extract and multi-ingredient products the main culprits. Technical: Navarro 2017, Hepatology (AASLD/NIH symposium): bodybuilding steroids typically cause prolonged cholestatic injury; green tea extract and many other products cause acute hepatitis-like injury; most cases involve multi-ingredient supplements. Read: Liver Health and Longevity → Related: Green tea extract (EGCG), Adulterated supplements Source: PubMed (DOI)

A lab value or measurement used in place of an outcome people care about, such as blood pressure instead of heart attacks. Surrogates can mislead: CPAP lowers blood pressure, yet in the SAVE trial it did not prevent cardiovascular events in people with sleep apnea and heart disease. Technical: McEvoy 2016, N Engl J Med (SAVE): no reduction in cardiovascular events despite CPAP's known effects on blood pressure; hard outcomes are needed to confirm benefits seen on surrogates. Related: MACE (Major Adverse Cardiovascular Events), CPAP (continuous positive airway pressure) Source: PubMed (DOI)

The junctions where nerve cells pass signals; their loss tracks memory decline in Alzheimer's disease. Technical: In 15 people with Alzheimer's disease, cognitive test scores correlated only weakly with plaques and tangles but strongly with the density of synapses in the neocortex; a model built mainly on synapse density reached a correlation of 0.96 with a dementia rating scale. Related: Hippocampus, Microglia Source: PubMed (DOI)

A review that searches for all studies on a question using a pre-specified method and appraises them, often combined with a meta-analysis. Cochrane reviews are a well-known example: one pooled 78 randomized trials with 296,707 participants to evaluate antioxidant supplements. Technical: Bjelakovic 2012, Cochrane: pre-specified search, risk-of-bias assessment and pooling of randomized trials of antioxidant supplements and mortality. Related: Meta-analysis, Umbrella review, Certainty of evidence (GRADE) Source: PubMed (DOI)

A proposed trial, designed with input from the FDA, to test whether metformin delays a composite of age-related diseases and death in older adults. Its aim is to establish delaying multiple age-related diseases as a valid trial endpoint. Technical: Barzilai 2016, Cell Metab: TAME was proposed as the first step toward trials that target aging itself, using metformin because of its protective associations with several age-related diseases; as of 2026 it has not reported results. Read: Metformin → Related: Metformin, Rapamycin Source: PubMed (DOI)

An amino-acid-like molecule whose blood levels fall with age; supplements extended healthy life in mice. Technical: Circulating taurine declines with aging in mice, monkeys and humans. Reversing the decline with supplements increased health span and life span in mice and health span in monkeys. Source: PubMed (DOI)

An enzyme that adds repeats to chromosome ends, partly offsetting telomere shortening. It is active in stem cells and most cancer cells. A small pilot study found higher telomerase activity after a comprehensive lifestyle program. Technical: The cellular enzyme that counteracts telomere shortening. Genetically caused variations in telomere maintenance can either raise or lower the risk and progression of cancers, depending on the cancer. Read: Telomeres → Related: Telomeres, Hayflick limit Sources: PubMed (DOI) · PubMed (DOI)

Repetitive DNA sequences (TTAGGG) capping chromosome ends that shorten with each cell division. Critically short telomeres trigger cellular senescence. Telomere length testing is commercially available but has significant limitations as a longevity biomarker. Technical: Protective end-complexes of chromosomes. Telomere attrition can block cell division and interfere with tissue replenishment, and greater overall attrition predicts mortality and aging-related diseases in inherited telomere syndromes and in general population cohorts. Read: Telomeres → Ranges and units: Biomarker Reference → Related: Telomerase, Hayflick limit, Cellular Senescence Source: PubMed (DOI)

The main male sex hormone. In a large study of middle-aged men, total testosterone fell by about 1.6% a year. The 2023 TRAVERSE trial found testosterone therapy noninferior to placebo for major cardiovascular events in men with low testosterone and high cardiovascular risk, with more atrial fibrillation, acute kidney injury and pulmonary embolism. Guidelines support treatment only for men with symptoms and confirmed low levels. Technical: In the Massachusetts Male Aging Study, total testosterone fell 1.6% a year within individuals and bioavailable testosterone 2 to 3% a year. The Endocrine Society recommends diagnosing hypogonadism only with symptoms and signs plus unequivocally and consistently low testosterone, confirmed by repeating a morning fasting measurement. Read: Testosterone → Ranges and units: Biomarker Reference → Related: SHBG (sex hormone-binding globulin), Free testosterone, DHEA-S (dehydroepiandrosterone sulfate) Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

Prescription testosterone for men with confirmed hypogonadism. In the Testosterone Trials of 790 men aged 65 and older with low levels, treatment improved sexual activity, desire and erectile function; in the TRAVERSE trial of 5,246 men at high cardiovascular risk it did not increase major cardiovascular events, but atrial fibrillation, acute kidney injury and pulmonary embolism were more common. Technical: Snyder 2016, N Engl J Med (TTrials): testosterone gel vs placebo for 1 year in men with testosterone below 275 ng/dL. Lincoff 2023, N Engl J Med (TRAVERSE): men aged 45 to 80; noninferior for major adverse cardiac events. Read: Hormones and Longevity → Related: Male hypogonadism, Testosterone, TRAVERSE trial Sources: PubMed (DOI) · PubMed (DOI)

The age-related shrinking of the thymus, the organ where T cells mature. Technical: Age-related regression of the thymus reduces the output of naive T cells, which is thought to contribute to lower T-cell diversity in older people and is linked with greater susceptibility to infection, autoimmune disease and cancer. Related: Naive T cells, Immunosenescence Source: PubMed (DOI)

The thyroid gland produces T4 (thyroxine), which is converted in the body to the more active T3 (triiodothyronine); TSH from the pituitary stimulates production. Subclinical hypothyroidism, a raised TSH with normal free T4, affects up to 10% of adults. Technical: Subclinical hypothyroidism is defined by an elevated TSH with normal free thyroxine and is most often caused by autoimmune (Hashimoto) thyroiditis. In pooled data from 11 cohorts, it was associated with coronary heart disease events and deaths mainly at TSH 10 mIU/L or above. Read: Thyroid Function → Ranges and units: Biomarker Reference → Related: Subclinical Hypothyroidism, Hashimoto's Thyroiditis, TPO antibodies (thyroid peroxidase antibodies) Sources: PubMed (DOI) · PubMed (DOI)

The share of the day that glucose stays within a target range, measured with continuous glucose monitoring. Technical: Reference values for people without diabetes come from a multicenter study of healthy, non-obese participants: median time between 70 and 140 mg/dL was 96% (interquartile range 93 to 98%), with about 30 minutes a day above 140 mg/dL and 15 minutes below 70 mg/dL. Related: CGM (Continuous Glucose Monitor), Glycemic Variability Source: PubMed (DOI)

Confining daily food intake to a set window, typically 8 to 12 hours. In a year-long trial, it added no weight-loss benefit beyond calorie restriction; a small controlled-feeding study found that eating early in the day improved insulin sensitivity even without weight loss. Technical: Liu 2022, N Engl J Med: 139 adults with obesity, all on calorie restriction for 12 months, with or without an 8-hour eating window; weight change did not differ significantly. Sutton 2018, Cell Metab: early time-restricted feeding (6-hour window) versus a 12-hour schedule for 5 weeks with weight held stable improved insulin sensitivity and blood pressure in men with prediabetes. Read: Time-Restricted Eating → Related: Intermittent Fasting, Caloric Restriction Sources: PubMed (DOI) · PubMed (DOI)

A timed test in which you rise from an armchair, walk 3 metres, turn, walk back and sit down. It is quick, needs no special equipment or training, and can track changes in mobility over time. Technical: Timed version of the Get-Up and Go test; reliable, and correlated with the Berg Balance Scale, gait speed and the Barthel Index in a geriatric day hospital study. Related: Gait speed, SPPB (Short Physical Performance Battery) Source: PubMed (DOI)

The idea that the effects of menopausal hormone therapy depend on when it starts. In a WHI analysis, women within 10 years of menopause had no excess heart disease risk from hormone therapy (hazard ratio 0.76), but in the ELITE trial, starting estradiol within 6 years of menopause did not affect memory or thinking differently from starting it 10 or more years later. Technical: Rossouw 2007, JAMA: absolute excess CHD risk of -6 per 10,000 person-years within 10 years of menopause. Henderson 2016, Neurology (ELITE, 567 women): no differential cognitive effect by timing. Related: Women's Health Initiative (WHI), HRT (Hormone Replacement Therapy) Sources: PubMed (DOI) · PubMed (DOI)

A dual GLP-1 and GIP receptor agonist sold as Mounjaro (diabetes) and Zepbound (weight management). In SURMOUNT-1 it produced up to 20.9% weight loss at 72 weeks; it outperformed semaglutide 1 mg in SURPASS-2, and in SURPASS-CVOT it was noninferior to dulaglutide for major cardiovascular events in people with type 2 diabetes and heart disease. Technical: SURMOUNT-1 (Jastreboff 2022, N Engl J Med; 2,539 adults with obesity): mean weight change up to -20.9% at 72 weeks vs placebo. SURPASS-2 (Frias 2021; 1,879 patients, 40 weeks): greater HbA1c reduction than semaglutide 1 mg. SURPASS-CVOT: noninferior to dulaglutide for cardiovascular death, heart attack or stroke in type 2 diabetes with atherosclerotic disease. Read: GLP-1 Agonists → Related: Semaglutide, GIP (Glucose-Dependent Insulinotropic Polypeptide), GLP-1 (Glucagon-Like Peptide-1) Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

An inflammatory protein first found as a blood factor that destroyed tumours in mice. Technical: TNF was described in 1975 as a factor in the serum of endotoxin-treated mice that caused haemorrhagic necrosis of tumours; it is released from host cells, probably macrophages, rather than being endotoxin itself. Related: Cytokines, Inflammaging Source: PubMed (DOI)

All the cholesterol in the blood, carried in every type of lipoprotein. Lower levels are linked to lower heart disease mortality, especially in middle age. Technical: In individual data on almost 900,000 adults from 61 prospective studies, 1 mmol/L lower total cholesterol was associated with about half, a third and a sixth lower ischemic heart disease mortality at ages 40 to 49, 50 to 69 and 70 to 89. The total/HDL cholesterol ratio was the strongest simple predictor, 40% more informative than non-HDL cholesterol. Read: Lab Unit Converter → Related: LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), Non-HDL cholesterol, ApoB/ApoA1 ratio Source: PubMed (DOI)

Antibodies against thyroid peroxidase, a main laboratory sign of Hashimoto's thyroiditis. Technical: In subclinical hypothyroidism, circulating thyroid peroxidase antibodies indicate a greater risk of progression to overt hypothyroidism; together with thyroglobulin antibodies and ultrasound, they underpin the diagnosis of Hashimoto thyroiditis. Related: Hashimoto's Thyroiditis, Subclinical Hypothyroidism, Thyroid (TSH, T4, T3) Sources: PubMed (DOI) · PubMed (DOI)

How many days a week each muscle group is trained. When total weekly volume is the same, a meta-analysis found no significant effect of training frequency on strength gains, so frequency can be chosen to fit your schedule. Technical: Ralston 2018, Sports Med: low (1 day/week), medium (2 days/week) and high (3+ days/week) frequencies compared; volume-equated studies showed no significant frequency effect on strength; higher frequency may help mainly by making more weekly volume practical. Read: Strength Training for Longevity → Related: Muscle-strengthening activity, Physical activity guidelines (US) Source: PubMed (DOI)

How training time is split between easy, moderate and hard intensities. Competitive endurance athletes typically perform about 80% of their training sessions at low intensity and most of the rest at high intensity, a pattern often called polarized training. Technical: Seiler 2010, Int J Sports Physiol Perform: descriptive studies of elite endurance athletes training 10 to 13 times a week converge on roughly 80% low-intensity work; how well this applies to recreational exercisers is less clear. Read: Zone 2 Training → Related: Zone 2 Training, HIIT (High-Intensity Interval Training), Lactate Threshold Source: PubMed (DOI)

Estrogen delivered through the skin by patch or gel rather than by mouth. In a French case-control study, oral estrogen raised the risk of blood clots in the veins while transdermal estrogen did not (odds ratios 4.2 and 0.9 vs non-users). Technical: Canonico 2007, Circulation (ESTHER): no significant association of VTE with micronized progesterone or pregnane derivatives; observational data. Read: HRT for Women → Related: HRT (Hormone Replacement Therapy) Source: PubMed (DOI)

The share of the iron-carrying protein transferrin that is loaded with iron; raised levels, together with high ferritin, point to iron overload. Technical: In the Melbourne Collaborative Cohort Study of 31,192 people of northern European descent, most HFE C282Y homozygotes had raised ferritin and transferrin saturation, and documented iron-overload-related disease developed in 28.4% of male but 1.2% of female homozygotes. Related: Ferritin, Anemia Source: PubMed (DOI)

A large randomized trial of testosterone therapy in 5,246 men aged 45 to 80 with low testosterone and existing or high risk of cardiovascular disease. Testosterone did not increase major cardiovascular events compared with placebo, but atrial fibrillation, acute kidney injury and pulmonary embolism were more frequent. Technical: Lincoff 2023, N Engl J Med: double-blind, placebo-controlled noninferiority trial in symptomatic men with low testosterone. Read: Hormones and Longevity → Related: Testosterone therapy, Male hypogonadism Source: PubMed (DOI)

Fats carried in the blood. A high triglyceride level, or a high ratio of triglycerides to HDL cholesterol, can flag insulin resistance. Technical: In overweight adults, plasma triglycerides, the triglyceride-to-HDL-cholesterol ratio and insulin concentration were the most useful simple markers of insulin resistance, with optimal cut-points of 130 mg/dL for triglycerides and 3.0 for the ratio in traditional units. Triglyceride-rich lipoproteins carry remnant cholesterol, which genetic studies link causally to ischemic heart disease. Read: Bloodwork Guide → Ranges and units: Biomarker Reference → Related: Remnant cholesterol, Insulin Resistance, Metabolic syndrome, TyG index (triglyceride-glucose index) Sources: PubMed (DOI) · PubMed (DOI)

A simple estimate of insulin resistance calculated from fasting triglycerides and fasting glucose. Technical: The index is the natural logarithm of fasting triglycerides (mg/dL) multiplied by fasting glucose (mg/dL), divided by 2. In a clamp study of 99 people it correlated with insulin-stimulated glucose metabolism (r = -0.681). Early validation studies reported cut-offs of 4.65 and 4.68, so check how a study computed the index before comparing cut-offs. Read: Insulin Resistance Calculator → Related: HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), Insulin Resistance, Triglycerides, Euglycemic clamp Sources: PubMed (DOI) · PubMed (DOI)

Blood sugar returning to below the diabetes range without diabetes medication, usually after substantial weight loss. In the DiRECT trial, a primary-care weight-management program put 46% of participants into remission at 1 year and 36% at 2 years. Technical: Lean 2019, Lancet Diabetes Endocrinol (DiRECT 24-month results): remission defined as HbA1c below 6.5% (48 mmol/mol) after withdrawal of antidiabetic drugs; remission was closely linked to the amount of weight lost. Read: Longevity Protocol with Type 2 Diabetes → Related: HbA1c (Glycated Hemoglobin), Insulin Resistance, Prediabetes Source: PubMed (DOI)

A urine test for albumin leakage, a sign of kidney damage. A ratio above 30 mg/g meets the KDIGO definition of chronic kidney disease even when eGFR is normal. Technical: In general-population cohorts, mortality rose with the ratio on a log-log scale without a threshold (hazard ratios 1.20 at 1.1 mg/mmol, 1.63 at 3.4 and 2.22 at 33.9, against 0.6), independently of eGFR; a ratio of 10 mg/g or more independently predicted death. Related: eGFR (Estimated Glomerular Filtration Rate), Chronic kidney disease (CKD) Sources: PubMed (DOI) · PubMed (DOI)

The reduced form of CoQ10. It is often marketed as better absorbed than ubiquinone (the oxidized form), but the body converts readily between the two, and evidence that it works better in practice is limited. Technical: The cited paper (2019) is a hypothesis piece proposing that ubiquinol might benefit people on statins; it does not show outcome benefits. Read: CoQ10 → Related: Bioavailability Source: PubMed (DOI)

The cell's tagging system for marking short-lived proteins for destruction. Technical: In the ubiquitin system, proteins are targeted for degradation by covalent attachment to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins controls processes including cell-cycle progression, signal transduction and transcriptional regulation. Related: Autophagy, Unfolded protein response (UPR) Source: PubMed (DOI)

Industrial food products typically made with five or more ingredients, including substances rarely used in home cooking such as emulsifiers, flavourings and sweeteners. Higher intake is associated with higher all-cause mortality in cohort studies. Technical: Defined by the NOVA classification, which groups foods by the extent and purpose of industrial processing (Monteiro 2019). Lane 2024 (BMJ umbrella review; 45 pooled analyses, 9.9 million participants): highly suggestive evidence linking greater intake to higher all-cause mortality (risk ratio 1.21) and convincing evidence for cardiovascular disease mortality; the data are observational. Read: Nutrition Blueprint → Related: Fiber (Dietary), Mediterranean Diet Sources: PubMed (DOI) · PubMed (DOI)

A review of existing systematic reviews and meta-analyses that grades how credible each finding is. For example, an umbrella review of 45 pooled analyses on ultra-processed food graded each association from convincing to weak or no evidence. Technical: Lane 2024, BMJ: evidence classified as convincing (class I), highly suggestive (II), suggestive (III), weak (IV) or no evidence (V) using pre-specified criteria. Related: Systematic review, Meta-analysis Source: PubMed (DOI)

A stress response cells switch on when unfolded proteins build up in the endoplasmic reticulum. Technical: Most secreted and surface proteins fold in the endoplasmic reticulum; a burden of unfolded proteins there (ER stress) activates signalling pathways, collectively the UPR, that adjust protein-folding capacity to need. Related: Proteostasis Source: PubMed (DOI)

Businesses that sell stem cell treatments directly to consumers for conditions such as joint pain or aging, mostly without regulatory approval or trial evidence. Researchers documented widespread marketing of such treatments by US businesses. Technical: Turner and Knoepfler 2016, Cell Stem Cell: analysis of internet marketing by US businesses offering direct-to-consumer stem cell interventions; legitimate stem cell therapies are offered through approved indications or clinical trials. Related: Hematopoietic stem cells (HSCs), Stem Cell Exhaustion Source: PubMed (DOI)

The end product of purine breakdown. Gout is treated by lowering it, but in two trials, lowering it with allopurinol did not slow the decline in kidney function. Technical: The 2020 American College of Rheumatology guideline recommends a treat-to-target approach to urate-lowering therapy in gout, with a serum urate target below 6 mg/dL. Higher urate is associated with diabetic kidney disease and with progression of chronic kidney disease, yet in randomized trials in type 1 diabetes (530 patients) and in stage 3 to 4 chronic kidney disease (369 patients), allopurinol did not slow kidney function decline. Read: Uric Acid → Ranges and units: Biomarker Reference → Related: eGFR (Estimated Glomerular Filtration Rate), Metabolic syndrome Sources: PubMed (DOI) · PubMed (DOI) · PubMed (DOI)

A compound made by gut bacteria from ellagitannins in pomegranates, berries and walnuts. In small human trials it was safe, improved markers of mitochondrial function and, in one trial, improved some measures of muscle endurance. Technical: Urolithin A is a metabolite made by gut microbes that stimulates mitophagy and improves muscle health in old animals. In a first-in-human trial in healthy, sedentary older adults it had a favourable safety profile, and 4 weeks at 500 or 1,000 mg modulated plasma acylcarnitines and muscle mitochondrial gene expression; a later trial tested it in adults aged 65 to 90. Read: Mitochondria → Related: Mitophagy, Mitochondria Sources: PubMed (DOI) · PubMed (DOI)

The longest cranial nerve, linking the brainstem with the heart, lungs and gut, and the main nerve of the parasympathetic system. Vagal signals can dampen inflammation (the inflammatory reflex), and vagal tone is often estimated from heart rate variability. Technical: Pavlov and Tracey 2012 describe the inflammatory reflex, in which vagus nerve signalling dampens inflammation, including obesity-related inflammation in animal studies. Read: HRV → Related: Gut-Brain Axis, HRV (Heart Rate Variability) Source: PubMed (DOI)

Hot flashes and night sweats, the most common symptoms of the menopause transition. Hormone therapy is the most effective treatment: a Cochrane review found it significantly reduced hot flash frequency versus placebo, and the North American Menopause Society judges the benefit-risk favorable for women under 60 or within 10 years of menopause. Technical: MacLennan 2004, Cochrane: oral oestrogen with or without progestogen vs placebo reduced weekly hot flush frequency and severity. NAMS 2022 position statement. Read: Perimenopause Longevity Guide → Related: HRT (Hormone Replacement Therapy), Menopause staging (STRAW+10) Sources: PubMed (DOI) · PubMed (DOI)

Diets that exclude meat (vegetarian) or all animal products (vegan). In the EPIC-Oxford cohort, vegans had more than twice the risk of hip fracture of meat eaters (about 15 more cases per 1,000 people over 10 years) and 43% higher risk of fractures overall, so attention to calcium, protein, vitamin D and B12 matters. Technical: Tong 2020, BMC Med (EPIC-Oxford): hip fracture hazard ratios vs meat eaters were 1.26 for fish eaters, 1.25 for vegetarians and 2.31 for vegans after adjustment including BMI; associations were slightly attenuated but remained significant after adjusting for dietary calcium and protein. Read: Longevity Guide for Vegans and Vegetarians → Related: Plant vs animal protein, Protein needs in older adults Source: PubMed (DOI)

Fat stored around the abdominal organs. It is suggested as an independent risk factor for heart and metabolic disease, and genetic studies support a causal role. Technical: In UK Biobank, predicted visceral fat mass was linked to hypertension, heart attack or angina, type 2 diabetes and high blood lipids, and Mendelian randomization showed it to be a causal risk factor for all four. Excess risk is not limited to people with obesity: in US national data, 23.5% of normal-weight adults had clustered cardiometabolic abnormalities, which went with larger waist circumference. Read: Visceral Fat → Related: Insulin Resistance, Brown Adipose Tissue (BAT) Sources: PubMed (DOI) · PubMed (DOI)

A vitamin needed by two enzymes, one of which converts homocysteine to methionine. Methylmalonic acid (MMA) is the most sensitive blood marker of B12 status. Technical: Serum methylmalonic acid is the most sensitive marker of vitamin B12 status and can help confirm deficiency (NIH Office of Dietary Supplements). Long-term metformin use is associated with low B12: in the Diabetes Prevention Program, low B12 was more common with metformin at 5 years (4.3% vs 2.3%). Ranges and units: Biomarker Reference → Related: Homocysteine, Folate (vitamin B9), Anemia Sources: NIH Office of Dietary Supplements: Vitamin B12 fact sheet (ods.od.nih.gov, checked 2026-10-01) · PubMed (DOI)

A fat-soluble vitamin; the blood level of 25-hydroxyvitamin D measures your status. In large trials of generally healthy adults, such as VITAL, supplements did not reduce cancer or cardiovascular events. The Endocrine Society's 2024 guideline suggests against routine testing without an established reason and found no clear evidence for any target level. Technical: In VITAL, 2,000 IU of vitamin D3 a day for a median of 5.3 years did not lower invasive cancer (hazard ratio 0.96) or major cardiovascular events (0.97). The 2024 Endocrine Society guideline suggests empiric supplementation for people aged 1 to 18 (including to prevent rickets), adults over 75, pregnancy and high-risk prediabetes, and suggests against routine 25(OH)D testing. Read: Vitamin D → Ranges and units: Biomarker Reference → Related: Magnesium, Omega-3 Index Sources: PubMed (DOI) · PubMed (DOI)

Vitamin D3 (cholecalciferol) taken as a supplement; the blood test is covered under 25-hydroxyvitamin D. In 25,871 generally healthy adults, vitamin D did not lower cancer or cardiovascular events (VITAL). Our Supplement Evidence Database rates it “Not supported in trials” for preventing cancer and heart disease (generally healthy adults). Technical: Manson 2019, N Engl J Med: In 25,871 generally healthy adults, vitamin D did not lower cancer or cardiovascular events (VITAL). Scragg 2018, JAMA Oncol: In 5,110 adults, monthly high-dose vitamin D for up to four years did not prevent cancer (ViDA, post hoc analysis). Read: Vitamin D3 in the Supplement Evidence Database → Related: Vitamin D (25-OH) Sources: PubMed (DOI) · PubMed (DOI)

Maximum oxygen uptake during exercise, measured in mL/kg/min. It is among the strongest predictors of mortality: in a study of more than 122,000 patients, those with the lowest fitness had about five times the risk of death of the fittest. Technical: Mandsager 2018 (122,007 patients): extremely high aerobic fitness was associated with the greatest survival, with benefit also in older patients and those with hypertension. Read: VO2 Max → Ranges and units: Biomarker Reference → Related: Cardiorespiratory fitness, 4x4 interval training Source: PubMed (DOI)

The distance around the waist, a simple measure of abdominal fat that adds risk information beyond BMI. Technical: A 2020 consensus statement from the IAS and ICCR working group on visceral obesity concluded that waist circumference provides independent and additive information to BMI for predicting illness and death, recommended reducing it as a treatment target, and noted that moderate exercise or diet can achieve clinically relevant reductions; threshold values still need refining by BMI, age, sex and ethnicity. Related: Waist-to-height ratio (WHtR), Visceral Fat, Metabolic syndrome Source: PubMed (DOI)

Waist circumference divided by height. In a meta-analysis of more than 300,000 adults, it detected cardiometabolic risk better than waist circumference or BMI. Technical: Compared with BMI, waist circumference improved discrimination of adverse cardiometabolic outcomes by 3% and waist-to-height ratio by 4 to 5%, across several ethnic groups and both sexes; the authors proposed it as a screening tool. Related: Waist circumference, Visceral Fat, Metabolic syndrome Source: PubMed (DOI)

An inherited disorder whose symptoms resemble premature aging. Technical: Caused by mutations in a gene whose 1,432-amino-acid protein resembles DNA helicases, implicating defective DNA metabolism. Related: Hutchinson-Gilford progeria syndrome, Genomic Instability Source: PubMed (DOI)

Bright areas on brain MRI scans linked to a higher risk of stroke, dementia and death. Technical: In a systematic review of 46 longitudinal studies, with a meta-analysis of 22, white matter hyperintensities were associated with higher risk of stroke (hazard ratio 3.3), dementia (1.9) and death (2.0). Related: Blood-brain barrier Source: PubMed (DOI)

A set of large US trials of menopausal hormone therapy. Its estrogen-plus-progestin trial was stopped early in 2002 because breast cancer cases exceeded a safety boundary; over 18 years of follow-up of 27,347 women, hormone therapy was not associated with higher all-cause mortality. Participants averaged 63 at enrollment, older than most women starting therapy for symptoms. Technical: Rossouw 2002 and Manson 2017, JAMA: the 2002 report stopped the estrogen plus progestin arm; the 2017 analysis covered 7,489 deaths over cumulative 18-year follow-up of both trials. Read: HRT for Women → Related: HRT (Hormone Replacement Therapy), Timing hypothesis (hormone therapy) Sources: PubMed (DOI) · PubMed (DOI)

Four transcription factors (Oct4, Sox2, Klf4 and c-Myc) that can reprogram specialized cells back into stem cells. Brief, partial reprogramming has reversed signs of aging in mice; it has not been tested for aging in people. Technical: Introducing Oct3/4, Sox2, c-Myc and Klf4 reprogrammed mouse fibroblasts into induced pluripotent stem (iPS) cells, which formed tumors when transplanted into mice. Short-term cyclic expression of the same factors improved hallmarks of aging and extended lifespan in a mouse model of premature aging. Read: Yamanaka Factors → Related: Partial reprogramming, Epigenetic alterations Sources: PubMed (DOI) · PubMed (DOI)

An essential mineral needed for immune function and the work of many enzymes. In a small trial in older adults, zinc lowered the rate of infections. Our Supplement Evidence Database rates it “Early or small trials” for infections in older adults. Technical: Prasad 2007, Am J Clin Nutr: In a small trial in older adults, zinc lowered the rate of infections. Read: Zinc in the Supplement Evidence Database → Related: Magnesium Source: PubMed (DOI)

Steady aerobic exercise just below the first lactate threshold, an intensity at which you can still talk and fat burning is near its peak. US guidelines recommend 150 to 300 minutes of moderate activity a week; Zone 2 is one way to meet them. Technical: San-Millán 2018: fat oxidation and lactate were inversely correlated across fitness levels, the physiological basis for training just below the first lactate threshold; US guidelines count this as moderate activity toward 150 to 300 minutes a week. Read: Zone 2 Training → Related: Lactate Threshold, Physical activity guidelines (US) Sources: PubMed (DOI) · PubMed (DOI)

A form of oestrogen tested for effects on ageing in mice: it extended median lifespan by 12% in males, with stronger effects at one test site than the others, and did not change lifespan in females. Technical: Same three-site lifespan study as acarbose; no significant effect on maximum lifespan in males. Read: Rapamycin → Related: Acarbose, Rapamycin Source: PubMed (DOI)

The number of times you can rise from a chair and sit back down in 30 seconds, used to measure lower-body strength in adults over 60. Technical: Validated against maximum leg-press performance (r = .78 men, .71 women); test-retest intraclass correlations .84 (men) and .92 (women). Related: SPPB (Short Physical Performance Battery), Grip Strength, Sarcopenia Source: PubMed (DOI)

A high-intensity interval format of four 4-minute hard efforts at about 85 to 95% of maximum heart rate with 3-minute easy recoveries. In the Generation 100 trial of 1,567 older adults, five years of supervised training including 4x4 intervals did not reduce mortality compared with recommended activity levels, although mortality trended lower in the interval group. Technical: Stensvold 2020, BMJ (Generation 100): mean age 72; combined MICT and HIIT had no effect on all-cause mortality versus control; exploratory comparison showed a lower mortality trend after HIIT. Read: HIIT vs Steady-State Cardio → Related: HIIT (High-Intensity Interval Training), VO2 Max Source: PubMed (DOI)