Inflammaging: How Chronic Low-Grade Inflammation Is Linked to Age-Related Disease
Short bursts of inflammation fight infection and heal injuries. Chronic, low-grade inflammation is different: it rises with age, and most age-related diseases share an inflammatory component, although whether it causes them is still largely unknown.1
- Inflammaging is the chronic, low-grade inflammation that develops with age, marked by higher levels of inflammatory signals such as IL-6 and CRP without an infection.1
- Proposed sources include senescent cells, whose secretions are pro-inflammatory,2 visceral fat, damaged mitochondria and a leaky gut barrier, although several of these links rest mainly on animal and cell studies.3,4
- Lifestyle factors such as physical inactivity, poor diet, psychological stress and environmental toxicants can promote chronic inflammation, which is linked to heart disease, cancer, diabetes and other leading causes of death.5
- The most practical blood marker is high-sensitivity CRP, measured in milligrams per liter; the CANTOS trial used a level of 2 mg/L or more to identify heart-attack survivors with raised inflammation.8 No blood target for inflammaging itself has been validated.
- Exercise has well-described anti-inflammatory effects,6 and in a small 17-week trial a diet high in fermented foods increased gut microbiome diversity and lowered inflammatory markers.7 The strongest proof that lowering inflammation itself can prevent disease comes from a drug trial, CANTOS.8
The term “inflammaging” was coined by the Italian immunologist Claudio Franceschi in 2000 to describe the rise in inflammatory signals seen with age, even in people without acute illness. Chronic, low-grade inflammation is now considered a significant risk factor for illness and death in older people, and most if not all age-related diseases share an inflammatory component. But a 2014 review by Franceschi and Judith Campisi stressed that its precise causes, and whether it actually drives poor health outcomes, remain largely unknown.1
The Sources of Inflammaging: Where the Fire Comes From
Senescent cells are one proposed source. These are cells that have stopped dividing, and many acquire a senescence-associated secretory phenotype (SASP) that turns them into pro-inflammatory cells.2 In a pilot in 9 people with diabetic kidney disease, a short course of senolytic drugs, which clear such cells, lowered some circulating SASP factors, including IL-6.9 Our article on cellular senescence covers what has and has not been tested.
The gut is another proposed source. In a mouse study, a 4-week high-fat diet raised blood levels of bacterial lipopolysaccharide (LPS) two to three times, a state the researchers called metabolic endotoxemia, and infusing LPS into mice for 4 weeks reproduced features of obesity and insulin resistance.3 Whether a leaky gut drives inflammaging in people is less clear.
Damaged mitochondria may also contribute. In immune cells called macrophages, loss of the cell’s recycling machinery let dysfunctional mitochondria build up and release their DNA into the cell, which helped drive the release of the inflammatory signals IL-1β and IL-18.4
The Vicious Cycles of Inflammaging
These sources may feed each other. In laboratory studies, inflammatory signals can push neighbouring cells into senescence, inflammation and impaired autophagy can reinforce one another, and oxidative stress damages DNA. A Nature Medicine review describes how mechanisms like these, together with risk factors such as infections, physical inactivity, poor diet, environmental toxicants and psychological stress, can sustain systemic chronic inflammation.5
The Most Effective Anti-Inflammaging Interventions
Exercise has well-described anti-inflammatory effects. During exercise, working muscle releases IL-6, which in this setting raises anti-inflammatory signals such as IL-1ra and IL-10 and inhibits the inflammatory signal TNF-alpha; regular exercise may protect against TNF-alpha-driven insulin resistance.6 It also reduces visceral fat, one of the proposed sources of inflammaging.
Diet may help too. 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, although the study’s primary immune score did not change.7 The strongest evidence that lowering inflammation itself can prevent disease comes from CANTOS: in 10,061 heart-attack survivors with raised CRP, the anti-inflammatory antibody canakinumab cut recurrent cardiovascular events (hazard ratio 0.85 at the 150 mg dose) without lowering cholesterol, but it raised the risk of fatal infection and did not change overall mortality.8 Supplements have not been tested this rigorously; see our Supplement Evidence Database.
Put this research into practice: Biomarker Reference Tool
References
- 1Franceschi C, Campisi J. "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases." J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-9. PubMed · DOI
- 2Coppé JP, et al. "The senescence-associated secretory phenotype: the dark side of tumor suppression." Annu Rev Pathol. 2010;5:99-118. PubMed · DOI
- 3Cani PD, et al. "Metabolic endotoxemia initiates obesity and insulin resistance." Diabetes. 2007;56(7):1761-72. PubMed · DOI
- 4Nakahira K, et al. "Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome." Nat Immunol. 2011;12(3):222-30. PubMed · DOI
- 5Furman D, et al. "Chronic inflammation in the etiology of disease across the life span." Nat Med. 2019;25(12):1822-1832. PubMed · DOI
- 6Petersen AM, Pedersen BK. "The anti-inflammatory effect of exercise." J Appl Physiol (1985). 2005;98(4):1154-62. PubMed · DOI
- 7Wastyk HC, et al. "Gut-microbiota-targeted diets modulate human immune status." Cell. 2021;184(16):4137-4153.e14. PubMed · DOI
- 8Ridker PM, et al. "Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease." N Engl J Med. 2017;377(12):1119-1131. PubMed · DOI
- 9Hickson LJ, et al. "Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease." EBioMedicine. 2019;47:446-456. PubMed · DOI
