Caloric Restriction and Longevity: What 90 Years of Research Tells Us About Eating Less
Caloric restriction, eating less without malnutrition, can ameliorate aging and age-related disease in invertebrates, rodents, primates and humans, though people find it hard to keep up.2 This article covers what the animal and human trials show, and the practical cautions, especially about protein.
- Eating less extends life in yeast and rodents.5 In rhesus monkeys, results differ: a Wisconsin study found improved survival,3 while a National Institute on Aging study did not.11
- In the two-year CALERIE trial in non-obese adults, people prescribed 25% fewer calories achieved about 12%, improved several cardiometabolic risk factors,9 and showed a slower pace of aging on DunedinPACE, though not on other epigenetic clocks.10
- In model organisms, reducing the activity of nutrient-sensing pathways with mutations or drugs has effects similar to eating less.5
- Protein matters when eating less, especially later in life: the PROT-AGE group recommends at least 1.0 to 1.2 g/kg of body weight a day for people over 65.12
- Drugs studied as "CR mimetics", such as metformin, remain unproven for aging in people; metformin is to be tested in the TAME trial.13
The first documented experiment, published in 1935 by Clive McCay, found that rats whose growth was slowed by a restricted diet lived longer.1 Since then, eating less without malnutrition has been found to ameliorate aging in organisms from invertebrates to primates.2
The human question is whether meaningful restriction is practical and safe, because people find dietary restriction difficult to maintain voluntarily.2
The Animal Evidence
When yeast and rodents eat less, they live longer than animals fed a normal diet, and in rodents restriction lowers age-related loss of function and disease, including tumors and neurodegeneration.5
In rhesus monkeys at the Wisconsin National Primate Research Center, moderate restriction lowered aging-related deaths: at the time point reported, 80% of restricted monkeys survived against 50% of controls, with less diabetes, cancer, cardiovascular disease and brain atrophy.3 A study at the National Institute on Aging, which started restriction in young and older monkeys, did not improve survival.11
The CALERIE Trial
CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) randomized 218 healthy young and middle-aged adults to a prescribed 25% calorie restriction or their usual diet for 2 years. Two years of moderate restriction significantly reduced multiple cardiometabolic risk factors.9
Participants achieved a mean 11.9% reduction in calorie intake, not the 25% target.9 The trial slowed the pace of aging measured by DunedinPACE, a DNA methylation measure,4 but did not change the PhenoAge or GrimAge clocks.10
Proposed Mechanisms
In model organisms, the effects of eating less are linked to nutrient-sensing pathways: reducing their activity by mutations or chemical inhibitors also extends life.5
Growth hormone and IGF-1: In worms, flies, mice and rats, inactivating the IGF-1 gene or the growth hormone receptor prolonged life, particularly in females.6
The Protein Adequacy Problem
The main practical issue for older adults is protein: eating less food usually means eating less protein unless you plan for it. The PROT-AGE group recommends at least 1.0 to 1.2 g/kg a day for people over 65, and at least 1.2 for those who exercise.12
Whether eating more protein improves health outcomes in older people has not been tested directly in randomized trials; the case for it rests on indirect evidence.7
Caloric Restriction Mimetics: The Best of Both Worlds?
A calorie restriction mimetic is a compound proposed to mimic the metabolic, hormonal and physiological effects of restriction without eating less. The idea has had setbacks: an early candidate, 2-deoxyglucose, caused heart toxicity in rats.8 Candidates include:
- Rapamycin: a prescription drug that inhibits mTOR, approved in transplant medicine and unproven for aging (see our Supplement Evidence Database).
- Metformin: a diabetes drug that is to be tested against aging in the TAME trial.13
- Resveratrol: rated “Possible harm” in our Supplement Evidence Database: in older men doing exercise training, it blunted the cardiovascular benefits of exercise.
If you want to eat less, aim for a modest, sustainable deficit with your clinician's input, and if you are over 65 keep protein at or above the PROT-AGE levels.12 Even in CALERIE, participants managed about half of the restriction prescribed.9
References
- 1McCay CM, et al. "The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935." Nutrition. 1989;5(3):155-71; discussion 172. PubMed
- 2Fontana L, Partridge L. "Promoting health and longevity through diet: from model organisms to humans." Cell. 2015;161(1):106-118. PubMed · DOI
- 3Colman RJ, et al. "Caloric restriction delays disease onset and mortality in rhesus monkeys." Science. 2009;325(5937):201-4. PubMed · DOI
- 4Belsky DW, et al. "DunedinPACE, a DNA methylation biomarker of the pace of aging." Elife. 2022;11. PubMed · DOI
- 5Fontana L, et al. "Extending healthy life span--from yeast to humans." Science. 2010;328(5976):321-6. PubMed · DOI
- 6Laron Z. "The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency." Hormones (Athens). 2008;7(1):24-7. PubMed · DOI
- 7Wolfe RR. "The role of dietary protein in optimizing muscle mass, function and health outcomes in older individuals." Br J Nutr. 2012;108 Suppl 2:S88-93. PubMed · DOI
- 8Ingram DK, Roth GS. "Calorie restriction mimetics: can you have your cake and eat it, too?" Ageing Res Rev. 2015;20:46-62. PubMed · DOI
- 9Kraus WE, et al. "2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial." Lancet Diabetes Endocrinol. 2019;7(9):673-683. PubMed · DOI
- 10Waziry R, et al. "Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial." Nat Aging. 2023;3(3):248-257. PubMed · DOI
- 11Mattison JA, et al. "Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study." Nature. 2012;489(7415):318-21. PubMed · DOI
- 12Bauer J, et al. "Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group." J Am Med Dir Assoc. 2013;14(8):542-59. PubMed · DOI
- 13Barzilai N, et al. "Metformin as a Tool to Target Aging." Cell Metab. 2016;23(6):1060-1065. PubMed · DOI