Protocol
Caloric restriction (sustained ~25%)
The first and only long-term randomized controlled trial People are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. of caloric restriction in healthy, non-obese adults.
Grade C: human trials exist, but they are small, mixed or not yet repeated. This is not a finding that it does not work. How to read a grade →
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How this letter has changedLatest: October 2026 · Corrected.
The record called Waziry 2023 (PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 37118425) a pre-specified analysis; the paper says post hoc, and it also reports that PhenoAge, GrimAge and other clocks did not change, now stated. Telomere length, Hastings 2024 (PMID 38504468), no net change, added. The trial randomized 218, not 220, and achieved about 12 percent restriction against the 25 percent target, now stated. The safety signal was missing: bone density fell at spine and hip (Romashkan 2016, PMID 26992237; Villareal 2016, PMID 26332798). Cardiometabolic improvement is now sourced to Kraus 2019 (PMID 31303390), and Racette 2017 (PMID 29045325) shows absolute fitness and strength fell. The DunedinPACE An epigenetic test that estimates how fast a person is aging now, in years of biological aging per calendar year. inventors' commercial license is disclosed. Letter unchanged.PMID 37118425 PMID 38504468 PMID 26992237 PMID 26332798 PMID 31303390 PMID 29045325
Sardeli et al. (Nutrients, 2018; PMID 29596307) pooled six randomized trials in older adults with obesity who were restricting calories. Adding resistance training three times a week prevented 93.5 percent of the lean mass lost with restriction alone, while fat and total weight loss did not differ significantly. The record now cites it beside CALERIE-2. It addresses the muscle cost of restriction rather than the aging endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score., so the C stays.PMID 29596307
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Caloric restriction means eating fewer calories over the long term. In the only long study in healthy adults who were not obese, people aimed to eat 25 percent less and managed about 12 percent less for two years. The main body measures they set out to change did not change for good. A later look found a slower estimated pace of aging, but that was not the main goal.
The first and only long-term randomized controlled trial of caloric restriction in healthy, non-obese adults. CALERIE-2 randomized 218 adults to a 25 percent restriction target or ad libitum eating for two years; the restriction group achieved about 12 percent. It did not durably move its primary metabolic endpoints. A post hoc analysis found a slowed pace of aging on the DunedinPACE clock (about 2 to 3 percent) while PhenoAge, GrimAge and other methylation clocks did not change, telomere length showed no net change at 24 months, and conventional cardiometabolic risk factors improved. Bone density fell at the spine and hip. A real human trial, but the aging readout is one surrogate clock among several that did not move, the effect is small, and no clinical longevity outcome has been reported. Grade C.
Why this gradeGrade C, small or unreplicated trials. The reasoning, and what the grade does not cover.
Grade C. CALERIE-2 is the only long-term randomized trial of caloric restriction in healthy non-obese adults: 218 adults aged 21 to 51, a 25 percent target, about 12 percent achieved over two years; its primary metabolic endpoints did not change durably (Ravussin et al., 2015; PMID 26187233). A post hoc analysis found a slower pace of aging on DunedinPACE, while PhenoAge, GrimAge and other clocks did not change (Waziry et al., 2023; PMID 37118425). Cardiometabolic risk factors improved (PMID 31303390), and bone density fell at the spine and hip (PMID 26332798).
WHAT THIS GRADE DOES NOT COVERlifespan or longevity in humans, people with obesity, people over 51, and restriction beyond two years, none of which CALERIE-2 studied.
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The evidence, in fullNine papers, each linked to its PubMed record.
Ravussin et al. (J Gerontol A Biol Sci Med Sci, 2015; PMID 26187233): the CALERIE-2 primary report, 218 non-obese adults aged 21 to 51 randomized 2:1 to 25 percent caloric restriction or ad libitum for 2 years; the restriction group achieved 11.7 percent and kept 10.4 percent weight loss; the primary endpoints The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight., resting metabolic rate The energy the body burns at rest, measured under looser conditions than the basal rate, such as a shorter fast. It usually runs slightly higher than the basal metabolic rate. adjusted for weight and core temperature, did not differ durably. Waziry et al. (Nature Aging, 2023; PMID 37118425): a post hoc analysis of the same trial; restriction slowed the DunedinPACE pace-of-aging measure with small effect sizes How large a difference the treatment made, as distinct from whether the difference could be detected at all., and biological-age estimates from PhenoAge, GrimAge and other clocks did not change; two authors are inventors of DunedinPACE, licensed to a commercial testing company. Hastings et al. (Aging Cell, 2024; PMID 38504468): telomere length, no net change over 24 months. Kraus et al. (Lancet Diabetes Endocrinol, 2019; PMID 31303390): exploratory cardiometabolic outcomes; LDL Low-density lipoprotein cholesterol, the cholesterol fraction most closely tied to plaque in the arteries. cholesterol, blood pressure, C-reactive protein and insulin sensitivity improved at 2 years. Il'yasova et al. (Aging Cell, 2018; PMID 29424490): urinary F2-isoprostanes, an oxidative-stress surrogate from the same trial, not independent support. Safety: Romashkan et al. (Oncotarget, 2016; PMID 26992237), the safety report, three participants withdrawn for safety, bone mineral density lower at lumbar spine, total hip and femoral neck at 12 and 24 months, monitoring for bone loss and anemia advised; Villareal et al. (J Bone Miner Res, 2016; PMID 26332798), the bone outcomes paper, with the density falls and higher bone-turnover markers. Racette et al. (Med Sci Sports Exerc, 2017; PMID 29045325): absolute VO2max The most oxygen the body can use during all-out exercise, a standard measure of aerobic fitness. and knee strength fell with restriction while values relative to body mass rose. Sardeli et al. (Nutrients, 2018; PMID 29596307): meta-analysis A study that pools the numbers from several trials into one combined estimate. of six randomized trials in older adults with obesity in which adding resistance training prevented most of the lean mass lost with calorie restriction; bears on the lean-mass cost, not on the aging endpoint. Grade C on a genuine long-term human trial reporting a small slowing of one surrogate aging clock, not a clinical outcome.
Total energy intake using validated dietary assessment weekly. Weight, lean mass (DEXA), and metabolic biomarkers A measurable sign in the body, such as a blood test value, used to track a condition or the effect of a treatment. (fasting glucose, insulin, lipids, hsCRP High-sensitivity C-reactive protein, a blood marker of low-grade inflammation., IGF-1) at baseline and 3 months. The CALERIE-2 trial used 25% CR sustained over 2 years. Lean mass loss, alongside protein intake.
Evidence notes: randomized trial, not independently replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away.
Endpoint graded: Metabolic markers and pace of aging in healthy non-obese adults (surrogate)
Last reviewed: July 2026
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