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caloric-restriction

Properties1
aliasesCR, caloric restriction, dietary restriction, DR

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Caloric restriction (CR)

Sustained reduction in caloric intake (typically 20–40% below ad libitum in animal studies; 12–25% in human trials) without malnutrition — micronutrient adequacy is preserved. The single most-studied longevity intervention in aging biology, extending mean and maximum lifespan in essentially every model organism tested for nearly a century, from yeast to mice. Human trials (CALERIE) demonstrate robust effects on aging biomarkers but have not — and likely cannot in any reasonable timeframe — establish lifespan extension as a primary endpoint.

This page covers caloric restriction as an intervention concept. Closely-related variants (intermittent fasting, time-restricted eating, methionine restriction, fasting-mimicking diet) deserve separate pages — see interventions/lifestyle/ for sibling entries when seeded.

Definitional clarifications

The literature uses multiple overlapping terms with different meanings — using them interchangeably hides important distinctions:

TermMeaning
Caloric restriction (CR)Sustained reduction in calories consumed; typically 20–40% below ad libitum for animals, 12–25% in human trials
Dietary restriction (DR)Often synonymous with CR; sometimes used to imply restriction without specifying the caloric component
Intermittent fasting (IF)Periodic complete or near-complete fasting (e.g., alternate-day fasting, 5:2). Time-averaged caloric reduction smaller than continuous CR
Time-restricted eating (TRE)Restricted feeding window (e.g., 8 hr/day) without explicit caloric reduction. Closer to circadian-aligned eating than CR
Methionine restriction (MetR)Restriction of methionine specifically (typically <0.17% of diet); recapitulates many CR effects without total caloric reduction
Fasting-mimicking diet (FMD)Periodic low-calorie, low-protein diet (e.g., 5 days/month) designed to trigger fasting responses without sustained restriction
Prolonged fastingVoluntary complete caloric restriction sustained ≥48–72 hr (water-only). Distinct from continuous CR: a multi-day total fast whose systemic proteome response begins only after ~3 days 1

CR is not synonymous with under-eating, malnutrition, or anorexia. The defining feature is preservation of micronutrient intake while reducing energy intake.

Mechanisms of geroprotection

CR engages many of the pathways independently identified by longevity-pathway studies:

PathwayEffectCross-link
mTORC1Reduced amino acid input → mTORC1 ↓Phenocopies rapamycin partially
ampkAMPK ↑ from reduced ATP/AMP ratioPhenocopies metformin partially
IISReduced insulin + IGF-1 (~25–30% IGF-1 decline in long-term CR humans)Connects to dwarf-mouse longevity story
autophagyRobustly induced via mTOR ↓, AMPK ↑Required for CR longevity in worms/flies (epistasis evidence)
SirtuinsNAD+ levels rise; SIRT1/3 activity increasedMechanism partially debated; not all CR organisms require sirtuins
Mitochondrial biogenesisPGC-1α activationImproves bioenergetic efficiency per cell

Genetic epistasis establishes mTOR + autophagy as major downstream effectors, but the picture is organism-specific:

  • In yeast and worms, DR does not further extend lifespan when TOR is already reduced — suggesting convergence on a final common pathway. unsourced (primary citation needed)
  • In Drosophila, rapamycin extends lifespan beyond the DR maximum at all food concentrations tested (Bjedov 2010; see mtor § Connection to other aging pathways) — indicating partial mechanistic independence in flies; CR and TOR-inhibition engage overlapping but non-identical mechanisms.
  • Autophagy-deficient organisms (worm/fly ATG knockdowns) show abolished CR longevity benefit — see autophagy for primary citations.

This convergence (partial in flies, more complete in yeast/worms) is one of the major arguments that CR is mechanistically equivalent — at least in part — to pharmacological mTOR inhibition. The fly data show CR also engages TOR-independent components.

Cross-organism evidence

OrganismEffectNotes
S. cerevisiae~20–40% chronological + replicative lifespan extension unsourcedClassic CR system; Lin et al. 2000 demonstrated SIR2-dependence
C. elegans~30–50% lifespan extension unsourcedVarious protocols (eat-2 mutants, peptone restriction); requires DAF-16/FOXO + autophagy
D. melanogaster~20–40% lifespan extension unsourcedYeast restriction (yeast = primary protein source); rapid response to refeeding
Rodents (rats)20–50% mean and max lifespan extension unsourced (McCay 1935 closed-access; range from review literature)McCay 1935 was the foundational study 2 no-fulltext-access; the most replicated CR system
Rodents (mice)10–30% lifespan extension; varies by strain, sex, CR onset age unsourced (range from review literature)ITP-style heterogeneous studies show large background effects
Vertebrates (meta-analysis, 2025)DR significantly extends lifespan across vertebrates; rapamycin matches DR magnitude; metformin does not 3911 effect sizes from 167 papers across 8 species; high heterogeneity + significant publication bias noted; effect robust to DR methodology
Rhesus macaqueConflicting between sites; Mattison 2017 joint reanalysis found significant survival benefit in UW adult-onset cohort; NIA cohorts showed healthspan improvement but no statistically significant lifespan effect 4Wisconsin (Colman/UW): HR 1.865 (95% CI 1.119–3.108), p=0.017 for adult-onset combined sexes. NIA J/A and old-onset: no significant survival effect. Diet quality differences between sites (purified vs. natural-ingredient diet) identified as confound.
HumansNo lifespan data; CALERIE I + II demonstrate aging-biomarker improvements at ~12–15% achieved restriction5 6

Human evidence — CALERIE and observational

CALERIE I (Phase 1, multi-site, 6 months)

Established feasibility of sustained CR in healthy non-obese adults. Demonstrated metabolic adaptations consistent with rodent CR (reduced T3, reduced fasting insulin, reduced core temperature).

CALERIE II (Phase 2, multi-site, 2 years; ~218 subjects enrolled)

The largest controlled CR trial in healthy humans to date. Target was 25% restriction. The full CALERIE II multi-centre trial enrolled ~218 subjects (NCT00427193). Achieved restriction across the trial was approximately 11.9% on average (Ravussin et al. 2015); individual site and sub-study analyses show slightly different values (see below).

Redman 2018 (CALERIE II metabolic sub-study, Pennington site) 5: An ancillary study of 53 subjects (34 CR, 19 AL control) with intensive metabolic chamber measurements. In this highly adherent sub-cohort, ~15% CR was achieved over 2 years (14.8% ± 1.5%), resulting in 8.7 kg mean weight loss. Primary findings:

  • Sleeping energy expenditure reduced ~7% beyond that expected from weight loss alone (metabolic adaptation; p<0.01 at Y1 and Y2)
  • Urinary F2-isoprostane (oxidative damage marker) significantly reduced vs controls (p<0.01 at both Y1 and Y2), supporting the oxidative damage theory of aging
  • T3 and T4 thyroid hormones significantly reduced; leptin significantly reduced; insulin showed early reduction at Y1 only
  • Note: LDL, blood pressure, and bone/mood/cognition safety outcomes are reported in other CALERIE II papers (Martin 2016 JAMA Intern Med; Rickman 2011), not in Redman 2018. PLA2G7 reduction is reported in Spadaro 2022, not Redman 2018.

Spadaro 2022 (CALERIE II immune sub-study) 6: Secondary analysis focused on thymic function and adipose tissue transcriptomics in CALERIE II participants. Achieved CR in this analysis was ~14% for 2 years (stated explicitly in abstract). Key findings:

  • CR significantly increased thymic mass and sjTREC (signal-joint T cell receptor excision circle) levels in both CD4 and CD8 cells in the majority of participants — indicating improved thymopoiesis (n=22 female, n=5 male for CD4; n=20 female, n=5 male for CD8)
  • 233 genes up-regulated, 131 down-regulated in subcutaneous adipose tissue after CR, including suppression of PLA2G7 (encoding platelet activating factor acetyl hydrolase, a pro-inflammatory lipid enzyme)
  • Pla2g7 knockout in mice partially phenocopied CR’s protective effects on thymic lipoatrophy and age-related inflammation, implicating PLA2G7 suppression as a mechanistic contributor

A landmark finding: CR improved thymopoiesis in middle-aged adults — a striking immunosenescence-relevant result suggesting CR can partially counter one of the most consistent age-related immune deficits. The paper does not claim full “restoration” of youthful thymic function.

CALERIE-2 follow-up analyses (2024–2026)

A wave of CALERIE-2 ancillary analyses have appeared since 2023, expanding the molecular and biological-age portrait of human CR. All draw from the same ~218-subject parent cohort (NCT00427193; ~12% achieved CR over 2 yr).

  • Senescence biomarkers — CR significantly reduced circulating SASP markers (machine-learning-selected senescence biomarkers predicted HOMA-IR, insulin sensitivity index, and resting metabolic rate residual changes) at 12 and 24 months vs. AL controls; adipose-tissue RNA-seq showed reduced expression of a senescence-focused gene set 7. Aligns with the Spadaro 2022 PLA2G7/thymic-lipoatrophy mechanism.
  • Complement / inflammaging — CR lowered the C3a/C3 ratio and dampened all three canonical complement pathways; circulating C3a is elevated with age in humans and mice; intra-adipose C3a-neutralizing antibody reduced inflammaging in mice 8. Identifies complement deactivation as an immunometabolic checkpoint linking CR to reduced chronic-inflammation.
  • Telomere length — Intent-to-treat analysis found no significant effect of CR on telomere length attrition over 24 months by either qPCR or DNAmTL 9. Effect-of-treatment-on-the-treated analyses showed transient, opposing-direction trends in the weight-loss vs. weight-maintenance phases — interpretation unclear.
  • Organ-specific biological age — A 5-organ BioAge analysis in n=185 CALERIE-2 participants showed CR mitigated age-related increases in metabolic (−0.63 yr at 24 mo, p=3×10⁻⁷), cardiovascular (−1.00 yr, p=2×10⁻⁶), whole-body (−1.27 yr, p=1×10⁻⁴), and immune (−0.62 yr, p=3×10⁻³) BioAge; liver age modestly slowed only at 24 mo; kidney age unaffected 10. Dose-response: ≥12.4% CR drove the metabolic + whole-body effects.
  • Glycomic age (GlycAge) — In a CALERIE-2 pilot subset (n=26, no concurrent control), 25% CR over 2 yr increased IgG galactosylation (p=0.016) and decreased IgG-based GlycAge (p=0.027) from 12 to 24 months; complement C3 protein and C3 N-glycoforms also fell 11. Pilot-only — single-arm, no AL control in this analysis.
  • Weight regain reverses benefits — Post-hoc analysis of n=190 CALERIE-2 participants stratified by post-month-12 weight trajectory: ~10% (n=20) regained >5% baseline weight, and this group lost CR-induced gains in insulin AUC, IGF-1/IGFBP-1 ratio, and biological age estimates. Sustained moderate weight loss preserved benefits 12. Reinforces that CR’s biological-age signature in humans is adherence-coupled and reversible.
  • Small-RNA mediators — 16 smRNAs associated with %CR and 41 with CR-vs-AL across plasma, muscle, and adipose; 17 miRNAs altered by CR in both humans and rhesus monkeys, implicating insulin-signaling, circadian-rhythm, and cell-cycle pathways as conserved CR effectors 13.

These results, in aggregate, strengthen the human-evidence claim that CR moves multiple molecular and biological-age signatures in a direction that animal data predict. None of them, however, address all-cause mortality.

Contrast with prolonged complete fasting — inflammation runs the opposite way. Sustained moderate CR is anti-inflammatory: it lowers the C3a/C3 ratio and dampens complement 8, reduces circulating SASP markers 7, and slows immune BioAge 10. Prolonged complete fasting does the reverse acutely — a ~10-day water-only fast raised hsCRP by 129% (and ≥66% of a 1,422-person validation cohort showed a significant CRP rise regardless of fast duration), activated the complement and coagulation cascades, activated platelets (urinary 11-dehydro-TXB2 ↑), and raised liver transaminases — though these normalized on refeeding 14. The two interventions therefore diverge sharply on inflammation despite sharing the mTOR/AMPK/autophagy/IIS mechanism base: chronic mild energy restriction quiets inflammaging, whereas acute total energy deprivation triggers an acute-phase response. This is a central reason prolonged fasting is not simply “more CR” — see prolonged-fasting for the full benefit-vs-harm picture.

Okinawan / observational evidence

The “Okinawan paradox” — historical Okinawan caloric intake was ~20% below mainland Japanese, with elevated centenarian density. Observational, confounded by other lifestyle factors; modernization has eliminated the longevity advantage in younger Okinawan generations.

CRON Society / human “CR enthusiasts”

Long-term self-imposed CR practitioners studied by Fontana / Holloszy show metabolic profiles resembling CR rodents (low IGF-1, low blood pressure, low inflammation). Self-selected; small n; not RCT evidence.

Side effects and limitations

  • Reduced bone density at sustained heavy restriction; mitigated by adequate calcium + vitamin D + resistance training
  • Reduced muscle mass — partly inevitable with caloric deficit; preserved by adequate protein intake + resistance training. The lean-mass-preservation evidence converges on ≥1.6 g/kg/day during energy deficit (Longland 2016 deficit RCT: 2.4 g/kg arm gained +1.2 kg lean mass while losing 4.8 kg fat over 40% deficit + 4 wk RT) — see protein-intake for the full dose-evidence base. Note the IGF-1 tradeoff: higher protein elevates serum IGF-1 (Fontana 2008: 1.67→0.95 g/kg dropped IGF-1 22%), partially offsetting one of CR’s geroprotective signaling effects — but lean-mass loss in older adults is the more proximal and irreversible risk.
  • Cold intolerance — reduced T3, lower core temperature
  • Reduced fertility / libido at heavy restriction
  • Wound healing — slowed in animal models; modest effect in humans
  • Frailty risk in elderly — CR is not recommended for adults > ~65 unless overweight; benefits in older adults less clear and risks more pronounced (potential exacerbation of sarcopenia)
  • Sustainability — even motivated CALERIE volunteers achieved only ~12–15% of the 25% target (i.e., roughly half); long-term adherence is the dominant practical limitation. Spadaro 2022 notes that “~14% sustained CR for 2 years” reflects what “humans achieve in free-living conditions” and is “much lower than the forced 25 to 40% restriction of calories in laboratory animals.”
  • Weight regain reverses benefits — Post-hoc CALERIE-2 analysis (Warmbrunn 2026 12) showed that participants who regained >5% baseline weight after the active CR phase lost the gains in insulin AUC, IGF-1/IGFBP-1 ratio, and biological-age estimates. Sustained moderate weight loss is required to preserve metabolic and biological-age benefits — rebound undoes them.

CR mimetics

Pharmacological agents that recapitulate CR effects without caloric reduction. Most-cited:

  • rapamycin — direct mTORC1 inhibition; the most-validated CR mimetic in mice (NIA ITP). A 2025 meta-analysis of 911 effect sizes from 167 vertebrate studies found rapamycin matches DR-driven lifespan extension while metformin does not 3
  • metformin — partial AMPK activation; observational evidence in diabetics; TAME trial design pending; failed to extend lifespan in the Ivimey-Cook 2025 vertebrate meta-analysis 3
  • Acarbose — α-glucosidase inhibitor; reduces post-prandial glucose; ITP-validated lifespan extension in mice
  • nmn / nr — NAD+ boosting; sirtuin substrate; emerging human data
  • spermidine — autophagy induction; observational signal (Bruneck) does not replicate in randomized trials. SmartAge 2022 (NCT03094546) null on primary cognition endpoint; CATIS 2025 contradictory direction in post-stroke cohort. Currently human-evidence-level: limited-negative.
  • fisetin — different mechanism (senolytic) but overlapping anti-inflammatory effects
  • Resveratrol — proposed sirtuin activator; controversial mechanism; failed to extend lifespan in non-obese mice

Cross-organism extrapolation

DimensionStatusNotes
Pathway conserved in humans?yesmTOR, AMPK, autophagy, IIS all conserved
Phenotype conserved in humans?partialBiomarker improvements robust; lifespan effect not measured
Replicated in humans?in-progressCALERIE-style protocols established; no long-term mortality endpoint completed

needs-human-replication — CR’s lifespan-extending effect in humans is inferred from biomarker improvements + animal data; no human RCT has measured all-cause mortality as a primary endpoint and is unlikely to in any reasonable timeframe given study duration requirements (decades).

dose-response-unclear — The optimal % restriction in humans is unknown. CALERIE-II achieved ~12–15% restriction across sites and sub-studies (Redman 2018 Pennington sub-study: ~15%; Spadaro 2022: ~14%; full trial average: ~12%); whether deeper restriction would yield proportionally greater benefit is unverified.

Key open questions

  1. Magnitude transfer to humans: rodent CR extends max lifespan ~30%; primate data from Mattison 2017 shows a significant survival benefit only in UW adult-onset animals (HR ~1.87), with no quantified “5–10% extension” figure stated in the paper — the survival curve medians in UW males shift from ~26 to ~28 years (control vs CR) by Kaplan-Meier, and the NIA cohorts show no significant effect. unsourced — the “5–10%” figure on this page has no direct support in Mattison 2017 and has been removed. Human translation magnitude on lifespan is unknown; CALERIE-2 ancillaries (Li 2026, Pribic 2025) suggest BioAge-trajectory slowing on the order of 0.5–1.3 years over 2 years of ~12% CR, but BioAge units are not lifespan units and the durability beyond the trial endpoint is unknown.
  2. Optimal protocol: continuous moderate CR vs IF vs TRE vs FMD — head-to-head efficacy comparisons in humans are limited; most practitioners adopt IF/TRE for sustainability rather than evidence.
  3. Onset timing: late-life CR has reduced benefit in mice (started at >18 months); human implementation timing unclear, though CALERIE II suggests middle-aged adults still benefit on biomarkers.
  4. Genotype × CR interactions: ITP-style heterogeneous mouse studies show large strain-dependent effects; human responses likely also vary substantially. No human pharmacogenomic CR data yet.
  5. Macronutrient composition: protein restriction (especially methionine) may capture much of CR’s benefit while allowing higher caloric intake — this is an active research area not yet tested in humans for longevity outcomes.

Biomarker effects

The CALERIE-2 trial (Waziry 2023) is the definitive dataset for CR effects on biological age clocks 15. The trial included four pre-specified clock endpoints:

ClockResponse to 2-year ~12% CRSignificance
DunedinPACESlowed (d=−0.25; ~2–3% per yr)p<0.003
PhenoAgeNo changeNS
GrimAgeNo changeNS
Horvath 2013No changeNS

Interpretation: CR slowed the pace-of-aging clock (DunedinPACE) but did not move the mortality-trained or chronological-age clocks. This selective response is consistent with DunedinPACE’s sensitivity to multi-system metabolic dynamics — the same systems CR most acutely modulates. Whether the DunedinPACE slowing represents durable biological-age retardation or acute metabolic confounding is unresolved. See biological-age-measurement for full cross-clock analysis. needs-replication — DunedinPACE CR response has not yet been independently replicated in a separate CR cohort.

Update (2024–2026): Subsequent CALERIE-2 ancillary analyses converge on the same direction: organ-specific BioAge clocks (Li 2026 10) showed metabolic and cardiovascular BioAge slowing of similar magnitude (~0.5–1.0 yr at 24 mo); GlycAge (Pribic 2025 11) decreased over months 12–24 in a single-arm pilot. These are correlated within-trial readouts, not independent-cohort replications, but they triangulate on a consistent biological-age signature beyond DunedinPACE alone.

Transcriptomic module-clock signature (rodent). The transcriptomic-clock framework of Tyshkovskiy et al. 2026 adds pathway resolution to how CR rejuvenates. Across 8 rodent CR liver datasets, CR reduced mortality-tAge relative to age-matched controls, with the strongest effects in metabolic modules — haem/ROS, lipid/PPAR signalling and cholesterol/mTOR signalling — and broad up-regulation of cellular respiration, oxidative phosphorylation and lipid/amino-acid metabolism genes 16. This contrasts sharply with chronic diseases (which accelerate inflammatory module tAge), and parallels Klotho biology (its deficiency drives metabolic/NRF2 module ageing). The key conceptual point: CR’s geroprotection is metabolically targeted, and module-specific clocks make this quantifiable — directly answering “which subsystem does CR rejuvenate?” at the network level.

Cross-references

Footnotes

Footnotes

  1. pietzner-2024-fasting-proteome · n=12 · in-vivo human, single-arm uncontrolled · 7-day water-only fast; daily plasma proteomics (2,923 targets, Olink Explore 3072) · doi:10.1038/s42255-024-01008-9 · Nat Metab 2024;6(4):764–777 · local PDF verified (PMC7617311) · systemic proteome response (1,044/2,923 targets, 35.9%) emerged only after 3 days of complete fasting · model: human · cited here only for the prolonged-fasting definitional contrast — full account on the prolonged-fasting + study pages ↩

  2. doi:10.1093/jn/10.1.63 · in-vivo (rat) · n=~unknown no-fulltext-access · model: Long-Evans rats fed restricted calories from weaning · authors: McCay CM, Crowell MF, Maynard LA · foundational CR paper; PDF not accessible (closed-access, not_oa in a local paper archive); n and specific magnitude figures unverified ↩

  3. doi:10.1111/acel.70131 · Ivimey-Cook ER, Sultanova Z, Maklakov AA · Aging Cell 2025;24(9):e70131 · meta-analysis · 911 effect sizes from 167 papers across 8 vertebrate species · DR robustly extended lifespan across log-response means and medians; rapamycin produced significant lifespan extension matching DR magnitude; metformin did NOT produce significant lifespan extension; effect of DR robust to DR methodology; high heterogeneity + significant publication bias acknowledged · model: cross-species vertebrate meta · verified-scope: PubMed efetch abstract only · PMID: 40532901 ↩ ↩2 ↩3

  4. doi:10.1038/ncomms14063 · in-vivo (rhesus macaque) · n=197 total (NIA: 121 monkeys in multiple age/sex groups; UW: 76 adult-onset monkeys) · pooled longitudinal comparison of NIA + Wisconsin primate cohorts · significant survival benefit in UW adult-onset animals (HR 1.865, 95% CI 1.119–3.108, p=0.017 by Cox regression); no significant survival effect in NIA J/A or old-onset cohorts · healthspan improvements (morbidity reduced ~2.7x in controls vs CR, HR 2.665 for UW, p=0.0006) conserved across both sites · diet quality differences (purified sucrose-based UW diet vs natural-ingredient NIA diet) identified as key confound affecting survival outcomes ↩

  5. doi:10.1016/j.cmet.2018.02.019 · randomized controlled trial (CALERIE II Pennington ancillary metabolic sub-study) · n=53 (34 CR, 19 AL control) · achieved CR ~15% (14.8% ± 1.5%) over 2 years · 8.7 kg mean weight loss in CR group · primary endpoints: sleeping energy expenditure (metabolic adaptation) and urinary F2-isoprostane (oxidative damage) · SleepEE reduced ~7% beyond weight-loss expectation (p<0.01); F2-isoprostane significantly reduced vs controls (p<0.01) · reduced T3, T4, leptin; no significant change in bone/mood/cognition (those outcomes in other CALERIE II papers) ↩ ↩2

  6. doi:10.1126/science.abg7292 · CALERIE II secondary immune analysis · ~14% CR achieved over 2 years (stated in abstract) · n=27 (22F + 5M) for CD4 sjTREC; n=25 (20F + 5M) for CD8 sjTREC · thymopoiesis significantly improved (increased thymic mass, increased sjTRECs in CD4 and CD8 cells, p<0.05) · 233 genes up-regulated / 131 down-regulated in subcutaneous adipose tissue · PLA2G7 suppressed by CR; Pla2g7 KO mice partially phenocopy CR immune-metabolic benefits ↩ ↩2

  7. doi:10.1111/acel.14038 · Aversa Z, White TA, Heeren AA et al. (LeBrasseur lab, Mayo) · Aging Cell 2024;23(2):e14038 · CALERIE-2 plasma + adipose secondary analysis · randomized · plasma senescence biomarkers significantly reduced at 12 + 24 mo vs AL; ML-selected SASP markers predicted HOMA-IR, insulin sensitivity index, RMR-residual change; adipose RNA-seq showed reduced senescence-focused gene-set expression · model: healthy non-obese human adults (CALERIE Phase 2) · verified-scope: PubMed efetch abstract only (full PDF not yet checked) · PMID: 37961856 ↩ ↩2

  8. doi:10.1038/s43587-026-01107-0 · Mishra M, Kim HH, Youm YH et al. (Dixit lab, Yale) · Nat Aging 2026 (online-ahead-of-print Apr 13) · CALERIE-2 plasma exoproteome (longitudinal; ~14% CR over 2 yr) · randomized · CR significantly lowered C3a/C3 ratio, dampening all three canonical complement pathways; identified non-senescent age-associated macrophage subset in visceral fat as predominant C3a source; intra-adipose C3a-neutralizing antibody reduced inflammaging in mice; FGF21 overexpression and Pla2g7 KO also lowered C3a · model: human + mouse · verified-scope: PubMed efetch abstract only · PMID: 41974968 ↩ ↩2

  9. doi:10.1111/acel.14149 · Hastings WJ et al. · Aging Cell 2024;23(6):e14149 · CALERIE-2 telomere ancillary · randomized · n=219 (intent-to-treat) · ITT analysis: NO significant CR effect on telomere length attrition over 24 months by qPCR (aTL) or DNAmTL · Effect-of-Treatment-on-the-Treated showed transient opposing-direction effects in 0–12 mo (loss phase) vs 12–24 mo (maintenance phase); net 0–24 mo effect null · model: healthy non-obese human adults · verified-scope: PubMed efetch abstract only · PMID: 38504468 ↩

  10. doi:10.1016/j.clnu.2026.106625 · Li Y, Xu X, Sehgal R et al. · Clin Nutr 2026;60:106625 · CALERIE-2 organ-specific BioAge ancillary · randomized · n=185 (120 CR, 65 AL) · ITT estimates at 24 mo: metabolic BioAge −0.63 yr (p=3.02×10⁻⁷); cardiovascular −1.00 yr (p=1.96×10⁻⁶); whole-body −1.27 yr (p=1.20×10⁻⁴); immune −0.62 yr (p=2.92×10⁻³); liver −0.54 yr (p=8.30×10⁻³); kidney NS · dose-response: ≥12.4% CR drove metabolic + whole-body effects · model: healthy non-obese human adults · verified-scope: PubMed efetch abstract only · PMID: 41895150 ↩ ↩2 ↩3

  11. doi:10.1038/s41514-025-00254-9 · Pribić T, Das JK, Đerek L et al. · NPJ Aging 2025;11(1):71 · CALERIE-2 glycomic pilot · n=26 (no concurrent control) · 25% CR target over 2 yr · IgG galactosylation increased BL→24mo (p=0.051) and 12→24mo (p=0.016); IgG-based GlycAge decreased 12→24mo (p=0.027); plasma high-branched glycans declined; bisecting GlcNAcs increased; complement C3 protein and C3-Man9 N-glycoforms reduced · pilot caveat: absence of control group · model: healthy non-obese human adults · verified-scope: PubMed efetch abstract only · PMID: 40750782 ↩ ↩2

  12. doi:10.2337/dc25-1911 · Warmbrunn MV, Yang L, Kishore Biswas R et al. (Fontana group) · Diabetes Care 2026;49(5):783–791 · CALERIE-2 weight-trajectory post-hoc · n=190 (analysis subset of n=220 randomized) · stratified by post-12-mo weight trajectory; ~10% (n=20) regained >5% baseline; weight-regain group lost CR-induced gains in insulin AUC, IGF-1/IGFBP-1 ratio, and biological-age estimates; sustained weight loss preserved benefits and was associated with greater BioAge reduction · model: healthy non-obese human adults · verified-scope: PubMed efetch abstract only · PMID: 41838032 ↩ ↩2

  13. doi:10.1016/j.isci.2025.114514 · Orenduff MC, Huffman KM, Belsky DW, Pieper CF, Kraus WE, Kraus VB · iScience 2026;29(1):114514 · CALERIE-2 small-RNA ancillary · plasma + muscle + adipose smRNA-seq at 12 + 24 mo · 16 smRNAs associated with %CR, 41 with CR-vs-AL; shared pathway enrichment in insulin signaling, circadian rhythm, cell cycle, stress response; cross-species: 17 miRNAs altered by CR in both humans and rhesus monkeys · model: human + cross-species · verified-scope: PubMed efetch abstract only · PMID: 41550774 ↩

  14. commissati-2025-prolonged-fasting-inflammation · n=20 (+ n=1,422 validation cohort) · in-vivo human, single-arm uncontrolled · ~10-day water-only fast + ~5-day refeeding; SOMAScan 1,317 proteins + targeted MS + ELISAs · doi:10.1016/j.molmet.2025.102152 · Mol Metab 2025;102152 · local PDF verified (accepted pre-proof) · prolonged fasting is acutely pro-inflammatory (hsCRP +129%; complement + coagulation activation; platelet activation via urinary 11-dehydro-TXB2; AST +65%/ALT +64%), all normalizing on refeeding · model: human · cited here for the CR-vs-prolonged-fasting inflammation contrast — full account on prolonged-fasting + study page ↩

  15. waziry-2023-calerie-epigenetic-clock · n=197 (128 CR, 69 AL; from 220 randomized) · rct · model: healthy non-obese human adults (CALERIE Phase 2, 2-year ~12% achieved CR) · doi:10.1038/s43587-022-00357-y · local PDF available · DunedinPACE: d=−0.25 95% CI (−0.41, −0.09) p<0.003; Horvath 2013: NS; PhenoAge: NS; GrimAge: NS ↩

  16. tyshkovskiy-2026-universal-transcriptomic-hallmarks · doi:10.1038/s41586-026-10542-3 · Nature 2026 · n=8 rodent CR liver datasets (within a 4-species, 11,165-transcriptome meta-analysis) · mixed-effects / module-specific elastic-net mortality clocks, P_adj<0.05 · model: mouse liver (C57BL/6J, DBA/2J, B6C3F1) · CR reduced mortality-tAge, strongest in haem/ROS, lipid/PPAR and cholesterol/mTOR modules ↩

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