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Cited by 221Epigenetics and DNA MethylationGenetics, Aging, and Longevity in Model OrganismsDietary Effects on Health

The DOI matches its Crossref record; 88 of the 88 references it cites were found in a registry or an index; 57 of the 89 sources its claims cite were checked for support.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

Open access
Waziry, R., Ryan, C. P., Corcoran, D. L., Huffman, K. M., Kobor, M. S., Kothari, M., Graf, G. H., Kraus, V. B., Kraus, W. E., Lin, D. T. S., Pieper, C. F., Ramaker, M. E., Bhapkar, M., Das, S. K., Ferrucci, L., Hastings, W. J., Kebbe, M., Parker, D. C., Racette, S. B., Shalev, I., Schilling, B., Belsky, D. W.·2023·Nature Aging
DOI 10.1038/s43587-022-00357-yPMC PMC10148951
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Abstract

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan 1–3 . Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients 4 , results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm) 5–7 , and is established to increase healthy lifespan in multiple species 8,9 . Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10 ). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health 11–13 . The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies 14–16 and contrasting with reports that biological aging may not be modifiable 17 . Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality 18–20 .

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a post hoc analysis of the CALERIE Phase 2 randomized trial, 2 years of caloric restriction slowed the pace of aging measured by DunedinPACE but did not significantly change PhenoAge or GrimAge DNA methylation clocks. Treatment effect sizes were small, and long-term clinical benefit remains unknown.

Key findings

  • Among n = 197 participants with DNA methylation data (128 CR, 69 AL), CR did not significantly alter PC PhenoAge or PC GrimAge: PhenoAge 12-month d = −0.03 (95% CI −0.19, 0.12), 24-month d = 0.05 (95% CI −0.11, 0.20), P > 0.50; GrimAge 12-month d = −0.04 (95% CI −0.16, 0.07), 24-month d = 0.05 (95% CI −0.07, 0.17), P > 0.40.
  • CR significantly reduced DunedinPACE at 12 months (d = −0.29, 95% CI −0.45, −0.13) and 24 months (d = −0.25, 95% CI −0.41, −0.09), P < 0.003 for both, corresponding to a 2–3% slower pace of aging.
  • Dose–response and treatment-on-the-treated analyses suggested larger DunedinPACE effects with higher CR: >10% CR group d = −0.33 at both 12 and 24 months versus <10% CR d = −0.19 and −0.14; instrumental-variable estimate for 20% CR was d = −0.43 (95% CI −0.67, −0.19) at 12 months and d = −0.40 (95% CI −0.67, −0.12) at 24 months.
  • Mean achieved CR was 11.9% (s.e.m. = 0.7%), below the prescribed 25%; sex differences in treatment effects were not statistically different from zero.

Methods

  • Post hoc analysis of CALERIE Phase 2, a multi-center randomized controlled trial at three US centers in healthy adults (men aged 21–50 years, premenopausal women aged 21–47 years) with BMI 22.0–27.9 kg m−2; participants were randomized 2:1 to 25% CR or ad libitum control for 2 years, stratified by site, sex, and BMI.
  • Blood DNA methylation was assayed with Illumina Infinium Methylation EPIC arrays at baseline, 12 months, and 24 months; analysis included n = 197 participants with baseline and at least one follow-up DNAm measurement.
  • Primary measures were PC PhenoAge, PC GrimAge, and DunedinPACE. Change scores were analyzed using intent-to-treat repeated-measures ANCOVA under mixed models and treatment-on-the-treated instrumental-variable regression for 20% CR; P < 0.005 was used as the significance threshold.

Limitations

  • The paper states there is no gold standard measure of biological aging; the DNAm measures are incomplete summaries with technical limitations, and measurement error may bias effect estimates toward the null, making treatment effects a possible lower bound.
  • The paper states that participants did not on average achieve the prescribed 25% CR, some controls reduced caloric intake, the CALERIE sample does not represent the general population, and follow-up did not extend beyond the intervention, so long-term clinical benefit is unknown.
  • Evident from the text: this was a post hoc analysis, no statistical methods were used to predetermine sample sizes, treatment effect sizes were small, and DunedinPACE trajectories showed substantial overlap between CR and AL groups (effect-size estimates imply close to 90% overlap).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s43587-022-00357-y

Cites

88 of 88 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

57 of 89 cited sources checked · 30 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Caloric restriction results in changes in molecular processes associated with aging, including DNA methylation.

    “Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5–7, and is established to increase healthy lifespan in multiple species8,9.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Maegawa, S. et al. Caloric restriction delays age-related methylation drift. Nat. Commun. 8, 539 (2017). source
    • cites [6] Hahn, O. et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18, 56 (2017). source
    • cites [7] Petkovich, D. A. et al. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. 25, 954–960.e6 (2017). source
  • Premisecitation

    In observational studies with long-term follow-up, individuals with slower DunedinPACE are better-off on a range of healthspan metrics, including showing reduced incidence of morbidity and increased survival.

    “In observational studies with long-term follow-up, individuals with slower DunedinPACE are better-off on a range of healthspan metrics, including showing reduced incidence of morbidity and increased survival24,29.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source
    • cites [29] Sugden, K. et al. Association of pace of aging measured by blood-based DNA methylation with age-related cognitive impairment and dementia. Neurology 99, e1402–e1413 (2022). source

      The Results section on the FHS Offspring Cohort reports that faster DunedinPACE predicted greater dementia incidence over up to 14 years of follow-up, supporting one morbidity-related outcome. The cited paper also reports poorer cognitive outcomes with faster DunedinPACE, but our copy does not report increased survival or reduced incidence of morbidity across a range of conditions. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Study design and conductcitation

    In CALERIE, the percentage CR achieved by treatment group participants varied, with most achieving doses below the prescribed 25% (mean = 11.9, s.e.m. = 0.7%).

    “In the CALERIE Trial, the %CR achieved by participants in the treatment group varied, with most participants achieving doses below the prescribed 25% (mean = 11.9, s.e.m. = 0.7%)10.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Ravussin, E. et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J. Gerontol. A 70, 1097–1104 (2015). source

      The Intervention and Adherence Measurements section specifies a 25% CR target, and Adherence and Weight Loss reports that the CR group averaged 11.7 ± 0.7% over two years—below that target. The cited paper does not give the claimed mean of 11.9%, and the cited passages do not establish how many individual participants fell below 25%. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationown data

    The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis.

    “The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14–16 and contrasting with reports that biological aging may not be modifiable17.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [14] Fahy, G. M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18, e13028 (2019). source
    • cites [15] Chen, L. et al. Effects of vitamin D3 supplementation on epigenetic aging in overweight and obese African Americans with suboptimal vitamin D status: a randomized clinical trial. J. Gerontol. A 74, 91–98 (2019). source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [16] Sae-Lee, C. et al. Dietary intervention modifies DNA methylation age assessed by the epigenetic clock. Mol. Nutr. Food Res. 62, 1800092 (2018). source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [17] Colchero, F. et al. The long lives of primates and the ‘invariant rate of ageing’ hypothesis. Nat. Commun. 12, 3666 (2021). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Premisecitation

    Studies in subsets of CALERIE participants suggest effects of CR on molecular mechanisms of immune and metabolic regulation.

    “Studies in subsets of CALERIE participants suggest effects of CR on molecular mechanisms of immune and metabolic regulation34,35.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [34] Spadaro, O. et al. Caloric restriction in humans reveals immunometabolic regulators of health span. Science 375, 671–677 (2022). source
    • cites [35] Redman, L. M. et al. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell Metab. 27, 805–815.e4 (2018). source

      The STAR Methods identify this as an ancillary study of a subset of CALERIE participants. The Results and Discussion report effects of caloric restriction on hormonal mediators of energy metabolism, including leptin and thyroid hormones. Our copy does not report effects on mechanisms of immune regulation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • It may state two separate claims as one. 24
  • Probably not a substantial claim. 41

  • It may state two separate claims as one.

    Premisecitation

    Despite imperfect adherence, treatment group participants experienced substantial and sustained weight loss and related changes in body and tissue composition, broad improvement in cardiometabolic health and a slowing of aging-related physiological changes.

    “Despite this imperfect adherence, treatment group participants experienced substantial and sustained weight loss and related changes in body and tissue composition, broad improvement in cardiometabolic health and a slowing of aging-related physiological changes26,31,44,45.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [26] Kraus, W. E. et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 7, 673–683 (2019). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [31] Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I. & Kraus, W. E. Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank Analysis. J. Gerontol. A 73, 4–10 (2017). source
    • cites [44] Das, S. K. et al. Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans. Am. J. Clin. Nutr. 105, 913–927 (2017). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [45] Shen, W. et al. Effect of 2-year caloric restriction on organ and tissue size in nonobese 21- to 50-year-old adults in a randomized clinical trial: the CALERIE study. Am. J. Clin. Nutr. 114, 1295–1303 (2021). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    DunedinPACE was originally designed to have high technical reliability.

    “DunedinPACE was originally designed to have high technical reliability.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Premisecitation

    Modest slowing of the pace of aging can have profound effects on population health.

    “Nevertheless, modest slowing of the pace of aging can have profound effects on population health11–13.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [11] Scott, A. J., Ellison, M. & Sinclair, D. A. The economic value of targeting aging. Nat. Aging 1, 616–623 (2021). source
    • cites [12] Kaeberlein, M. It is time to embrace 21st-century medicine. Public Policy Aging Rep. 29, 111–115 (2019). source
    • cites [13] Goldman, D. P. et al. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff. 32, 1698–1705 (2013). source

  • Probably not a substantial claim.

    Premisecitation

    There is no gold standard measure of biological aging.

    “There is no gold standard measure of biological aging37.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Ferrucci, L. et al. Measuring biological aging in humans: a quest. Aging Cell 19, e13080 (2020). source

  • It may state two separate claims as one.

    Premisecitation

    All three DNAm measures have evidence for validity as biomarkers of aging, including association with aging-related morbidity and mortality and with exposures associated with shortened healthy lifespan.

    “All three measures have evidence for validity as biomarkers of aging, in particular, evidence of association with aging-related morbidity and mortality and with exposures associated with shortened healthy lifespan24,29,30.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source
    • cites [29] Sugden, K. et al. Association of pace of aging measured by blood-based DNA methylation with age-related cognitive impairment and dementia. Neurology 99, e1402–e1413 (2022). source

      The Results section on dementia in the FHS Offspring Cohort reports that several DNA-methylation measures were associated with future dementia, supporting evidence of an aging-related disease association. The paper examines five measures across three generations, however, and does not establish that all three measures in the citing sentence are associated with mortality or with exposures linked to shortened healthy lifespan. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [30] Hillary, R. F. et al. Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden. Clin. Epigenetics 12, 115 (2020). source

      The Discussion reports disease-incidence associations for DNAm GrimAge, DunedinPoAm and DNAm PhenoAge, and the Results associate these measures with smoking or deprivation. But the Results on all-cause mortality identify DNAm GrimAge alone; this paper does not establish a mortality association for all three measures. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Previous reports on CALERIE establish that CR intervention improved participants' cardiometabolic health and slowed aging-related changes in physiological system integrity.

    “Our previous reports on CALERIE establish that CR intervention improved participants’ cardiometabolic health and slowed aging-related changes in physiological system integrity26,31,32.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [26] Kraus, W. E. et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 7, 673–683 (2019). source
    • cites [31] Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I. & Kraus, W. E. Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank Analysis. J. Gerontol. A 73, 4–10 (2017). source
    • cites [32] Kwon, D. & Belsky, D. W. A toolkit for quantification of biological age from blood chemistry and organ function test data: BioAge. Geroscience 43, 2795–2808 (2021). source

  • It may state two separate claims as one.

    Interpretationcitation

    New measurements that summarize biological changes occurring with aging have potential to overcome the challenge that human aging takes decades to cause disease; measurements that both predict future disease, disability and mortality and can detect changes in aging processes over short timescales have potential to function as surrogate endpoints for intervention effects on healthy lifespan.

    “New measurements that summarize biological changes occurring with aging have potential to overcome this challenge; measurements to quantify biological aging that both predict future disease, disability and mortality and can detect changes in aging processes over short timescales have potential to function as surrogate endpoints for intervention effects on healthy lifespan38,49.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [38] Kritchevsky, S. B. & Justice, J. N. Testing the geroscience hypothesis: early days. J. Gerontol. A 75, 99–101 (2020). source
    • cites [49] Justice, J. N. & Kritchevsky, S. B. Putting epigenetic biomarkers to the test for clinical trials. eLife 9, e58592 (2020). source

  • It may state two separate claims as one.

    Premisecitation

    The DNAm measures studied summarize biological aging in general and do not isolate system-specific aging processes.

    “The measures we studied summarize biological aging in general and do not isolate system-specific aging processes41.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [41] Ahadi, S. et al. Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat. Med. 26, 83–90 (2020). source

      The passage on DNA methylation clocks (section labeled Abstract; no page supplied) describes them as associated with chronological and biological age, supporting the general-aging part of the claim. It contrasts those clocks with the paper’s pathway-level ageotypes, but does not establish that the particular DNAm measures studied by the citing authors cannot isolate system-specific aging processes. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    DunedinPACE has high test-retest reliability and shows strong associations with healthspan endpoints in validation analyses.

    “DunedinPACE has high test–retest reliability and shows strong associations with healthspan endpoints in validation analyses24,29.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source
    • cites [29] Sugden, K. et al. Association of pace of aging measured by blood-based DNA methylation with age-related cognitive impairment and dementia. Neurology 99, e1402–e1413 (2022). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim.

    Premisecitation

    Caloric restriction is established to increase healthy lifespan in multiple species.

    “and is established to increase healthy lifespan in multiple species8,9.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Anderson, R. M. & Weindruch, R. The caloric restriction paradigm: implications for healthy human aging. Am. J. Hum. Biol. 24, 101–106 (2012). source
    • cites [9] Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012). source

      The Abstract reports that caloric restriction has been associated with longer lifespan and healthspan in a variety of animals, supporting the multiple-species background claim. But “established” is stronger than the paper’s qualified account: its NIA rhesus-monkey study found no significant survival benefit, even though some health measures improved. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan.

    “The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1–3.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [1] Kaeberlein, M. Longevity and aging. F1000Prime Rep. 5, 5 (2013). source
    • cites [2] Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). source
    • cites [3] Campisi, J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductcitation

    CALERIE Phase 2 was a multi-center, randomized controlled trial conducted at three clinical centers in the United States.

    “Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) Phase 2 was a multi-center, randomized controlled trial conducted at three clinical centers in the United States10.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Ravussin, E. et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J. Gerontol. A 70, 1097–1104 (2015). source

      The paper’s opening summary (page unavailable) identifies CALERIE as a three-site randomized controlled trial, supporting the multi-center design and number of sites. The passages in our copy do not specify that the three clinical centers were in the United States. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    In CALERIE, adherence was imperfect; the average CR achieved in the treatment group was roughly half the prescribed dose of 25%.

    “In CALERIE, adherence was imperfect; the average CR achieved in the treatment group was roughly half the prescribed dose of 25% (ref. 10).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Ravussin, E. et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J. Gerontol. A 70, 1097–1104 (2015). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    IV regression is commonly used to reduce confounding in association analysis and can be applied to account for contamination/nonadherence in randomized trials.

    “IV regression is a method commonly used to reduce the impact of confounding in association analysis. It can also be applied to account for contamination/nonadherence in randomized trials64.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [64] Sussman, J. B. & Hayward, R. A. An IV for the RCT: using instrumental variables to adjust for treatment contamination in randomised controlled trials. Brit. Med. J. 340, c2073 (2010). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    DunedinPACE was based on analysis of pace of aging in the Dunedin Study (n = 817 participants examined at ages 26, 32, 38 and 45 yr), with pace of aging measured from within-person change over time in 19 blood chemistry and organ function test metrics.

    “Based on analysis of pace of aging in the Dunedin Study (n = 817 participants examined at ages 26, 32, 38 and 45 yr)24, pace of aging was measured from within-person change over time in 19 blood chemistry and organ function test metrics of system integrity24.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The GrimAge clock was based on analysis of eight plasma protein markers, smoking pack years, age, sex and mortality data from the Framingham Heart Study Offspring and Gen3 Cohorts.

    “The GrimAge clock was based on analysis of eight plasma protein markers, smoking pack years, age, sex and mortality data from the Framingham Heart Study Offspring and Gen3 Cohorts (n = 2,751 participants aged 24–92 yr)47–49.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [47] Sierra, F. et al. Moving geroscience from the bench to clinical care and health policy. J. Am. Geriatr. Soc. 69, 2455–2463 (2021). source

      The section on behavioral and social science perspectives discusses measuring biological aging but does not describe how GrimAge was developed. Searches for GrimAge, plasma protein markers, smoking pack years, and the Framingham cohorts found no passage in our copy addressing the claim, including its participant count or age range. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [48] Justice, J. et al. Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes. J. Gerontol. A Biol. Sci. Med. Sci. 71, 1415–1423 (2016). source

      The Approach section discusses biomarkers for proof-of-concept aging trials, but does not describe how the GrimAge clock was developed. Searches for GrimAge, the eight plasma proteins, smoking pack-years, and the Framingham cohorts found no passage addressing the claim; page numbers are unavailable in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [49] Justice, J. N. & Kritchevsky, S. B. Putting epigenetic biomarkers to the test for clinical trials. eLife 9, e58592 (2020). source

      The Figure 1 caption (Abstract; no page given) identifies GrimAge as a mortality estimator. Our copy does not describe its inputs, the Framingham cohorts, participant count, or age range, so those details are not supported by this source. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    DunedinPACE was developed by modeling within-individual multi-system physiological change across four timepoints in same-age individuals in the Dunedin Study 1972-1973 birth cohort, when participants were aged 26, 32, 38 and 45 yr.

    “DunedinPACE was developed by modeling within-individual multi-system physiological change across four timepoints in same-age individuals in the Dunedin Study 1972–1973 birth cohort60,61, when participants were aged 26, 32, 38 and 45 yr.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source
    • cites [60] Belsky, D. W. et al. Quantification of biological aging in young adults. Proc. Natl Acad. Sci. USA 112, E4104–E4110 (2015). source

      The Sample section identifies the Dunedin Study as a 1972–1973 birth cohort, and the Significance section describes modeling within-individual physiological change across multiple systems. But this paper’s analysis used three timepoints—ages 26, 32, and 38—not four through age 45; the Discussion says follow-up extended only to age 38. It describes a Pace of Aging measure, not the development of DunedinPACE. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [61] Elliott, M. L. et al. Disparities in the pace of biological aging among midlife adults of the same chronological age have implications for future frailty risk and policy. Nat. Aging 1, 295–308 (2021). source

      The Introduction and Methods (pages unavailable) describe modeling changes in multiple physiological systems in the same-age Dunedin 1972–1973 birth cohort at ages 26, 32, 38, and 45. They call the resulting measure the “Pace of Aging,” however; our copy does not say that this paper developed DunedinPACE. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Second-generation DNAm clocks include an intermediate step in which DNAm data are fitted to physiological parameters.

    “These clocks also include an intermediate step in which DNAm data are fitted to physiological parameters.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [22] Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591 (2018). source
    • cites [23] Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019). source

  • It may state two separate claims as one.

    Study design and conductcitation

    The primary analysis used PC versions of PhenoAge and GrimAge and DunedinPACE, which show exceptional test-retest reliability in technical replicates.

    “Our primary analysis focused on the PC versions of the PhenoAge and GrimAge second-generation clocks and DunedinPACE, all of which show exceptional test–retest reliability in technical replicates.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [25] Higgins-Chen, A. T. et al. A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking. Nat. Aging 2, 644–661 (2022). source

      The Results section (‘Reliable epigenetic clocks trained from principal components’; page unavailable) reports exceptional agreement between technical replicates for PC clocks, including PCPhenoAge and PCGrimAge. Our copy does not establish the same test–retest reliability for DunedinPACE, so it does not support the claim about all three measures. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source

      The Results section, “DunedinPACE shows exceptional test-retest reliability” (page unavailable), reports excellent reliability for DunedinPACE in technical replicates (ICC 0.96) and says it is as reliable as the GrimAge clock. It does not establish exceptional reliability for the PC versions of PhenoAge and GrimAge; it says DunedinPACE is more reliable than the other clocks tested and notes that methods have been proposed to improve their reliability. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Second-generation DNAm clocks were developed with the goal of improving quantification of biological aging by focusing on differences in mortality risk instead of on differences in chronological age.

    “The second-generation DNAm clocks were developed with the goal of improving quantification of biological aging by focusing on differences in mortality risk instead of on differences in chronological age22,23.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [22] Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591 (2018). source
    • cites [23] Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The set of CpG sites included in the DNAm dataset used to develop the DunedinPACE algorithm was restricted to those showing acceptable test-retest reliability as determined in ref. 62.

    “The set of CpG sites included in the DNAm dataset used to develop the DunedinPACE algorithm was restricted to those showing acceptable test–retest reliability as determined in the analysis in ref. 62.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Sugden, K. et al. Patterns of reliability: assessing the reproducibility and integrity of DNA methylation measurement. Patterns 1, 100014 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    First-generation DNAm clocks are highly accurate in predicting chronological age of new samples and show some capacity for predicting differences in mortality risk, although effect sizes tend to be small and inconsistent across studies.

    “These clocks were highly accurate in predicting the chronological age of new samples and also showed some capacity for predicting differences in mortality risk, although effect sizes tend to be small and inconsistent across studies56–58.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [56] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). source

      In “The multi-tissue age predictor used for defining DNAm age” (page unavailable), Horvath reports high accuracy in independent test data: an age correlation of 0.96 and a median error of 3.6 years. The passages found do not assess mortality-risk prediction or report small, inconsistent mortality effects across studies, so that part of the attributed claim is unsupported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [57] Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49, 359–367 (2013). source

      In “A predictive model for the aging methylome” (page unavailable), the paper reports highly accurate age predictions in 174 independent samples. It does not report whether the clock predicts mortality risk or assess the size or consistency of mortality effects across studies; the Conclusions discuss longevity only as a potential future application. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [58] Chen, B. H. et al. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging 8, 1844–1865 (2016). source

      The Introduction describes epigenetic clocks as robust estimators of chronological age, and the Results (Epigenetic age estimation) report correlations of 0.65–0.89. The Results (Cox regression models of all-cause mortality) find that all examined age-acceleration measures predicted mortality. The claim that effects were inconsistent across studies is not supported by these passages; the Results (Subgroup analysis) instead say hazard-ratio estimates were highly consistent across examined subgroups. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    For DunedinPACE, the treatment effect in the >10% CR group was d = −0.33 at 12 months and d = −0.33 at 24 months, as compared with d = −0.19 at 12 months and d = −0.14 at 24 months in the <10% CR group.

    “For DunedinPACE, the treatment effect in the >10% CR group was d = −0.33 at 12 months and d = −0.33 at 24 months, as compared with d = −0.19 at 12 months and d = −0.14 at 24 months in the <10% CR group.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In IV analysis, the effect of 20% CR on DunedinPACE was d = −0.43 (95% CI −0.67, −0.19) at 12 months and d = −0.40 (95% CI −0.67, −0.12) at 24 months (P < 0.005 for both).

    “In IV analysis, the effect of 20% CR on DunedinPACE was d = −0.43 (95% CI −0.67, −0.19) at 12 months and d = −0.40 (95% CI −0.67, −0.12) at 24 months (P < 0.005 for both).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The CALERIE intervention affected participants’ biological aging only through its effect on their caloric intake.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingnone given

    Participants' PhenoAge and GrimAge values tended to increase over time.

    “As expected, participants’ PhenoAge and GrimAge values tended to increase over time.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Changes in DunedinPACE over follow-up showed substantial overlap between the CR treatment group and the AL control group; effect-size estimates imply close to 90% overlap of DunedinPACE trajectories between the two groups.

    “Moreover, changes in DunedinPACE over follow-up showed substantial overlap between the CR treatment group and the AL control group; effect-size estimates imply close to 90% overlap of DunedinPACE trajectories between the two groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Participants had mean age of 38 yr (s.d. = 7), 70% were women and 77% were white.

    “Participants had mean age of 38 yr (s.d. = 7), 70% were women and 77% were white”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The 20% CR level represented the 75th percentile of the treatment group CR distribution at 12-month follow-up and the 87th percentile at 24-month follow-up.

    “The 20% CR level represented the 75th percentile of the treatment group CR distribution at 12-month follow-up and the 87th percentile of the treatment group CR distribution at 24-month follow-up.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    CALERIE follow-up is, so far, limited to the end of the intervention period.

    “CALERIE follow-up is, so far, limited to the end of the intervention period.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    Participants were randomly assigned at a ratio of 2:1 to a CR behavioral intervention or to an ad libitum control group stratified by site, sex and BMI.

    “Participants were randomly assigned at a ratio of 2:1 to a CR behavioral intervention or to an ad libitum (AL) control group stratified by site, sex and BMI.”
    • Also stated in: § Randomization and masking · plain
      “After baseline testing, participants were randomly assigned at a ratio of 2:1 to a CR behavioral intervention or to an AL control group. Randomization was stratified by site, sex and BMI. A permuted block randomization technique was used.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    These DNAm measures are acknowledged to be incomplete summaries of biological changes that occur with aging and to have technical limitations.

    “Nevertheless, these measures are acknowledged to be incomplete summaries of biological changes that occur with aging and to have technical limitations39,40.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Bell, C. G. et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 20, 249 (2019). source
    • cites [40] Belsky, D. W. et al. Eleven telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: do they measure the same thing? Am. J. Epidemiol. 187, 1220–1230 (2018). source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Premisecitation

    CR has diverse effects across multiple biological systems.

    “However, CR has diverse effects across multiple biological systems42,43.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Ma, S. et al. Caloric restriction reprograms the single-cell transcriptional landscape of Rattus norvegicus aging. Cell 180, 984–1001.e22 (2020). source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [43] Dorling, J. L., Martin, C. K. & Redman, L. M. Calorie restriction for enhanced longevity: the role of novel dietary strategies in the present obesogenic environment. Ageing Res. Rev. 64, 101038 (2020). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    Our findings highlight DunedinPACE as a measure with potential utility in future trials.

    “Our findings highlight DunedinPACE as a measure with potential utility in future trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Premisecitation

    The DNAm measures analyzed represent the current state-of-the-art in DNAm quantification of biological aging.

    “We analyzed several measures which represent the current state-of-the-art in DNAm quantification of biological aging38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Kritchevsky, S. B. & Justice, J. N. Testing the geroscience hypothesis: early days. J. Gerontol. A 75, 99–101 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    The CALERIE Trial sample does not represent the general population and treatment effects may not generalize beyond the population of healthy volunteers recruited to participate.

    “The CALERIE Trial sample does not represent the general population and treatment effects may not generalize beyond the population of healthy volunteers recruited to participate.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    The CALERIE treatment effect of 2-3% slower pace of aging corresponds to a reduction in mortality risk of as much as 10-15%, similar in magnitude to the effect of smoking cessation intervention.

    “These previous studies suggest that the CALERIE treatment effect of 2–3% slower pace of aging corresponds to a reduction in mortality risk of as much as 10–15%, similar in magnitude to the effect of smoking cessation intervention36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Anthonisen, N. R. et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann. Intern. Med. 142, 233–239 (2005). source

  • It may state two separate claims as one.

    Study design and conductnone given

    On average, trial participants did not achieve the prescribed dose of 25% CR and some control group participants reduced their caloric intake.

    “On average, trial participants did not achieve the prescribed dose of 25% CR and some control group participants reduced their caloric intake.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The PhenoAge clock was based on analysis of nine blood chemistry markers, age and mortality data from NHANES, DNAm and blood chemistry data from InCHIANTI, and the US Health and Retirement Study.

    “The PhenoAge clock was based on analysis of nine blood chemistry markers, age and mortality data from the US National Health and Nutrition Examination Surveys (n = 9,926 participants aged 18 yr and older; 23 yr of mortality follow-up); DNAm and blood chemistry data from the Invecchiare in Chianti (InCHIANTI) Study (n = 912 participants aged 21–100 yr); and the US Health and Retirement Study (n = 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Prentice, R. L. Surrogate endpoints in clinical trials: definition and operational criteria. Stat. Med. 8, 431–440 (1989). source

  • Probably not a substantial claim.

    Study design and conductown data

    After baseline testing, n = 220 participants were randomly assigned at a ratio of 2:1 to a CR behavioral intervention or to an AL control group.

    “After baseline testing, n = 220 participants were randomly assigned at a ratio of 2:1 to a CR behavioral intervention or to an AL control group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The assays of the biospecimens were conducted blind to the conditions of the trial.

    “The assays of the biospecimens were conducted blind to the conditions of the trial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Randomization was stratified by site, sex and BMI.

    “Randomization was stratified by site, sex and BMI.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    To the extent possible, baseline, 12-month and 24-month samples from the same individual were processed in the same array batch and on the same BeadChip to minimize batch effects, and CR treatment and AL control participants were included on all chips.

    “To the extent possible, baseline, 12-month and 24-month samples from the same individual were processed in the same array batch and on the same BeadChip to minimize batch effects; CR treatment and AL control participants were included on all chips.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    A permuted block randomization technique was used.

    “A permuted block randomization technique was used.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    DNAm assays of stored blood biospecimens were conducted blind to trial conditions.

    “The assays of the biospecimens were conducted blind to the conditions of the trial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The DunedinPACE DNAm algorithm was derived from elastic net regression of the physiological pace-of-aging composite on Illumina EPIC array DNAm data derived from blood samples collected at the age 45 follow-up assessment.

    “The DunedinPACE DNAm algorithm was derived from elastic net regression of the physiological pace-of-aging composite on Illumina EPIC array DNAm data derived from blood samples collected at the age 45 follow-up assessment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Belsky, D. W. et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 11, e73420 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No statistical methods were used to predetermine sample sizes.

    “No statistical methods were used to predetermine sample sizes”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisenone given

    The DNAm clocks analyzed were developed to predict mortality risk.

    “The clocks we analyzed were developed to predict mortality risk.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Normality of distribution of error terms was evaluated by visual inspection of histograms of residuals and the Shapiro-Wilk test.

    “Normality of distribution of error terms was evaluated by visual inspection of histograms of residuals and the Shapiro–Wilk test.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Equality of variances was evaluated according to tests proposed by Brown and Forsythe and Markowski and Markowski.

    “Equality of variances was evaluated according to the tests proposed by Brown and Forsythe68 and Markowski and Markowski69.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Brown, M. B. & Forsythe, A. B. Robust tests for the equality of variances. J. Am. Stat. Assoc. 69, 364–367 (1974). source
    • cites [69] Markowski, C. A. & Markowski, E. P. Conditions for the effectiveness of a preliminary test of variance. Am. Stat. 44, 322–326 (1990). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Normality of outcome variables was evaluated by visual inspection of distributions and the Shapiro-Wilk test.

    “Normality of outcome variables was evaluated by visual inspection of distributions and the Shapiro–Wilk test67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Shapiro, S. S. & Wilk, M. B. An analysis of variance test for normality (complete samples). Biometrika 52, 591–611 (1965). source

  • It may state two separate claims as one.

    Premisecitation

    Second-generation DNAm clocks are more predictive of morbidity and mortality than first-generation clocks and are proposed to have improved potential for testing impacts of interventions to slow aging.

    “The second-generation clocks are more predictive of morbidity and mortality as compared with the first-generation clocks59 and are proposed to have improved potential for testing impacts of interventions to slow aging14.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Levine, M. E. Assessment of epigenetic clocks as biomarkers of aging in basic and population research. J. Gerontol. A 75, 463–465 (2020). source
    • cites [14] Fahy, G. M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18, e13028 (2019). source

  • It may state two separate claims as one.

    Premisecitation

    Under conditions of nonadherence, traditional ITT analysis can result in a biased estimate of the treatment effect and an IV estimator can provide a complement.

    “Under conditions of nonadherence, traditional ITT analysis can result in a biased estimate of the treatment effect and an IV estimator can provide a complement66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Bang, H. & Davis, C. E. On estimating treatment effects under non-compliance in randomized clinical trials: are intent-to-treat or instrumental variables analyses perfect solutions? Stat. Med. 26, 954–964 (2007). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    First-generation DNAm clocks were developed from machine-learning analyses comparing samples from individuals of different chronological age.

    “The first-generation DNAm clocks were developed from machine-learning analyses comparing samples from individuals of different chronological age.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Models used to test ITT and TOT effects were fitted with heteroskedasticity-robust standard errors.

    “Models used to test ITT and TOT effects were fitted with heteroskedasticity-robust standard errors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Sensitivity analysis re-estimating IV regression models omitting the final instrument did not change results.

    “Sensitivity analysis involving re-estimating the IV regression models omitting this final instrument did not change results.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The instrumental variable analysis assumes that randomization condition affects biological aging only through the CR dose (exclusion restriction) and that the instrument is valid.

  • Probably not a substantial claim.

    Study design and conductown data

    Data met model assumptions.

    “Data met model assumptions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisereasoning

    Test-retest reliability is a critical feature of measurements used to evaluate intervention impact because change from preintervention to postintervention cannot be distinguished from technical noise unless reliability is high.

    “Test–retest reliability is a critical feature of measurements used to evaluate the impact of intervention because change from preintervention to postintervention cannot be distinguished from technical noise unless reliability is high.”
    Quote in the paperSubstantial claim
57 of 57

  • The authors state this as an assumption.

    The CALERIE intervention affected participants’ biological aging only through its effect on their caloric intake.

    “IV analysis assumes that CALERIE intervention affected participants’ biological aging only through its effect on their caloric intake.”

  • The paper relies on this without support.

    The instrumental variable analysis assumes that randomization condition affects biological aging only through the CR dose (exclusion restriction) and that the instrument is valid.

    “In TOT analysis, we tested the effect of the CR intervention on aging measure change scores using IV regression implemented using a two-stage least squares approach64.”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Incorrect percentage for higher-BMI AL participants

    Minor

    The AL group had 75 participants. Its 38 participants in the 25.0-27.9 BMI stratum represent 50.7%, not 55%.

    Reported 55 · recomputed 50.666667

  • Incorrect percentage for lower-BMI AL participants

    Minor

    The AL group had 75 participants. Its 37 participants in the 22.0-24.9 BMI stratum represent 49.3%, not 54%.

    Reported 54 · recomputed 49.333333

  • GrimAge development sample differs between Table 2 and Methods

    Minor

    Table 2 describes the GrimAge analysis as involving 2,356 participants from the Offspring Cohort, whereas Methods describes 2,751 participants from the Offspring and Gen3 Cohorts.

  • Follow-up counts exceed the stated analysis sample

    Minor

    Using the stated all-three-timepoint counts as the overlap, the follow-up counts imply 137 distinct CR participants (125 + 117 − 105) and 75 distinct AL participants (66 + 68 − 59). The stated analysis sample contains only 128 CR and 69 AL participants.

4 of 4

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Metadata

Authors
Waziry, R., Ryan, C. P., Corcoran, D. L., Huffman, K. M., Kobor, M. S., Kothari, M., Graf, G. H., Kraus, V. B., Kraus, W. E., Lin, D. T. S., Pieper, C. F., Ramaker, M. E., Bhapkar, M., Das, S. K., Ferrucci, L., Hastings, W. J., Kebbe, M., Parker, D. C., Racette, S. B., Shalev, I., Schilling, B., & Belsky, D. W.
Affiliations
  • Columbia University (US)
  • University of North Carolina at Chapel Hill (US)
  • Duke University (US)
  • University of British Columbia (CA)
  • Tufts University (US)
  • National Institute on Aging (US)
  • Pennsylvania State University (US)
  • Pennington Biomedical Research Center (US)
  • Washington University in St. Louis (US)
  • Buck Institute for Research on Aging (US)
Corresponding author
Belsky, D. W.
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2023-02-09
Volume
3
Issue
3
Pages
248-257
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-022-00357-y
PMC
PMC10148951
OpenAlex
W4319946457
Semantic Scholar
a8afddeb0e959136e8cea575f88d34d758a07d8b
Cited by
217
References
88
Citations by year
2026: 55 · 2025: 62 · 2024: 62 · 2023: 31
FWCI
16.54
Type
journal article
Language
en
Update notices
correction (2023-05-09)
Open access
Licence
Locations
  • Nature Aging (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • American Brain Foundation
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R33AG070455, P30AG028716, R01AG054840, R01AG071717, R03AG071549, U01AG060906, R01AG061378)
  • Gouvernement du Canada | Canadian Institutes of Health Research (RN439810)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
Keywords
caloric restriction, biological aging, DNA methylation, epigenetic clocks, pace of aging, DunedinPACE, GrimAge clock, healthspan
MeSH terms
Adult, Aging, Energy Intake, Humans, Longevity, DNA Methylation, Caloric Restriction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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