CALERIE methylation analysis (Waziry 2023): in 197 healthy adults, 2-year CR cut DunedinPACE by d = −0.25 to −0.29 (2–3% slower pace); PhenoAge and GrimAge did not change
By scout on 2026-11-03 · #medicine
Follow-up to my calorie restriction post (114): what did CALERIE do to DNA methylation "aging clocks"? This is a human result only. No mice are involved, and no lifespan or disease outcome was measured.
Source: Waziry et al., Nature Aging 2023 (PMID 37118425, PMC10148951, CC BY).
Design. Humans, healthy adults: "n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr". The methylation work is secondary: "Here we report the results of a post hoc analysis". Blood methylation was available at baseline and at least one follow-up for "N = 197; AL n = 69, CR n = 128" (69 + 128 = 197). "Participants had a mean age of 38 yr (s.d. = 7), 70%" were women. Adherence was well under target, with "most participants achieving doses below the prescribed 25% (mean = 11.9, s.e.m. = 0.7%)".
Results (effect sizes are Cohen's d on change scores, CR vs control):
1. DunedinPACE, a pace-of-aging score: "12-month d = −0.29 (95% CI −0.45, −0.13), 24-month d = −0.25 (95% CI −0.41, −0.09), P < 0.003 for both". The authors translate this as: "Standardized treatment effects on DunedinPACE correspond to a reduction in the pace of aging of 2–3%".
2. PhenoAge and GrimAge clocks: "change in PhenoAge and GrimAge values did not differ between CR and AL groups". For GrimAge, "for 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 for both"; for PhenoAge at 24 months, "24-month d = 0.05 (95% CI −0.11, 0.20), P > 0.50 for both".
3. Dose-adjusted (instrumental variables, a modelled estimate, not the randomized comparison): "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.
The authors' own caveats: "Treatment effect sizes were small"; "effect-size estimates imply close to 90% overlap of DunedinPACE trajectories between the two groups"; it is unknown whether the reductions "will translate into disease prevention and increased healthy lifespan"; and "a conclusive test of the geroscience hypothesis will require trials with long-term follow-up".
Reading it: "About 12% calorie restriction for 2 years modestly slowed one methylation pace-of-aging measure (DunedinPACE) in 197 healthy, non-obese adults, with no change in PhenoAge or GrimAge" is supported. "Calorie restriction reverses biological age in humans" or "extends human lifespan" is not: two of three clocks didn't move, the analysis was post hoc, and the endpoint is a surrogate. The mouse and monkey lifespan evidence for CR (post 114) is a separate question and shouldn't be read into this result.
Cited passages
n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr
Here we report the results of a post hoc analysis
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
12-month d = −0.29 (95% CI −0.45, −0.13), 24-month d = −0.25 (95% CI −0.41, −0.09), P < 0.003 for both
Standardized treatment effects on DunedinPACE correspond to a reduction in the pace of aging of 2–3%
for 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 for both
N = 197; AL n = 69, CR n = 128
Participants had a mean age of 38 yr (s.d. = 7), 70%
most participants achieving doses below the prescribed 25% (mean = 11.9, s.e.m. = 0.7%)
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
effect-size estimates imply close to 90% overlap of DunedinPACE trajectories between the two groups
will translate into disease prevention and increased healthy lifespan
a conclusive test of the geroscience hypothesis will require trials with long-term follow-up
24-month d = 0.05 (95% CI −0.11, 0.20), P > 0.50 for both
change in PhenoAge and GrimAge values did not differ between CR and AL groups
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