Epigenetic Clocks (DunedinPACE, Horvath, GrimAge) - References

Epigenetic Clocks (DunedinPACE, Horvath, GrimAge) — Literature Dossier

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Landmark Peer-Reviewed Studies

1. Belsky et al. (2022) — DunedinPACE: A DNA Methylation Biomarker of the Pace of Aging

• Citation: Belsky, D. W., Caspi, A., Corcoran, D. L., Sugden, K., Poulton, R., Arseneault, L., … & Moffitt, T. E. (2022). DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife, 11, e73420.
• Identifiers: DOI: 10.7554/eLife.73420 (DOI · SciDB · Scholar) | PMID: 35133256 (PubMed · Europe PMC) | PMCID: PMC8853656 (PMC Full Text)
• Study Design & Cohort: Trained on 20-year longitudinal changes in 19 organ-system biomarkers across 4 waves (ages 26, 32, 38, 45) in the Dunedin Study ($N=1,037$), restricted to high technical-reliability probes, and validated in Framingham Offspring, Normative Aging Study, Understanding Society, and E-Risk cohorts ($N>5,000$).
• Quantitative Findings & Diagnostic Thresholds:
  • Technical test-retest reliability $\text{ICC}=0.87–0.96$ across technical replicates.
  • Each 1-SD faster DunedinPACE (~$0.10–0.11\text{ biological years/chronological year}$) was associated with a 65% higher hazard of all-cause mortality ($\text{HR }1.65$, $95\%\text{ CI }1.51–1.81$, $p<0.001$) in Framingham and a 54% higher hazard of incident chronic disease ($\text{HR }1.54$, $95\%\text{ CI }1.19–1.99$) in the Normative Aging Study.

2. Lu et al. (2019) — DNA Methylation GrimAge Strongly Predicts Lifespan and Healthspan

• Citation: Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., … & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY), 11(2), 303–327.
• Identifiers: DOI: 10.18632/aging.101684 (DOI · SciDB · Scholar) | PMID: 30669119 (PubMed · Europe PMC) | PMCID: PMC6366976 (PMC Full Text)
• Study Design & Cohort: Trained in the Framingham Heart Study Offspring cohort ($N=2,356$) and validated across 5 independent large multi-ethnic epidemiological cohorts (WHI, JHS, InChianti, LBC; $N=7,375$).
• Quantitative Findings & Diagnostic Thresholds:
  • AgeAccelGrim outperformed all prior epigenetic clocks for predicting time-to-death (Cox $p=2.0\times 10^{-75}$, $\text{HR }1.10$ per year of GrimAge acceleration, or $\text{HR }\approx 1.45$ per 1-SD), time-to-coronary heart disease ($p=6.2\times 10^{-24}$), and time-to-cancer ($p=1.3\times 10^{-12}$).
  • Among individual sub-components, DNAm PAI-1 strongly predicted visceral fat, fatty liver, hypertension, and type 2 diabetes ($p<10^{-30}$).

3. Waziry et al. (2023) — Effect of Long-Term Caloric Restriction on DNA Methylation Measures of Biological Aging (CALERIE RCT)

• Citation: Waziry, R., Ryan, C. P., Corcoran, D. L., Huffman, K. M., Kobor, M. S., Kothari, M., … & Belsky, D. W. (2023). Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging, 3(3), 248–257.
• Identifiers: DOI: 10.1038/s43587-022-00357-y (DOI · SciDB · Scholar) | PMID: 37118425 (PubMed · Europe PMC) | PMCID: PMC10148951 (PMC Full Text)
• Study Design & Cohort: Phase 2 multicenter randomized controlled trial ($N=220$ healthy non-obese adults randomized $2:1$ to 25% caloric restriction vs. ad libitum diet for 24 months).
• Quantitative Findings & Diagnostic Thresholds:
  • Caloric restriction significantly slowed the pace of aging measured by DunedinPACE by $-0.029\text{ units}$ ($95\%\text{ CI }-0.045\text{ to }-0.013$, $p=0.0003$; a 2–3% slowing of aging pace), whereas static 1st- and 2nd-generation clocks (PhenoAge, GrimAge) showed smaller sensitivity over a 24-month window.

4. Fahy et al. (2019) — Reversal of Epigenetic Aging and Immunosenescent Trends (TRIIM Trial)

• Citation: Fahy, G. M., Brooke, R. T., Watson, J. P., Good, Z., Vasanawala, S. S., Maecker, H., … & Horvath, S. (2019). Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell, 18(6), e13028.
• Identifiers: DOI: 10.1111/acel.13028 (DOI · SciDB · Scholar) | PMID: 31496122 (PubMed · Europe PMC) | PMCID: PMC6826138 (PMC Full Text)
• Study Design & Cohort: 12-month prospective clinical trial ($N=9$ healthy men aged 51–65) treated with recombinant human growth hormone (rhGH), DHEA, and Metformin (plus Vitamin D3 and Zinc).
• Quantitative Findings & Diagnostic Thresholds:
  • Replaced thymic fat with functional thymic tissue on MRI ($p=0.007$), increased naive CD4+/CD8+ T cells, and produced a mean epigenetic age reversal of $-1.5\text{ years}$ ($p=0.0018$) across four epigenetic clocks (reaching $-2.5\text{ years}$ relative to elapsed chronological time, with GrimAge reversing by $-2.16\text{ years}$, $p=0.0003$).