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Cited by 211Epigenetics and DNA MethylationGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality

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Faul, Jessica D., Kim, Jung Ki, Levine, Morgan E., Thyagarajan, Bharat, Weir, David R., Crimmins, Eileen M.·2023·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2215840120PMC PMC9992763
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Abstract

Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using “second and third generation clocks,” PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.

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  • Compared to chronological age, epigenetic clocks provide more sensitive measures of how stressors influence biological aging and health.

    “Compared to chronological age, epigenetic clocks provide more sensitive measures of how stressors influence biological aging and health (Faul et al., 2023).”

    From Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States (2026) · cites this paper as Faul et al., 2023

    The Abstract says DNA-methylation biomarkers are thought to be influenced by external exposures and reports associations between epigenetic age acceleration and health outcomes in older US adults. The Methods describe age acceleration as a measure with the effect of chronological age removed. Neither section establishes that epigenetic clocks are more sensitive than chronological age to the effects of stressors. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Epigenetic age deceleration and a lower pace of aging are associated with better health and a lower risk of chronic conditions, infection, cognitive decline, and all-cause mortality.

    “Conversely, epigenetic age deceleration and a lower pace of aging are associated with better health and a lower risk of the aforementioned conditions (Faul et al., 2023).”

    From Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States (2026) · cites this paper as Faul et al., 2023

    The Results and Discussion (page numbers unavailable) associate faster epigenetic aging, including a faster DunedinPACE measure, with multimorbidity and mortality; this supports the converse association for slower aging. The paper reports cognitive dysfunction measured at the same time as DNA methylation, not subsequent cognitive decline, and the passages do not establish an association with infection risk. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Higher epigenetic age acceleration and pace of aging are associated with chronic conditions, increased infection risk, cognitive decline, and general all-cause mortality.

    “Higher EAA and pace of aging are associated with chronic conditions, increased infection risk, cognitive decline, and general all-cause mortality.”

    From Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States (2026) · cites this paper as Faul et al., 2023

    The Results (page not provided) associate epigenetic age acceleration and DunedinPACE with multimorbidity, concurrent cognitive dysfunction, and four-year mortality. They do not establish cognitive decline over time: the paper says cognition could only be analyzed cross-sectionally. Our copy also does not report an association with infection risk (searched: infection, infection risk). (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Stress can alter the epigenomic landscape of cells, a dynamic map of gene expression in response to external factors.

    “Stress can alter the epigenomic landscape of cells—a dynamic map of how genes are expressed (activated or suppressed) in response to external factors (Faul et al., 2023).”

    From Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States (2026) · cites this paper as Faul et al., 2023

    The opening text following the Abstract says DNA methylation is thought to be influenced by external exposures and to modify gene expression. It does not specifically identify stress as an exposure or define the epigenomic landscape as a dynamic map of gene expression; the Discussion also notes that DNA methylation is only one measure of epigenetic modification. No page number is available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Chronic conditions were excluded from primary models because they are often endogenous with epigenetic aging, but included in sensitivity analyses.

    “Because chronic conditions are often endogenous with epigenetic aging, they were excluded from primary models, but included in sensitivity analyses (Faul et al., 2023).”

    From Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States (2026) · cites this paper as Faul et al., 2023

    The Analytic Approach lists the primary model adjustments without chronic conditions, which supports their exclusion as covariates. It does not say they were excluded because of endogeneity or included in sensitivity analyses; the additional models instead adjust for blood-based biomarkers. The Chronic disease assessment section treats chronic conditions as components of the multimorbidity outcome. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 32

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Authors
Faul, J. D., Kim, J. K., Levine, M. E., Thyagarajan, B., Weir, D. R., & Crimmins, E. M.
Affiliations
  • University of Michigan (US)
  • University of Southern California (US)
  • Yale University (US)
  • University of Minnesota (US)
Corresponding author
Crimmins, Eileen M.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2023-02-21
Volume
120
Issue
9
Pages
e2215840120-e2215840120
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2215840120
PMC
PMC9992763
OpenAlex
W4321440558
Cited by
211
References
5
Citations by year
2026: 53 · 2025: 78 · 2024: 58 · 2023: 22
FWCI
18.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
HHS | NIH | National Institute on Aging (R01 AG AG060110, U01 AG009740)
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 › Telomeres, Telomerase, and Senescence
Keywords
epigenetic aging, DNA methylation, accelerated aging, biological age, mortality prediction, cognitive impairment, functional limitations, chronic disease, socioeconomic status, health behavior, PhenoAge, GrimAge, DunedinPACE, older adults, health outcome prediction
MeSH terms
Acceleration, Aged, Aging, Cross-Sectional Studies, Humans, Biomarkers, DNA Methylation, Epigenesis, Genetic

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