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Age-associated epigenetic change in chimpanzees and humans.

ABSTRACT: Methylation levels have been shown to change with age at sites across the human genome. Change at some of these sites is so consistent across individuals that it can be used as an 'epigenetic clock' to predict an individual's chronological age to within a few years. Here, we examined how the pattern of epigenetic ageing in chimpanzees compares with humans. We profiled genome-wide blood methylation levels by microarray for 113 samples from 83 chimpanzees aged 1-58 years (26 chimpanzees were sampled at multiple ages during their lifespan). Many sites (greater than 65 000) showed significant change in methylation with age and around one-third (32%) of these overlap with sites showing significant age-related change in humans. At over 80% of sites showing age-related change in both species, chimpanzees displayed a significantly faster rate of age-related change in methylation than humans. We also built a chimpanzee-specific epigenetic clock that predicted age in our test dataset with a median absolute deviation from known age of only 2.4 years. However, our chimpanzee clock showed little overlap with previously constructed human clocks. Methylation at CpGs comprising our chimpanzee clock showed moderate heritability. Although the use of a human microarray for profiling chimpanzees biases our results towards regions with shared genomic sequence between the species, nevertheless, our results indicate that there is considerable conservation in epigenetic ageing between chimpanzees and humans, but also substantial divergence in both rate and genomic distribution of ageing-associated sites. This article is part of the theme issue 'Evolution of the primate ageing process'.

SUBMITTER: Guevara EE

PROVIDER: S-EPMC7540949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe trajectory of frailty in older adults is important to public health; therefore, markers that may help predict this and other important outcomes could be beneficial. Epigenetic clocks have been developed and are associated with various health-related outcomes and sociodemographic factors, but associations with frailty are poorly described. Further, it is uncertain whether newer generations of epigenetic clocks, trained on variables other than chronological age, would be more strongly associated with frailty than earlier developed clocks. Using data from the Canadian Longitudinal Study on Aging (CLSA), we tested the hypothesis that clocks trained on phenotypic markers of health or mortality (i.e., Dunedin PoAm, GrimAge, PhenoAge and Zhang in Nat Commun 8:14617, 2017) would best predict changes in a 76-item frailty index (FI) over a 3-year interval, as compared to clocks trained on chronological age (i.e., Hannum in Mol Cell 49:359-367, 2013, Horvath in Genome Biol 14:R115, 2013, Lin in Aging 8:394-401, 2016, and Yang Genome Biol 17:205, 2016).ResultsWe show that in 1446 participants, phenotype/mortality-trained clocks outperformed age-trained clocks with regard to the association with baseline frailty (mean = 0.141, SD = 0.075), the greatest of which is GrimAge, where a 1-SD increase in ΔGrimAge (i.e., the difference from chronological age) was associated with a 0.020 increase in frailty (95% CI 0.016, 0.024), or ~ 27% relative to the SD in frailty. Only GrimAge and Hannum (Mol Cell 49:359-367, 2013) were significantly associated with change in frailty over time, where a 1-SD increase in ΔGrimAge and ΔHannum 2013 was associated with a 0.0030 (95% CI 0.0007, 0.0050) and 0.0028 (95% CI 0.0007, 0.0050) increase over 3 years, respectively, or ~ 7% relative to the SD in frailty change.ConclusionBoth prevalence and change in frailty are associated with increased epigenetic age. However, not all clocks are equally sensitive to these outcomes and depend on their underlying relationship with chronological age, healthspan and lifespan. Certain clocks were significantly associated with relatively short-term changes in frailty, thereby supporting their utility in initiatives and interventions to promote healthy aging.

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Age-associated epigenetic change in chimpanzees and humans.

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