DNA methylation age analysis of rapamycin in common marmosets

Steve Horvath,Adam B Salmon,Julie A Mattison,Anna J Jasinska,Ken Raj,Amin Haghani,Joseph A Zoller,Ake T Lu

doi:10.1007/s11357-021-00438-7

Abstract

Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging (“epigenetic clocks”). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets (Callithrix jacchus) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here two epigenetic clocks for marmosets that are applicable to whole blood samples. We find that the human-marmoset clock for relative age exhibits moderately high age correlations in two other non-human primate species: vervet monkeys and rhesus macaques. In a separate cohort of marmosets, we tested whether intervention with rapamycin, a drug shown to extend lifespan in mice, would alter the epigenetic age of marmosets, as measured by the marmoset epigenetic clocks. These clocks did not detect significant effects of rapamycin on the epigenetic age of marmoset blood. The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). Overall, the epigenetic clocks developed here for the common marmoset are expected to be useful for age estimation of wild-born animals and for anti-aging studies in this species.

Highlights

Substantial progress in the basic biology of aging, including discovery of interventions that extend longevity, have come from studies of invertebrates and rodents
The blood samples came from 2 groups of animals: those that were used for developing an epigenetic clock and those that were from an interventional study, testing the effect of rapamycin
We found no significant effect on the DNAmAge in blood in multivariate linear regression model (Table 2), which suggests no effect of rapamycin in DNA methylation age in relatively healthy, middle‐aged marmosets

Summary

Introduction

Substantial progress in the basic biology of aging, including discovery of interventions that extend longevity, have come from studies of invertebrates and rodents. It remains challenging to translate this basic research to clinical application in relatively healthy and genetically varied groups of people. Rodents such as mice and rats are only distantly related to humans and have undergone different evolutionary pressures that may have driven species-specific idiosyncrasies of aging. Due to the long lifespans of humans, any outcomes of longevity interventions in human studies are likely to require very long follow-up at high cost. To overcome this hurdle, a case can be made for testing promising interventions in non-human primate (NHP) models. The long lifespans of rhesus monkeys required decades-long commitment to accomplish the goals of the calorie restriction study [3,4,5,6]

Methods

Results

Conclusion