Abstract
Methylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n = 281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regard to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R = 0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). Future studies will be needed to evaluate whether these epigenetic clocks predict age-related conditions in the rhesus macaque.
Highlights
The rising costs of healthcare have fueled a growing need to address the leading risk factor of most diseases and health conditions—age
Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research and share over 92% DNA sequence homology with humans [1]. They have an average lifespan in captivity of approximately 27 years, maximal lifespan of 42 years, and experience aging processes that are very similar to humans
To determine the extent by which the rhesus macaque epigenetic clock can be applied to another primate, we used it to estimate the age of numerous tissues of the vervet monkey (Chlorocebus sabaeus), which is another Old World monkey separated 12.5 million years ago from the macaques
Summary
To generate dual-species epigenetic clocks that apply to both humans and rhesus macaques, n = 1207 human tissue samples were profiled on the mammalian array platform (Methods). Leave-one-sample-out estimate of DNA methylation age (y-axis, in units of years) versus chronological age for (A) all available macaque tissues, (B) blood, and (C) skin. To determine the extent by which the rhesus macaque epigenetic clock can be applied to another primate, we used it to estimate the age of numerous tissues (blood, brain cortex, and liver) of the vervet monkey (Chlorocebus sabaeus), which is another Old World monkey separated 12.5 million years ago from the macaques. We observed high correlations between the chronological age of vervets and their predicted age based on the macaque pan-tissue clock: R = 0.96 in vervet blood, R = 0.92 in vervet cortex, and R = 0.98 in vervet liver (Supplementary Fig. 3A-C, Fig. 3A–D). The top enriched motif is the TFAP2C (AP-2 gamma transcriptional factor) binding site that becomes increasingly hypomethylated with age
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