Sex-chromosome-dependent aging in female heterogametic methylomes

Recent research in humans and both model and non-model animals has shown that DNA methylation (DNAm), an epigenetic modification, is one of the mechanisms underlying the aging process. DNAm-based indices predict mortality and provide valuable insights into biological aging mechanisms. Although sex-dependent differences in lifespan are ubiquitous and sex chromosomes are thought to play an important role in sex-specific aging, they have been largely ignored in epigenetic aging studies. We characterized the genome-wide distribution of age-related CpG sites from longitudinal samples in two avian species (zebra finch and jackdaw), including for the first time the avian sex chromosomes (Z and the female-specific, haploid W). In both species, we find a small fraction of the CpG sites to show age-related changes in DNAm with the majority of them being located on the haploid, female-specific W chromosome where DNAm levels predominantly decrease with age. Age-related CpG sites were overrepresented on the zebra finch but underrepresented on the jackdaw Z chromosome. Our results highlight distinct age-related changes in sex chromosome DNAm compared to the rest of the genome in two avian species, suggesting this previously understudied feature of sex chromosomes may be instrumental in sex-dependent aging. Moreover, studying the DNAm of sex chromosomes might be particularly useful in aging research, facilitating the identification of shared (sex-dependent) age-related pathways and processes between phylogenetically diverse organisms.