Summary Sex and gender differences in aging and other health outcomes are frequently severely confounded by behavioral and environmental factors, mandating the use of animal models. Epigenetic age estimators provide a powerful tool in determining the epigenetic age alleviating the necessity of monitoring cohorts of animals throughout their lives in captivity or in the wild. The present study, by using outbred deer mice (Peromyscus) will explore how genetic relatedness of parents, history of social interactions, and CDK8/19 inhibition impact epigenetic age. The study relies on preliminary data indicating differences in the rate of epigenetic aging between males and females upon these interventions. Mechanistically, to link genetic relatedness with aging we will focus on the induction of endoplasmic reticulum (ER) stress, that reportedly differs between men and women. For our studies both monogamous and polygamous Peromyscus will be used. Specifically, we will (a). test if ER stress in females is more dependent on overall heterozygosity status than in males. Peromyscus male and female offspring of parents that differ in their genetic relatedness, as well as fibroblasts cultured in vitro, will be evaluated for ER stress and the resulting UPR, by analyzing the levels of a roster of chaperones that reflect ER stress. For our analysis we will utilize animals from all different stocks of Peromyscus as well as F1 hybrids between different stocks and species. (b). we will explore how the biobehavioral environment impacts epigenetic age estimators. We propose to test how pair bonding, disruption and biparental care, impact comparatively epigenetic aging in males and females, both the offspring as well as their parents. (c). we will explore the impact of CDK8/19 inhibition in epigenetic aging. Pharmacological interventions aiming to alleviate aging, besides providing avenues for the development of anti-aging therapies they also point to disparities impacting differentially the different sexes. Preliminary findings in mice indicate that inhibition of cyclin dependent kinases (CDK) 8/19, which regulate signal-induced transcription represents an avenue that may hold significant anti-aging value, preferentially towards females. Here we propose to explore if CDK8/19 inhibition decreases the epigenetic age, and alleviates telomere attrition and mitochondrial abundance of outbred deer mice. The proposed study constitutes a first effort to describe sex-based disparities in epigenetic aging in relation socioenvironmental factors and choices that impact the women’s social environment in the context of pair bonding and parents’ genetic relatedness. A. pharmacological intervention that prevents agent preferably in women will also be evaluated.

Narrative Epigenetic age estimators provide a powerful tool in determining epigenetic age, alleviating the necessity of monitoring cohorts of animals throughout their lives in captivity or in the wild. Sex and gender differences in aging and other health outcomes are frequently severely confounded by behavioral and environmental factors, mandating the use of animal models. The present study, by using outbred deer mice (Peromyscus) will explore how genetic relatedness of parents, history of social interactions, and CDK8/19 inhibition impact epigenetic age.