Sex differences in epigenetic age in Mediterranean high longevity regions

Abstract

Sex differences in aging manifest in disparities in disease prevalence, physical health, and lifespan, where women tend to have greater longevity relative to men. However, in the Mediterranean Blue Zones of Sardinia (Italy) and Ikaria (Greece) are regions of centenarian abundance, male-female centenarian ratios are approximately one, diverging from the typical trend and making these useful regions in which to study sex differences of the oldest old. Additionally, these regions can be investigated as examples of healthy aging relative to other populations. DNA methylation (DNAm)-based predictors have been developed to assess various health biomarkers, including biological age, Pace of Aging, serum interleukin-6 (IL-6), and telomere length. Epigenetic clocks are biological age predictors whose deviation from chronological age has been indicative of relative health differences between individuals, making these useful tools for interrogating these differences in aging. We assessed sex differences between the Horvath, Hannum, GrimAge, PhenoAge, Skin and Blood, and Pace of Aging predictors from individuals in two Mediterranean Blue Zones and found that men displayed positive epigenetic age acceleration (EAA) compared to women according to all clocks, with significantly greater rates according to GrimAge (β = 3.55; p = 1.22 × 10−12), Horvath (β = 1.07; p = 0.00378) and the Pace of Aging (β = 0.0344; p = 1.77 × 10−08). Other DNAm-based biomarkers findings indicated that men had lower DNAm-predicted serum IL-6 scores (β = -0.00301, p = 2.84 × 10−12), while women displayed higher DNAm-predicted proportions of regulatory T cells than men from the Blue Zone (p = 0.0150, 95% Confidence Interval [0.00131, 0.0117], Cohen’s d = 0.517). All clocks showed better correlations with chronological age in women from the Blue Zones than men, but all clocks showed large mean absolute errors (MAE >30 years) in both sexes, except for PhenoAge (MAE <5 years). Thus, despite their equal survival to older ages in these Mediterranean Blue Zones, men in these regions remain biologically older by most measured DNAm-derived metrics than women, with the exception of the IL-6 score and proportion of regulatory T cells.

Differing effects of alcohol use on epigenetic and brain age in adult children of alcoholic parents

“…Contrary to previous work showing men have higher epigenetic aging rates than women (Engelbrecht et al, 2022, Kankaanpää et al, 2022, Horvath et al, 2016, we found no significant effect of sex on epigenetic aging. However, this is likely due to the restricted age group used in this study, as all participants were currently attending college.…”

“…This finding is consistent with previous studies showing that increased alcohol consumption is associated with an increased epigenetic age estimation (Luo et al, 2020, Mills et al, 2019, Rosen et al, 2018); however, a family history of alcohol consumption is not. Contrary to previous work showing men have higher epigenetic aging rates than women (Engelbrecht et al, 2022, Kankaanpää et al, 2022, Horvath et al, 2016), we found no significant effect of sex on epigenetic aging. However, this is likely due to the restricted age group used in this study, as all participants were currently attending college.…”

Longitudinal progression of choroid plexus enlargement is associated with female sex, cognitive decline and ApoE E4 homozygote status

“…Sex divergent CP structure changes have been described, e.g., in the case of calcifications ( 58 ). In terms of age and CP relationship, women were younger in terms of our sample, but they also tend to be younger in metabolic age ( 59 ), telomere length ( 60 ), and complex differences in metabolism including mitochondrial function ( 61 ). Thus, the negative longitudinal association between CP volume and age in men could be a sign of a ceiling effect: lack in CP increase after a certain volume threshold (which could possibly occur around 77.5–91.4 years of age for men, as is our last quartile).…”

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections

“…The present findings provide additional support for the contention that an epigenetic biomarker of prenatal exposure to phthalates may be evident in infants as young as three months of age [76], and indicates that epigenetic markers of biological aging, EAA, in young infants are sensitive to prenatal exposure to DEHP. This may be influenced by sex differences in aging, as men have been found to display positive EAA compared to women, across epigenetic clocks (e.g., Horvath pan-tissue, Horvath skin and blood, Hannum, GrimAge, PhenoAge, and Pace of Aging) [77,78]. Additional investigations examining associations between prenatal phthalate exposures, as well as other environmental chemicals (e.g., metals, air pollutants, pesticides), and epigenetic clocks in very young pediatric samples may provide novel insights into the early molecular programming of disease susceptibility and contribute to the continued evolution of the DOHaD paradigm [79].…”