The role of genetics and epigenetics in sex differences in human survival

Sex differences in human survival have been extensively investigated in many studies that have in part uncovered the biological determinants that promote a longer life in females with respect to males. Moreover, researches performed in the past years have prompted increased awareness about the biological effects of environmental factors that can modulate the magnitude of the sex gap in survival. Besides the genetic background, epigenetic modifications like DNA methylation, that can modulate cell function, have been particularly studied in this framework. In this review, we aim to summarize the role of the genetic and epigenetic mechanisms in promoting female advantage from the early in life ("INNATE" features), and in influencing the magnitude of the gap in sex differences in survival and ageing ("VARIABLE" features). After briefly discussing the biological bases of sex determination in humans, we will provide much evidence showing that (i) "innate" mechanisms common to all males and to all females (both genetic and epigenetic) play a major role in sex differences in lifespan; (ii) "variable" genetic and epigenetic patterns, that vary according to context, populations and exposures to different environments, can affect the magnitude of the gap in sex differences in survival. Then we will describe recent findings in the use of epigenetic clocks to uncover sex differences in biological age and thus potentially in mortality. In conclusion, we will discuss how environmental factors cannot be kept apart from the biological factors providing evidence from the field of human ecology.