Sex‐dimorphism in aging: are we missing half of the picture?

Abstract

Aging is accompanied by striking changes in chromatin and gene expression across cell types and species. Yet, how chromatin landscapes change with age and regulate transcription, and how epigenomic changes in turn influence aging in response to external or internal cues, is largely unknown. In addition, accumulating evidence indicates that sex hormones play a key role in driving aspects of cellular and molecular sex‐dimorphism. In parallel to sex hormones, karyotypic sex (i.e. XX vs. XY) is also likely to have important impact outside of gonadal sex determination. A key compartment whose activity can be actively modulated by sex‐dimorphic mechanisms throughout life is the immune system, whose function declines sharply with aging and may be actively modulated by sex. Indeed, aspects of the immune responses differ between sexes, with a more robust immune response in females and an increased susceptibility to infection in males. Thus, our main cell models of study are key components of the innate immune system and the inflammatory response: macrophages, which accomplish key tasks such as phagocytosis, antigen presentation and cytokine production, and neutrophils, the most abundant leukocyte type serving as a “first line of defense” against infection. Excitingly, we and others have observed strong sex‐related differences in the transcriptional and functional phenotypes of these cells and have observed sex‐dimorphic “omic” trajectories for these cells with aging. Based on our data and published literature, it is likely that mechanisms involving both gonadal hormones and sex chromosomes may fine‐tune different aspects of immunity and, thus, overall health and lifespan.