Men do not live as long as women. This is a consistent effect across populations and eras, and there are any number of theories as to why this is the case. This might lead us to expect measurable aspects of aging to be more pronounced in older males than in older females, and researchers here show that this is the case for the age-related dysfunction of the immune system. As we age, the immune system becomes both overactive and less capable, leading to chronic inflammation alongside decreased resistance to infection and cancer. This is an important contribution to age-related frailty, disease, and mortality.
Human peripheral blood mononuclear cells (PBMCs) undergo both cell-intrinsic and cell-compositional changes (i.e., cell frequencies) with age, where certain immune functions are impaired and others are remodeled1. Analyses of human blood samples uncovered significant aging-related changes in gene expression and DNA methylation levels. Recent studies revealed that chromatin accessibility of purified immune cells, especially CD8+ T cells, change significantly with aging, impacting the activity of important receptor molecules, signaling pathways, and transcription factors. Together, these changes likely contribute to aging-related immunodeficiency and ultimately to increased frequency of morbidity and mortality among older adults. However, it is unclear to what extent these aging-associated changes are shared between men and women.
Immune systems of men and women function and respond to infections and vaccination differently. For example, 80% of autoimmune diseases occur in women, who typically show stronger immune responses than males. Stronger responses in women produce faster pathogen clearance and better vaccine responsiveness, but also contribute to increased susceptibility to inflammatory and autoimmune diseases. Although not systematically described, these differences likely stem from differences in both cell frequencies and cell-intrinsic programs. For example, a study in young individuals showed that women have more B cells (percentage and absolute cell counts) in their blood than men. Moreover, hundreds of genes are differentially expressed between young men and young women in sorted B cells.
Despite the importance of sex and age in shaping immune cell functions and responses, it is not known whether men's and women's immune systems go through similar changes throughout their lifespan, and whether these changes occur at the same time and at the same rate. To study this, we profiled PBMCs of healthy adults by carefully matching the ages of male and female donors. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity.