Male Monocyte-Like Cells are Prone to a Senescence-Induced Pro-inflammatory State

Chronic systemic inflammation in the elderly is a hallmark of aging and a major contributor to age-related diseases. It both results from and promotes the accumulation of senescent immune cells. While the sex difference in the aging process has been widely studied, the impact of cellular sex on immune cell senescence remains unclear and was the focus of this present study. Senescence was induced in human male (THP-1) and female (HL-60) monocyte-like cells by treatment with D-galactose for 48 h. The expression of metabolic sensors (Sirt1 and pAMPK), mitochondrial biogenesis and respiration, reactive oxygen species formation, as well as pro-inflammatory markers was investigated alongside senescence markers. Treatment with D-galactose resulted in significant reduction of the nuclear proteins HMGB1 and lamin B1, and an upregulation of senescence-associated secretory phenotype factors including IL-6, VEGF, TGF-β, and MMP-9, in male and female cells. The expression of the metabolic sensors Sirt1 and pAMPK was reduced, whereas mitochondrial ROS production and mitochondrial gene expression were elevated in both male and female cells to a similar extent. In contrast, D-Galactose-induced senescence was accompanied by a significant elevation of pro-inflammatory markers (NF-κB, TNF-α, IL-1β, HLA-DR, and MCP-1) primarily in male monocytes, whereas primary monocytes did not display sex differences. This study suggests that male immune cells are more prone to developing a pro-inflammatory state under senescent stimuli. These findings highlight the potential significance of sex-specific anti-inflammatory therapies.