Age-Associated Inflammatory Monocytes Are Increased in Menopausal Females and Reversed by Hormone Replacement Therapy.

Older females have increased inflammatory intermediate and non-classical monocytes compared to young females.

• Intermediate and non-classical monocyte subsets were identified as the most inflammatory ex vivo among the three human monocyte subsets.
• The frequency of these monocyte subsets correlated with markers of inflammageing.
• The age-associated increase in these subsets was observed in females but the study dissected the impact of both increasing age and biological sex on monocyte phenotype and function.

Proteomic analysis of sorted monocyte populations demonstrated that the three human monocyte subsets have largely distinct phenotypes.

• Proteomic analysis was performed on sorted classical, intermediate, and non-classical monocyte populations.
• Key age-associated protein pathways identified included the complement cascade and phagocytosis.
• The three monocyte subsets were found to have largely distinct proteomic profiles.

Circulating C3 concentrations were reduced with age in females but not males.

• The reduction in circulating C3 with age was sex-specific, occurring in females but not males.
• This finding was confirmed following the proteomic analysis which identified complement cascade as a key age-associated pathway.
• The decrease in complement in older females resulted in reduced monocyte phagocytosis.

Reduced complement (C3) in older females resulted in impaired monocyte phagocytosis.

• The age-associated decrease in circulating C3 concentrations in females was functionally linked to reduced monocyte phagocytosis.
• This finding connected the proteomic pathway analysis to a functional immune deficit in older females.
• Phagocytosis was identified as one of the key age-associated protein pathways in the proteomic analysis.

Hormone replacement therapy (HRT) reversed the expansion of intermediate monocytes and decreased circulating CRP in peri/menopausal females compared to age-matched controls.

• Peri/menopausal females on HRT were compared to age-matched controls not on HRT.
• HRT reversed the expansion in intermediate monocytes observed in menopausal females.
• HRT decreased circulating CRP concentrations in peri/menopausal females.
• These findings indicate the importance of menopause in driving aging monocyte phenotype changes.

Peri/menopausal females on HRT had increased C3 serum concentrations and significant improvement in monocyte phagocytosis.

• HRT was associated with increased C3 serum concentrations in peri/menopausal females.
• Monocyte phagocytosis showed significant improvement in peri/menopausal females receiving HRT.
• These findings suggest HRT may restore monocyte function and potentially improve anti-pathogen immunity in aging females.

Biological sex is a crucial variable in age-related susceptibility to infection, with menopause playing an important role in aging monocyte phenotype and function.

• The study aimed to dissect the impact of increasing age and biological sex on human monocyte phenotype and function.
• Changes in monocyte populations are associated with increased susceptibility to infection.
• Prior to this work, there was limited research on the impact of age and sex on human monocyte phenotype and function.
• The data highlight the potential use of HRT in restoring monocyte function in females during aging.