Emerging evidence demonstrates association of depression with both immune malfunctioning and worsened course of diverse aging-related diseases, but there is no explanation for the pathway(s) controlling this dual association. Here, we report that in post-reproductive and evolutionarily “blind” years, depression may weaken pathogen–host defense, compatible with the antagonistic pleiotropy hypothesis. In 15,532 healthy volunteers, depression scores associated with both inflammatory parameters and with increased circulation cholinesterase activities, implicating debilitated cholinergic blockade of inflammation as an underlying mechanism; furthermore, depression, inflammation and cholinesterase activities all increased with aging. In the entire cohort, combined increases in inflammation and the diabetic biomarker hemoglobin A1c associated with elevated depression. Moreover, metabolic syndrome patients with higher risk of diabetes showed increased cholinesterase levels and pulse values, and diabetic patients presented simultaneous increases in depression, inflammation and circulation cholinesterase activities, suggesting that cholinergic impairment precedes depression. Our findings indicate that dysfunctioning cholinergic regulation weakens the otherwise protective link between depression and pathogen–host defense, with global implications for aging-related diseases.