Associations Between Antiprotozoal Treatments and Reduced Mortality Across Populations Suggest That Protozoal Colonization May Contribute Significantly to Human Mortality and Age-Related Morbidity

We conducted a stepwise pharmacoepidemiologic investigation, an unbiased medication-wide screen followed by matched cohort validation and external replication, to identify medications associated with longevity and aging-related morbidity. The initial screen, performed in a large national health system, identified two antiprotozoals, atovaquone-proguanil and mefloquine, as being associated with increased survival. Matched exposed-unexposed cohorts were then constructed to validate mortality associations and examine incident outcomes, revealing reduced risks for diabetes, dementia, cardiovascular, renal, hepatic, pulmonary, and selected cancers, alongside increased risks for hearing loss, dry eye/Sjogrens, and lichen planus. These patterns were externally replicated in the US TriNetX network, where similar associations were observed for atovaquone-proguanil, mefloquine, and nirmatrelvir-ritonavir. Because nirmatrelvir-ritonavir is prescribed to older, multimorbid individuals, its associations are unlikely to reflect healthy-traveler conditioning. The concordant protective and tissue-specific adverse associations across datasets and antiprotozoal drug classes support a testable hypothesis: short antiprotozoal courses may reduce aging-related morbidity by decreasing persistent protozoal burden, particularly Toxoplasma gondii.