Antiprotozoal medications associated with increased longevity and reduced morbidity in two national cohorts.

We conducted a stepwise pharmacoepidemiologic investigation to identify medications associated with longevity and aging-related morbidity. An exploratory medication-wide screen in a large national health system identified two antiprotozoals, atovaquone-proguanil and mefloquine, that were associated with increased survival. Matched exposed-unexposed cohorts were then constructed to validate mortality associations and examine incident outcomes, showing reduced risks for diabetes, dementia, cardiovascular, renal, hepatic, pulmonary, and selected cancers, alongside increased risks for hearing loss, dry eye/Sjögren's, and lichen planus. These findings were externally validated in the US TriNetX network, where the same patterns were observed for atovaquone-proguanil, mefloquine, and nirmatrelvir-ritonavir. Because nirmatrelvir-ritonavir is prescribed to older, multimorbid individuals with COVID-19, its associations are unlikely to reflect healthy traveler bias. The concordant protective and tissue-specific adverse associations across datasets and antiprotozoal drug classes support a testable mechanistic hypothesis: short antiprotozoal courses may mitigate aging-related morbidity, plausibly by reducing protozoal burden, such as Toxoplasma gondii .