{
  "abstract": "Introduction: Medications may affect age-related morbidity and overall survival beyond their original indications. Systematic identification of such effects may inform drug repurposing strategies for healthy aging. We aimed to identify medications associated with longevity and reduced age-related morbidity using large-scale electronic health record data.\n\nMethods: We conducted a stepwise pharmacoepidemiologic investigation in two independent healthcare systems. Using electronic health records from a nationwide health provider, we performed an exploratory medication-wide case-control screen comparing medication exposure during a 10-year window between 14,986 individuals who died before sex-specific median life expectancy and matched controls who survived beyond their life expectancy. Two leading candidate drugs, atovaquone-proguanil and mefloquine, are antiprotozoal agents with activity against Toxoplasma gondii. Their effects on mortality and age-related morbidity were further evaluated within a historical cohort of 3,876 exposed individuals and 77,520 matched controls using Cox proportional hazards models adjusted for baseline characteristics. External validation was performed in the United States-based TriNetX network, including cohorts exposed to atovaquone-proguanil (n = 24,498), mefloquine (n = 3,400), and nirmatrelvir-ritonavir (n = 124,681), each matched to unexposed controls.\n\nResults: Atovaquone-proguanil and mefloquine, together with nirmatrelvir-ritonavir, a protease inhibitor with reported antiprotozoal effects, were associated with consistent reductions in all-cause mortality across cohorts and lower incidence of multiple age-related conditions, including dementia, diabetes mellitus, cardiovascular disease, chronic kidney disease, and selected malignancies. Consistent increases in specific conditions were also observed, including hearing loss, Sjögren’s syndrome/dry eye, and lichen planus, suggesting shared underlying mechanisms, although confounding cannot be excluded.\n\nDiscussion: Findings were consistent across healthcare systems and drug classes, including in populations exposed to non-travel-associated medications. While causality cannot be established, these results support further investigation into potential links between chronic protozoal infections and aging-related diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Epidemiology and Preventive Medicine, School of Public Health, Gray Faculty of Medical and Health Sciences, Tel Aviv University",
    "Leumit Research Institute, Leumit Health Services",
    "Research Unit, Geha Mental Health Center, Felsenstein Medical Research Center, and Sagol School of Neurosciences, Faculty of Medical & Health Sciences, Tel Aviv University",
    "Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem",
    "Adelson School of Medicine, Ariel University",
    "Department of Infectious Diseases, Schneider Children’s Medical Center",
    "Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health",
    "Department of Family Medicine, Gray Faculty of Medical and Health Sciences, Tel Aviv University",
    "Medicine A Department, Assuta Ashdod University Medical Center, Ben Gurion University of the Negev"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Ariel Israel"
    },
    {
      "affs": [
        2
      ],
      "name": "Abraham Weizman"
    },
    {
      "affs": [
        3
      ],
      "name": "Sarah Israel"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Shai Ashkenazi"
    },
    {
      "affs": [
        6
      ],
      "name": "Eytan Ruppin"
    },
    {
      "affs": [
        1,
        7
      ],
      "name": "Shlomo Vinker"
    },
    {
      "affs": [
        8
      ],
      "name": "Eli Magen"
    },
    {
      "affs": [
        1,
        4
      ],
      "name": "Eugene Merzon"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a9e6trdf5vrvn.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1861376",
  "fulltext_url": null,
  "id": "a9e6trdf5vrvn",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1861376/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2717|Pharmaceutical Practices and Patient Outcomes"
    ]
  ],
  "openalex": "W7223817301",
  "pdf_url": "https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1861376/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/a9e6trdf5vrvn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1861376",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1861376/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:1663-9812",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Antiprotozoal drug exposure and reduced long-term mortality and morbidity: a multi-cohort pharmacoepidemiologic study",
  "title_text": "Antiprotozoal drug exposure and reduced long-term mortality and morbidity: a multi-cohort pharmacoepidemiologic study",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:06Z",
  "url": "https://research.draconitic.com/paper/a9e6trdf5vrvn",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}