{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:47:40Z","timestamp":1791092860332,"version":"4.1.0"},"posted":{"date-parts":[[2026,3,26]]},"group-title":"Pharmacology and Therapeutics","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) used for HIV treatment and pre-exposure prophylaxis have been proposed as gerotherapeutics based on their capacity to suppress age-associated retrotransposon activity. However, evidence in humans is currently lacking. Here we evaluated DNA methylation\u2013based measures of biological aging in healthy people without HIV (aged 18\u201350) using samples from two separate randomized, directly observed dosing pharmacokinetic studies of FDA-approved NRTI regimens containing emtricitabine\u2013tenofovir-alafenamide (FTC\/TAF;200 mg\/25 mg) or FTC-tenofovir-disoproxil fumarate (FTC\/TDF; 200 mg\/300 mg) for 12 weeks. In the FTC\/TAF study (N=36), epigenetic aging measures based on DNA methylation (DNAm) profiling decreased over follow-up, including DunedinPACE (\u22120.061, p=0.019) and PhenoAge (\u22126.33, p=0.008), with concordant reductions (p&lt;0.05) across additional systems-specific epigenetic clocks including those estimating brain aging. DNAm\u2013based proxies of inflammatory biomarkers also declined, with significant reductions in epigenetic IL-6 (\u22120.058, p=0.029) and a trend toward reduced C-reactive protein (\u22120.231, p=0.059). In contrast, the FTC\/TDF study (N=43) showed no significant changes across epigenetic clocks and proxies. These findings are consistent with TAF\u2019s more favorable cellular pharmacology compared with TDF and support gerotherapeutic effects of FTC\/TAF. Prospective placebo-controlled studies are warranted that integrate clinical pharmacology, direct transposable element readouts, and prespecified geroscience and DNA methylation\u2013based aging endpoints.<\/jats:p>","DOI":"10.64898\/2026.03.23.26349105","type":"posted-content","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T22:45:23Z","timestamp":1774565123000},"source":"Crossref","is-referenced-by-count":4,"title":["An FDA-Approved Tenofovir Alafenamide-Based Antiretroviral Therapy Reduces Biological Age in Healthy Adults: First Human Proof-of-Concept for Retrotransposon-Targeted Gerotherapeutics"],"prefix":"10.64898","author":[{"given":"Peter L.","family":"Anderson","sequence":"first","affiliation":[{"name":"University of Colorado Anschutz Medical Center, Department of Pharmaceutical Sciences, Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina PS","family":"Pang","sequence":"additional","affiliation":[{"name":"University of California San Diego, Department of Medicine, Division of Geriatrics and Palliative Care, Stein Institute for Research on Aging & Center for Healthy Aging, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan P.","family":"Coyle","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Center, Department of Pharmaceutical Sciences, Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Schlachetzki","sequence":"additional","affiliation":[{"name":"University of California San Diego, Department of Neurosciences, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.A.","family":"Molina","sequence":"additional","affiliation":[{"name":"University of California San Diego, Department of Medicine, Division of Geriatrics and Palliative Care, Stein Institute for Research on Aging & Center for Healthy Aging, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lane","family":"Bushman","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Center, Department of Pharmaceutical Sciences, Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Aguado","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Center, Department of Pharmaceutical Sciences, Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Hill","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Center, Department of Pharmaceutical Sciences, Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert Y.","family":"Liu","sequence":"additional","affiliation":[{"name":"Bridge HIV, San Francico Department of Public Health; 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