An FDA-Approved Tenofovir Alafenamide-Based Antiretroviral Therapy Reduces Biological Age in Healthy Adults: First Human Proof-of-Concept for Retrotransposon-Targeted Gerotherapeutics

Apr 3, 2026medRxiv : the preprint server for health sciences

FDA-Approved Tenofovir Alafenamide Treatment May Lower Biological Age in Healthy Adults by Targeting Mobile DNA Elements

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Abstract

In a study of 36 healthy individuals, DNA methylation-based measures of biological aging decreased significantly after 12 weeks of treatment with FTC/TAF.

Epigenetic aging measures, including DunedinPACE and PhenoAge, showed significant reductions after FTC/TAF treatment.
Significant declines were observed in epigenetic proxies for inflammatory biomarkers, including IL-6.
No significant changes were noted in the FTC/TDF group of 43 participants.
These results suggest potential gerotherapeutic effects of FTC/TAF compared to FTC/TDF.
Further placebo-controlled studies are needed to explore these findings and their implications for aging.

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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-based measures of biological aging in healthy people without HIV (aged 18-50) using samples from two separate randomized, directly observed dosing pharmacokinetic studies of FDA-approved NRTI regimens containing emtricitabine-tenofovir-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 (-0.061, p=0.019) and PhenoAge (-6.33, p=0.008), with concordant reductions (p<0.05) across additional systems-specific epigenetic clocks including those estimating brain aging. DNAm-based proxies of inflammatory biomarkers also declined, with significant reductions in epigenetic IL-6 (-0.058, p=0.029) and a trend toward reduced C-reactive protein (-0.231, 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's 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-based aging endpoints.

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Longevity & AgingIssue #31

FDA-approved HIV drug reduces biological aging in healthy adults by 6+ years

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An FDA-Approved Tenofovir Alafenamide-Based Antiretroviral Therapy Reduces Biological Age in Healthy Adults: First Human Proof-of-Concept for Retrotransposon-Targeted Gerotherapeutics

Abstract

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