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.

PLA receives research contracts from Gilead Sciences and Merck paid to his institution. AL receives research contracts from Gilead Sciences, Viiv Healthcare, and Merck paid to his institution. AL serves on a scientific review board for a research scholars program for Gilead Sciences. All other authors declare no other competing interests.

NCT02022657, NCT02962739

This work was supported by the National Institutes of Health (U01 AI106499) and an investigator initiated study from Gilead Sciences (CO-US-412-3992). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funders or NIH. This publication was supported by the James B. Pendleton Charitable Trust and by the San Diego Center for AIDS Research (SD CFAR), an NIH-funded program (P30 AI036214), which is supported by the following NIH Institutes and Centers: NIAID, NCI, NHLBI, NIA, NICHD, NIDA, NIDCR, NIDDK, NIGMS, NIMH, NIMHD, FIC, and OAR.

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The FTC/TDF study was conducted at the San Francisco Department of Health and University of Colorado Anschutz Medical Campus, approved by the respective Institutional Review Boards, and was registered on ClinicalTrials.gov (NCT02022657); specimens were biobanked under a Colorado Multiple Institutional Review Board approved protocol. The FTC/TAF study was conducted at the University of Colorado Anschutz Medical Campus under a Colorado Multiple Institutional Review Board approved protocol and was registered on ClinicalTrials.gov (NCT02962739). All participants provided written informed consent prior to enrollment including consent for using stored samples for future genetic and other testing.

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