Abstract
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.