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

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