A sizable body of evidence indicates that transposons contribute to degenerative aging. Transposons of various categories are DNA sequences that code for molecular machinery capable of writing copies of the original DNA into other locations in the genome. They are largely the remnants of ancient retroviral infections, altered and degraded over evolutionary time, while likely remaining an important mechanism of mutational change for future evolution. Transposons are suppressed in youth, the nuclear DNA sequences spooled and hidden from transcriptional machinery, but one of the noteworthy aspects of aging is a loss of epigenetic control over nuclear DNA structure and thus over gene expression. Stretches of DNA containing transposons unspool and become accessible to transcriptional machinery. Transposon expression produces molecules that are sufficiently virus-like for evolved defenses to react with inflammatory signaling, while the haphazard insertion of transposon sequences is a form of DNA damage, breaking genes.
Just like retroviruses, retrotransposons require reverse transcription to function. That part of the research and development community focused on HIV, human immunodeficiency virus, has spent decades developing ever better means of sabotaging reverse transcription. In today's open access paper, researchers report on their investigation of the effects of such antiretroviral drugs on measures of biological age. The researchers made use of data and samples originating from pharmacokinetic clinical studies of combinations of antiretroviral drugs in healthy volunteers. One combination of drugs did reduce measures of biological age, while the other did not. This suggests that there is indeed something interesting here, but that the fine details matter when it comes to the implementation of transposon suppression.
Nearly half of the human genome (∼45%) is composed of transposable elements (TEs). Aging is accompanied by a progressive erosion of epigenetic silencing that permits the transcriptional reactivation of these TEs, particularly retrotransposons such as LINE-1 and endogenous retroviruses. In young somatic cells, these elements are maintained in a transcriptionally inert state by DNA methylation, heterochromatin, and KRAB-ZFP/KAP1 surveillance. However, with age the fidelity of these mechanisms declines, and retrotransposon-derived transcripts and cytoplasmic DNA accumulate. This age-dependent retroelement reactivation is now recognized as a proximal driver of biological aging hallmarks including a senescence-associated secretory phenotype (SASP) and age-related tissue dysfunction.
The dependence of retroelements on reverse transcription has made nucleoside reverse transcriptase inhibitors (NRTIs), which were developed and licensed for HIV treatment and prevention, attractive candidate gerotherapeutics. For instance, a retrospective analysis of longitudinal aging intervention studies identified antiretroviral therapy as one of the most consistent interventions associated with reductions across 16 epigenetic clocks. Early mechanistic work showed that multiple NRTIs including 3TC (lamivudine), tenofovir disoproxil fumarate (TDF), stavudine, and zidovudine can directly suppress human LINE-1 retrotransposition in cell-based reporter systems. Consistent with this, 3TC (lamivudine) blunted LINE-1 cDNA-triggered type I interferon signaling and components of the SASP in senescent human cells and reduced age-associated inflammatory signatures across multiple tissues in aged mice.
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) and PhenoAge (-6.33), with concordant reductions 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) and a trend toward reduced C-reactive protein (-0.231). 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.
View the full article at FightAging
