A small-molecule compound named TAC has been identified that reawakens the catalytic subunit of telomerase (TERT) in somatic cells and, in doing so, stalls multiple hallmarks of natural aging without provoking cancer. Administered intraperitoneally to middle-aged mice, the 400 Da lipophilic agent crosses the blood–brain barrier, elevates TERT transcription within brain, heart and skeletal muscle, and lengthens telomeres while suppressing DNA damage foci. Over a six-month regimen it improved hippocampal neurogenesis, reversed neuromuscular decline and enhanced cognition; mechanistically, these gains trace to a MEK/ERK/FOS/AP-1 signalling cascade that drives TERT expression and, in turn, epigenetically silences p16^INK4a^ via DNMT3b-mediated promoter hypermethylation. Concomitantly, the senescence-associated secretory phenotype (IL-1β, IL-6, MMP-3, VEGF) is down-regulated, systemic low-grade inflammation subsides and no neoplastic lesions appear.
Telomere attrition and the resulting genomic instability have long been viewed as a central driver of organismal aging. In most adult human somatic cells, TERT is transcriptionally repressed, causing progressive telomere shortening with each division. Reactivation strategies risk oncogenesis because telomerase is up-regulated in ~90 % of human tumours; yet controlled, physiologic induction might rejuvenate tissues without malignant transformation. Screening 653 000 compounds in human fibroblasts carrying an hTERT-Rluc reporter flagged TAC as a potent hit that doubled TERT mRNA within hours and retained activity in post-mitotic neurons and cardiomyocytes. Chromatin immunoprecipitation confirmed FOS occupancy at two AP-1 sites on the TERT promoter, and selective inhibition of AP-1 DNA binding abolished the effect, establishing the upstream kinase cascade as druggable.
Aged C57BL/6 mice (26–27 months) treated daily for half a year exhibited thicker muscle fibres, faster rotarod performance and superior spatial memory in the Morris water maze. Hippocampal sections revealed increased DCX-positive newborn neurons, elevated mature BDNF and reduced IBA1 microgliosis. Serum IL-1β and IL-6 fell by more than 60 %, while telomere restriction fragments lengthened 8–12 %. Importantly, p16^INK4a^ expression plummeted in brain, heart and liver, correlating with dense CpG methylation at its promoter and direct TERT binding to the DNMT3b regulatory region. Crossing TAC-treated mice into a late-generation Terc-knockout background confirmed that the compound fails to rescue phenotypes when telomerase is absent, proving on-target specificity.
Translational considerations dominate the discussion. Humans possess markedly shorter telomeres (5–15 kb) than laboratory mice (≥50 kb) and lack constitutive telomerase, so lifespan extension expectations must be tempered. A newly engineered mouse strain harbours humanised telomere length and regulation patterns and awaits TAC validation. Safety data so far reveal no excess tumours in aged cohorts, but long-term surveillance is obligatory given telomerase biology. Optimal age for intervention, dosing frequency and pharmacokinetics in primates remain open questions. If favourable, TAC could complement lifestyle measures and other gerotherapeutics, offering a chemical route to compress morbidity rather than merely lengthen life.
DOI: 10.1007/s11684-025-1139-1