Hypothesis: Dasatinib+quercetin (D+Q) senolytic therapy preferentially eliminates senescent cells with high mitochondrial membrane potential heterogeneity, and the surviving non-senescent neighboring cells donate healthy mitochondria via tunneling nanotubes (TNTs) to partially reprogrammed cells in a 50-μm radius. This mitochondrial transfer resets local Horvath epigenetic clock age by 2–5 years in recipient cells within 8 weeks, mediated by mitochondrial-derived peptide MOTS-c activating AMPK-dependent TET2 demethylation at clock CpG sites.

Testable prediction: In human adipose tissue biopsies pre- and post-D+Q treatment (3 monthly cycles), single-cell DNA methylation sequencing will show bimodal epigenetic age distributions at week 12, with TNT-connected cell pairs (identified by MitoTracker Deep Red transfer) showing concordant clock regression (Δage correlation r>0.7, p<0.001) while isolated cells show no age reversal. MOTS-c knockdown via antisense oligonucleotides in ex vivo tissue explants should abolish this effect.

Significance: This mechanism would explain why senolytics produce tissue-level rejuvenation disproportionate to the fraction of senescent cells eliminated (<15% of total), and suggests MOTS-c supplementation could amplify senolytic efficacy by enhancing mitochondrial transfer-mediated epigenetic reprogramming in aging tissues.