Telomere-Position-Effect Silencing of TERT-Adjacent Mitophagy Genes Creates a Feedforward Loop of Mitochondrial Dysfunction and Telomere Attrition Reversible by Urolithin A

Background: Telomere shortening is a hallmark of aging, yet the mechanism by which critically short telomeres propagate systemic mitochondrial dysfunction remains poorly defined. Telomere position effect (TPE) — epigenetic silencing of genes near telomeres — has been demonstrated for loci up to 10 Mb from chromosome ends. Notably, several key mitophagy regulators (BNIP3L/Nix on chr8p, FUNDC1 on chrXp) reside within TPE-sensitive distances.

Hypothesis: As telomeres shorten with age, TPE-dependent silencing of BNIP3L and FUNDC1 impairs receptor-mediated mitophagy, leading to accumulation of damaged mitochondria with elevated ROS. This ROS surplus accelerates telomeric 8-oxoguanine lesions — which are preferentially repaired poorly at telomeres due to shelterin-mediated BER exclusion — creating a feedforward loop: short telomeres → silenced mitophagy genes → damaged mitochondria → ROS → faster telomere attrition.

Testable Prediction: (1) Single-cell ATAC-seq of replicatively aged human fibroblasts will show progressive loss of chromatin accessibility at BNIP3L and FUNDC1 loci correlating with telomere length (measured by FISH). (2) Urolithin A — a mitophagy inducer acting downstream of BNIP3L/FUNDC1 via PINK1-independent pathways — will break the feedforward loop, reducing telomeric 8-oxoG lesions (immunofluorescence-FISH) and decelerating DunedinPACE in a 12-week RCT of adults aged 60-75. (3) CRISPR activation of BNIP3L in TPE-silenced cells will phenocopy urolithin A effects on mitochondrial membrane potential (JC-1) and telomere attrition rate.

Intersection with Rheumatic Disease: Accelerated telomere shortening is documented in RA and SLE lymphocytes. If TPE-driven mitophagy failure contributes to the premature immunosenescence seen in these conditions, urolithin A supplementation adjunctive to DMARDs could reduce the bioenergetic crisis underlying lymphopenia and infection susceptibility in autoimmune patients.

Falsification Criteria: If BNIP3L/FUNDC1 accessibility does not correlate with telomere length in aged fibroblasts, or if urolithin A fails to reduce telomeric oxidative lesions despite rescuing bulk mitophagy, the TPE-mitophagy feedforward model is refuted.