Category: cell_death
Telomeres are TTAGGG-tandem-repeat caps at chromosome ends, protected by the shelterin protein complex (TRF1, TRF2, POT1, TIN2, TPP1, RAP1). Without protection, chromosome ends would be recognized as double-strand DNA breaks and trigger DDR (ATM/ATR + p53/p21) → senescence or apoptosis. The "end-replication problem": DNA polymerase cannot fully replicate the 3' end of the lagging strand → progressive telomere shortening (~50-100 bp per cell division). Without compensation: replicative senescence (Hayflick limit, ~50-60 divisions) → tissue aging phenotypes. Compensation by telomerase: the ribonucleoprotein reverse transcriptase TERT (catalytic) + TERC/TR (RNA template) extends telomeres. Expression: active in germline + stem cells + most cancers (~85-90% of tumors reactivate telomerase); suppressed in most somatic adult cells (limits tumor formation but causes aging). ALT (alternative lengthening of telomeres) pathway: ~10-15% of cancers — homologous recombination-based; common in mesenchymal tumors + osteosarcoma. Disease relevance: dyskeratosis congenita + telomere biology disorders (TERT, TERC, DKC1, TINF2, RTEL1, CTC1 mutations) → bone marrow failure, pulmonary fibrosis, hepatic fibrosis, premature aging. Therapeutic landscape: telomerase inhibition (imetelstat — first-in-class, FDA-approved 2024 for transfusion-dependent MDS); telomerase activators (TA-65 — astragalus-derived, modest evidence); G-quadruplex stabilizers (BRACO-19) preclinical. Lifestyle: chronic stress + smoking + obesity → faster telomere shortening; exercise + Mediterranean diet → slower attrition. Cross-links: [[senescence_sasp_senolytics]] (replicative senescence end-state), [[apoptosis_bcl2_axis]] (cellular response to uncapped telomeres), [[hpa_axis]] (chronic stress affects telomere attrition).