A Review of Telomere Biology and Therapeutic Strategies

Telomeres protect chromosome ends and shorten with cellular replication, contributing to cellular senescence, pro-inflammatory senescence-associated secretory phenotype (SASP), genomic instability at critical lengths, and age‑related pathology. This review examines telomere biology, its role in aging and disease, and related therapies. While telomere attrition suppresses tumors, critically short telomeres can lead to telomere crisis and genomic instability. To overcome this, 85-95% of human cancers reactivate the enzyme telomerase or utilize ALT pathways. Telomere Biology Disorders (TBDs), genetic diseases caused by mutations in telomere-maintenance genes, act as accelerated aging models and demonstrate the consequences of telomere attrition. Leading therapeutic strategies include telomerase activation via small molecules (e.g., TA-65) or adeno-associated virus (AAV)-based gene therapy, both shown to extend lifespan in animal models without increasing cancer risk. Advanced methods, such as CRISPR-mediated epigenetic editing (CRISPRa) and modified mRNA delivery, are precise and have transient effects. Additional methods include inhibiting alternative lengthening (ALT) pathways in cancer and senolytics (e.g., Dasatinib and Quercetin), which clear senescent cells. The most promising direction emerging from this review is a combined approach: transient telomerase activation to restore telomere length while avoiding permanent genomic modification and its associated cancer risk, paired with senolytics to eliminate the senescent cells responsible for chronic inflammation. Together, these strategies address telomere attrition at both its cause and its consequences.