Molecular Mechanisms of Stem Cell Aging and Their Challenges and Applications in Regenerative Medicine

Stem cell aging is a complex biological process characterized by diminished self-renewal capacity and impaired differentiation potential, directly contributing to decreased tissue regeneration and age-related diseases. This review systematically examines the molecular mechanisms underlying stem cell aging, including telomere shortening, DNA damage accumulation, metabolic imbalance, mitochondrial dysfunction, epigenetic modifications, and inflammatory responses. These interconnected mechanisms form a complex regulatory network driving stem cell functional decline. The challenges posed by stem cell aging to regenerative medicine are substantial: aging reduces tissue regenerative capacity across hematopoietic, neural, and muscular systems, limits the efficacy of stem cell transplantation due to poor survival rates and altered differentiation bias, and increases the risk of malignant transformation. To address these challenges, researchers have developed various intervention strategies, including cell reprogramming technology, gene editing approaches, metabolic regulation, antioxidant therapies, exosome applications, and microenvironment optimization. While significant progress has been made, challenges remain, particularly regarding off-target effects in gene editing, dose-dependent toxicity in metabolic regulation, and standardization issues in exosome production. Future research directions include developing aging-specific biomarkers for precision intervention, analyzing tissue-specific aging mechanisms, and exploring metabolism-epigenetic-immunity regulatory networks. The advancement of stem cell aging intervention has profound implications for both regenerative medicine and anti-aging therapies, offering promising approaches to address age-related diseases and improve quality of life.