Neuroendocrine-associated epigenetic factors in cellular senescence: mechanisms and therapeutic implications

Ageing is a progressive biological process causing a reduction in tissue and cellular function due to accumulated molecular damage over time. Cellular senescence is a stable cellular state characterized by irreversible cell-cycle arrest accompanied by distinct molecular, epigenetic, and secretory alterations. Moreover, neuroendocrine signalling and epigenetic regulation have had a great impact on controlling ageing and senescence. As a part of the neuroendocrine system, the hypothalamic-pituitary-adrenal (HPA) axis and insulin-like growth factor-1 (IGF-1) mediate stress responses, circadian regulation, and homeostasis. Notably, fluctuations in the hormonal levels, including elevated glucocorticoid levels and reduced IGF-1 levels, result in chronic inflammation, tissue dysfunction, and compromised repair mechanisms as people age. As such, these hormonal changes affect the epigenome function and disrupt gene expression and hasten senescence through chromatin remodelling, histone modifications, and DNA methylation. Together, these effects worsen the condition by causing prolonged psychological stress, which activates the HPA axis over time, resulting in genomic instability, telomere shortening, and mitochondrial dysfunction. Thus, neuroendocrine imbalance and epigenetic drift act as major factors playing a regulatory role in ageing. Hence, hormonal regulation in conjunction with epigenetic treatments, such as DNA methyltransferase and histone deacetylase inhibitors, may provide effective ways to postpone senescence and prolong life. This review explores the regulation of cellular senescence by neuroendocrine-associated epigenetic mechanisms, highlighting their impact on age-related diseases and emerging therapeutic strategies. Gaining a deeper understanding of these interconnected pathways provides a foundation for developing precision medicine approaches targeting the molecular drivers of ageing and its associated disorders.