Aging-Related Mechanisms Underlying Carcinogenesis: Therapeutic Opportunities

Aging is a gradual loss of tissue homeostasis that leads to impaired physiological organ functions and constitutes a major risk factor for cancer initiation and progression. Despite advances in antitumor therapies, cancer remains the second leading cause of death worldwide. The rising incidence of cancer is intimately associated with increased lifespan and the growing proportion of older adults, with 64% of cancers diagnosed in people aged 60 and above. Mechanisms underlying aging include accumulation of somatic mutations, deficient DNA damage repair machinery, telomere shortening, enhanced genomic instability, epigenetic alterations, loss of heterochromatin, chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence and its associated secretory phenotype, stem cell exhaustion, aberrant intercellular communications, remodeling of extracellular matrix and microenvironment, impaired nutrient sensing and alterations in the proteome. Additionally, dysregulation of the circadian clock, the endocannabinoid system and the microbiota may also play important roles. Given that many of these processes are also crucial for cancer development, it is widely admitted that aging and cancer are tightly interconnected. Consequently, many therapies aimed at delaying or mitigating aging, such as physical exercise, specific dietary regimens, chronotherapy, epigenetic drugs and senotherapeutics, might also prevent or retard cancer development and progression and reduce the side effects of cancer therapies. However, special caution must be taken in older cancer patients due to their comorbidities and possible frailty, selecting specific patients' treatments and balancing the extended survival with the preservation of independence and quality of life.