Hallmarks of Aging

The hallmarks of aging are a set of common denominators of aging enumerated across different organisms, with special emphasis on mammalian aging, that represent the biological processes underlying the progressive loss of physiological integrity characteristic of aging. ^[1] The original 2013 framework enumerated nine tentative hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. ^[1] The framework was subsequently expanded to twelve hallmarks by adding disabled macroautophagy, chronic inflammation, and dysbiosis to the original set. ^[2] To qualify as a hallmark, a process should fulfil three premises: its age-associated manifestation, the acceleration of aging when it is experimentally accentuated, and the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on it. ^[2]

The hallmarks are interconnected among each other, and a major challenge is to dissect this interconnectedness and the relative contributions of each hallmark to aging. ^{[1] [2]} Mitochondrial dysfunction and cellular senescence are hallmarks of aging that are closely interconnected, with mitochondrial dysfunction acting as both a cause and a consequence of cellular senescence. ^[3] Malfunctioning of autophagy with age contributes to the loss of proteostasis that characterizes all old organisms, and autophagy interacts reciprocally with several of the hallmarks of aging. ^[4] Low-grade chronic inflammation during aging, termed inflammaging, has a bidirectional relationship with the other hallmarks in which its crosstalk drives a vicious cycle that exacerbates the decline in cellular functions and promotes aging. ^[5]

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death, and this deterioration is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. ^[1] Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease and Parkinson disease, which have been described in relation to the biological hallmarks of ageing. ^[6] Several hallmarks of aging, including genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis, are similar to specific cancer hallmarks and constitute common meta-hallmarks shared between aging and cancer. ^[7]

A final goal of the hallmarks framework is to identify pharmaceutical targets to improve human health during aging with minimal side effects. ^[1] Metformin has been proposed to attenuate hallmarks of aging by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, and lowering telomere attrition and senescence. ^[8] Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target, giving rise to senotherapeutic drugs such as senolytics, which selectively kill senescent cells, and senomorphics, which suppress markers of senescence. ^[9]