Scores of animal studies provide compelling evidence for cellular senescence to contribute meaningfully to many age-related conditions, and yet more such studies demonstrate rapid and sizable rejuvenation via targeted removal of senescent cells in old animals using varieties of senolytic therapy. Senescent cells are created constantly in the body, the result of cells reaching the Hayflick limit on replication, tissue injury, or encountering cellular damage or toxicity. When an individual is young, these newly senescent cells are near all removed by a combination of programmed cell death and the actions of the immune system. Later in life, this balance between creation and destruction shifts, however, particularly because the immune system becomes less capable. As a result senescent cells begin to accumulate in tissues throughout the body.
While the absolute numbers of senescence cells do not become very large in most tissues, they are highly active. When maintained over time, the secreted molecules produced by senescent cells contribute to chronic inflammation, detrimental changes in cell function, pathological alterations in tissue structure, and more. This is an active maintenance of ever more degraded tissue function, leading into all of the common fatal age-related diseases. Thus removing senescent cells can allow tissues to rapidly recover to a better, more youthful state. This makes the targeted destruction of senescent cells a very desirable goal in the treatment of aging.
Cellular senescence: a key therapeutic target in aging and diseases
Aging is a complex process driven, at least in part, by hallmarks of aging, including cellular senescence, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular communication. Of these hallmarks, cellular senescence has been directly implicated as a key driver of aging and age-related diseases. Senescent cells (SnCs) are characterized by stable exit from the cell cycle and loss of proliferative capacity, even in the presence of mitogenic stimuli. In addition to replicative senescence caused by telomeric erosion and induction of a DNA damage response, cellular senescence can be induced by other stressors, including but not limited to epigenetic changes, genomic instability, mitochondrial dysfunction, reactive metabolites, oxidative stress, inactivation of certain tumor suppressor genes, oncogenic- and therapy-induced stress, and viral infections.
Although SnCs are growth arrested in the cell cycle, they are still metabolically active. Many SnCs secrete a wide spectrum of bioactive factors, including inflammatory cytokines, chemokines, growth factors, matrix metalloproteinases, lipids, nucleotides, extracellular vesicles, and soluble factors, termed the senescence-associated secretory phenotype (SASP).
Cellular senescence is thought to have evolved as an antitumor mechanism where the SASP induced by oncogene-induced senescence recruits immune cells to facilitate SnC removal. nCs play an essential role in multiple physiological processes, including embryogenesis, cellular reprogramming, tissue regeneration, wound healing, immunosurveillance, and tumor suppression. However, SnCs can also contribute to the pathology of many chronic diseases, including diabetes, cancer, osteoarthritis, and Alzheimer's disease. SnCs accumulate with age in most tissues, and SASP factors can act to induce secondary senescence, thus propagating and enhancing the SnC burden. The SASP also serves to sustain and enhance inflammaging, whereby enhanced chronic, low-grade systemic inflammation occurs in the absence of pathogenic processes.
Cellular senescence not only contributes to aging but also plays a causal role in numerous age-related diseases. SnC accumulation frequently occurs at pathogenic sites in many major age-related chronic diseases, including Alzheimer's and cardiovascular diseases, osteoporosis, diabetes, renal disease, and liver cirrhosis. Notably, transplanting a small number of SnCs into young healthy animals recapitulates age-related impaired physical functions. This supports the threshold hypothesis, which proposes that once the SnC burden increases beyond sustainability in a tissue, it activates age-related pathological changes and eventually results in disease.
The deleterious effects of SnCs in aging and many age-related diseases are likely mediated by increased SASP expression. SASP factors, such as TGF-β family members, VEGF, and chemokines, are known to accelerate senescence accumulation by spreading senescence to neighboring cells. The SASP crosstalk with immune cells, including NK cells, macrophages, and T cells, exacerbates both local and systemic inflammation. Proteases and growth factors in the SASP are known to disrupt tissue microenvironments and promote cancer metastasis. Fibrogenic factors and tissue remodeling factors in the SASP contribute to fibrosis in multiple tissues, including skin, liver, kidney, lung, cardiac tissue, pancreas, and skeletal muscle.
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