Since persistent telomeric DNA damage is a

Since persistent telomeric DNA damage is a feature of replicative, stress- and oncogene-induced senescence, it has been suggested that unrepaired telomeres provide a source of persistent DDR signaling which is important to the establishment of senescence (Fumagalli et al., 2012). However, damage at non-telomeric sites also contributes to the senescent phenotype. Short-lived, non-telomeric lesions are constantly renewed during replicative and stress-induced senescence. In fact, these make up about half of the DNA damage foci, and their constant turnover has been suggested to be a result of increased ROS production during senescence, as inhibiting ROS generation results in a rescue of the proliferation arrest in a number of cells (Passos et al., 2010; Hewitt et al., 2012). Therefore, DNA damage signaling emanating from both telomeric and non-telomeric regions are important for the senescent phenotype, although distinguishing the extent of their individual contribution to senescence may prove technically challenging.
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Cellular Senescence: Causes and Consequences. Cellular senescence is a cell fate that involves essentially irreversible replicative arrest, apoptosis resistance, and frequently increased protein synthesis, metabolic shifts with increased glycolysis, decreased fatty dna ligase oxidation, increased reactive oxygen species generation, and acquisition of a senescence-associated secretory phenotype (SASP; Fig. 1) (Tchkonia et al., 2013; LeBrasseur et al., 2015). The SASP entails secretion of cytokines, bradykines, prostenoids, miRNA\'s, damage-associated molecular pattern proteins (DAMPs), and other pro-inflammatory mediators, chemokines that attract immune cells, factors that cause stem cell dysfunction such as activin A, hemostatic factors such as PAI-1, pressors, and extracellular matrix-damaging molecules, including proteases (Xu et al., 2015a, Xu et al., 2015b; Coppé et al., 2006). Senescence can occur in response to potentially oncogenic mutations, activated oncogenes, metabolic insults, and damage/danger signals.
Aging, Chronic Diseases, and Cellular Senescence Aging is the major risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health costs in the developed and developing worlds (Kirkland, 2016; Goldman et al., 2013). Chronic diseases, including dementias, atherosclerosis, diabetes, blindness, kidney dysfunction, and osteoarthritis among many others, become more prevalent with increasing age and tend to cluster together within older individuals (St Sauver et al., 2015). Risk for geriatric syndromes, including frailty, immobility, mild cognitive impairment, and incontinence, increases with aging. These conditions also cluster within individuals and are associated with age-related chronic diseases. Additionally, loss of physiological resilience, the capacity to recover following stresses such as surgery or pneumonia, occurs with advancing age and tends to precede onset of chronic diseases and geriatric syndromes (Kirkland et al., 2016). Fundamental aging processes, including chronic “sterile”, low-grade inflammation, macromolecular and organelle dysfunction, stem/progenitor cell dysfunction, and cellular senescence, are not only associated with development of age-related phenotypes, but are also frequently apparent at sites of pathogenesis in age-related chronic diseases (Kirkland, 2016). For example, senescent cells accumulate in adipose tissue in diabetes and with age-related metabolic dysfunction (Minamino et al., 2009; Tchkonia et al., 2010; Xu et al., 2015a), osteoarthritic joints (Xu et al., 2016), the aorta in vascular hyporeactivity and atherosclerosis (Roos et al., 2016), and the lung in idiopathic pulmonary fibrosis (Schafer et al., 2017). Indeed, transplantation of small numbers senescent cells around the knee joint can cause osteoarthritis (Xu et al., 2016). Senescent cells can be eliminated from transgenic INK-ATTAC mice by administering a drug, AP20187, that does not affect normal cells. AP20187 activates the “suicide” protein, ATTAC, which is expressed only in senescent cells due to a senescence-induced promoter, p16Ink4a (Baker et al., 2011). Activating ATTAC alleviates multiple phenotypes in progeroid mice, naturally-aged mice, or mice with age-related diseases (Baker et al., 2011; Xu et al., 2015a; Roos et al., 2016; Schafer et al., 2017). These include adipose tissue and metabolic dysfunction, vascular hyporeactivity and calcification, chemotherapy-induced pulmonary fibrosis, and progeria-associated cataracts, lipodystrophy, and muscle dysfunction, among others. Thus, targeting senescent cells is a promising potential approach for delaying, preventing, or alleviating multiple age- and cellular senescence-associated conditions.