Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

Abstract

Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions.

Figure 1. Aging is the leading risk factor for most serious chronic diseases and disabilities, including strokes, heart disease, cancers, dementias, osteoporosis, arthritis, diabetes, metabolic syndrome, kidney failure, blindness, and frailty.

Figure 2. A disruption of the intersection between fundamental aging mechanisms and processes that lead to chronic diseases may delay age-related diseases and disabilities as a group and thereby lengthen health span.

The increasing burden of senescent cells might contribute to the early etiology of age-related diseases and accelerate progression of these diseases following their initiation. Chronic disease pathology, coupled with the spread of senescence to neighboring healthy cells, might further drive cellular senescence, thus contributing to a spiral of increasing inflammation and dysfunction. Among other possibilities, chronic inflammation associated with the SASP, combined with with inflammation from preclinical and overt chronic disease, may predispose to frailty, sarcopenia, and eventually mortality.

Figure 3. A number of inducers can act alone or in combination to push cells into the senescent cell fate through pathways involving p16^INK4a/Rb, p53/p21, and likely other pathways.

Triggers may include DNA damage (e.g., telomere shortening and single- and double-strand breaks); oncogenic mutations (e.g., Ras, Myc, B-Raf); reactive metabolites (e.g., ROS, ceramides, fatty acids, high glucose); high mitogen and nutrient signals that increase mTOR activity; and proteotoxic stress (e.g., protein aggregation and unfolded proteins). These may contribute to widespread changes in gene expression and chromatin remodeling (heterochromatin formation) that underlie senescence-associated growth arrest, the SASP, and changes in morphology. In these respects, cellular senescence can be viewed as a cell fate reminiscent of differentiation, replication, or apoptosis (external and internal inducers, transcription factor cascades, gene expression changes and chromatin remodeling, leading to changes in function). Evidence is better for some of the initiators and mediators of senescence than for others, and future research is likely to uncover additional initiators and mediators. Intracellular autocrine loops reinforce progression to irreversible replicative arrest, heterochromatin formation, and initiation of the SASP over a matter of days to weeks. In addition to removing cells from the progenitor/stem cell pool, senescence may contribute to tissue dysfunction and chronic disease predisposition through the SASP and associated chronic sterile inflammation and degradation of the extracellular matrix.