Senescence and aging: Causes, consequences, and therapeutic avenues

Abstract

Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens.

Figure 1.

Senescence as a central hallmark of aging. Telomere damage, epigenetic dysregulation, DNA damage, and mitochondrial dysfunction are primary drivers of damage in aging. Several of these drivers of damage can induce senescence. Senescence can in turn drive the consequential aging hallmarks in response to damage: stem cell exhaustion and chronic inflammation. Other responses to damage, such as proteostatic dysfunction and nutrient signaling disruption, are also integrally linked with the senescence response. Adapted from López-Otín et al. (2013).

Figure 2.

Pathways regulating senescence-mediated arrest. The senescence growth arrest is regulated through two main pathways, p16^INK4a/Rb and p53/p21^CIP1, both which converge on repression of CDK4/6. The INK4A/ARF locus is normally silenced by Polycomb repressive complexes (PRCs) and becomes activated during senescence. The p53/p21^CIP1 pathway is activated downstream of the DNA damage response (DDR) from repair-resistant DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).

Figure 3.

Functions of the SASP. The SASP mediates many of the cell-extrinsic functions of senescent cells. Among those it reinforces several aspects of senescence including growth arrest and the SASP itself via an autocrine loop. The SASP also recruits immune cells, such as macrophages, neutrophils, and natural killer (NK) cells to phagocytose and eliminate the senescent cell. Secretion of MMPs and factors such as VEGF can remodel the surrounding tissue, inducing angiogenesis and reducing fibrosis. Finally, secretion of molecules such as TGF-β can spread the senescence phenotype in a paracrine manner to surrounding cells.

Figure 4.

Involvement of senescence in disease. Establishment of robust biomarkers of senescence, usage of genetic knockout models and senolytic models are expanding our knowledge on the age-related diseases in which senescence plays a role.