Cellular senescence: a link between cancer and age-related degenerative disease?

Abstract

Cellular senescence is an established cellular stress response that acts primarily to prevent the proliferation of cells that experience potentially oncogenic stress. In recent years, it has become increasingly apparent that the senescence response is a complex phenotype, which has a variety of cell non-autonomous effects. The senescence-associated secretory phenotype, or SASP, entails the secretion of numerous cytokines, growth factors and proteases. The SASP can have beneficial or detrimental effects, depending on the physiological context. One recently described beneficial effect is to aid tissue repair. Among the detrimental effects, the SASP can disrupt normal tissue structures and function, and, ironically, can promote malignant phenotypes in nearby cells. These detrimental effects in many ways recapitulate the degenerative and hyperplastic pathologies that develop during aging. Because the SASP is largely a response to genomic or epigenomic damage, we suggest it may be a model for a cellular damage response that can propagate damage signals both within and among tissues. We propose that both the degenerative and hyperplastic diseases of aging may be fueled by such damage signals.

Figure 1

Relationship among age-related diseases. Age increases the susceptibility to a wide variety of pathologies, which can be binned into two broad categories. The first category, loss-of-function pathologies, are dengenerative in nature, such that cells and tissues lose the ability to function optimally – or to function at all. Examples include neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), cardiovascular disease, and musculoskeletal decrements (e.g., bone and muscle loss). The second category, gain-of-function pathologies, are generally hyperplastic in nature, such that cells proliferate and/or gain new functions that are deleterious to the organism. Examples include benign hyperplasias such as benign prostatic hyperplasia, the smooth muscle cell hyperproliferation that gives rise to intimal thickening in arterial walls, and, of course, cancer. An important outstanding question is: do the loss-of-function and gain-of-function age-related pathologies have distinct etiologies, or is there a common biology that links all these pathologies of aging?

Figure 2

Signaling mechanisms used by senescent cells. An early event in the senescence response is an increase in the expression of IL-1α, a cytokine that is rarely secreted but rather is membrane-associated where it binds its juxtaposed receptor (juxtacrine signaling). IL-1αreceptor engagement triggers a signaling cascade that ultimately activates the NF-kB transcription factor that transcribes the genes for many of the pro-inflammatory components of the SASP. The senescence response also activates pathways, such as the p38MAPK pathway, which ultimately stimulates the transcription of genes that enforce the senescence growth arrest. SASP components also include secreted factors such as IL-6 and IL-8, which can reinforce the senescence growth arrest by autocrine signaling. Finally, SASP components can markedly affect the behavior of neighboring cells by paracrine signaling.

Figure 3

Senescent cells, by virtue of their SASP, may promote both the degenerative and neoplastic diseases of aging. Both senescent cells and preneoplastic cells increase with age in many tissues. The SASP of senescent cells can cause normal cells within tissues to lose optimal function, leading to tissue degeneration. The SASP can also cause premalignant cells to proliferate and adopt more malignant phenotypes, leading to full-blown cancer.