Aging, cellular senescence, and cancer

Abstract

For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

Figures

Figure 1

Causes and consequences of cellular senescence. Cellular senescence is a response to potentially oncogenic stimuli. These stimuli include damage to DNA, whether at telomeres or elsewhere in the genome; strong mitogenic signals, including those produced by activated oncogenes; damage or disruptions to the epigenome; and ectopic expression of certain tumor suppressors. The consequences of cellular senescence are myriad: The essentially irreversible growth arrest can suppress tumorigenesis; other phenotypes of senescent cells can promote optimal tissue repair; senescent cell phenotypes can also, ironically, fuel the development of cancer; and they can cause or promote the degenerative diseases of aging.

Figure 2

Regulation of senescence growth arrest and the senescence-associated secretory phenotype (SASP). Cellular senescence is initiated by genomic or epigenomic damage, which activates a DNA damage response (DDR). The DDR ultimately becomes persistent or chronic, which leads to activation of p38MAPK and protein kinase C (PKC) and increased reactive oxygen species (ROS) and, ultimately, expression of the p16INK4a tumor suppressor. Stress that does not entail direct genomic or epigenomic damage can also induce p16INK4a expression and in some cases can indirectly trigger a DDR (dashed line). p16INK4a activates the pRB tumor suppressor, which silences certain proproliferative genes by heterochromatinization, thereby instituting a stringent arrest of cell proliferation. Persistent DDR signaling also induces the SASP and activates the p53 tumor suppressor, which restrains the SASP. p53 also causes growth arrest, principally by inducing expression of the cell cycle inhibitor p21. In some forms of oncogene-induced senescence, the SASP reinforces the senescence growth arrest (dashed line). NF-κB denotes nuclear factor κB.

Figure 3

The myriad activities of the senescence-associated secretory phenotype (SASP). The many factors that compose the SASP have numerous biological activities, all highly dependent upon physiological context. These activities include stimulation of angiogenesis, stimulation and inhibition of cell proliferation, creation of a chemoresistant niche during cancer chemotherapy, stimulation of an epithelial-to-mesenchymal transition, chronic inflammation, alterations to stem cell renewal and/or differentiation, and optimization of tissue repair. Hexagons represent SASP factors that act within and outside the senescent cell.