Senescent cells: a novel therapeutic target for aging and age-related diseases

Abstract

Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells--damaged cells that have lost the ability to divide--drive the deterioration that underlies aging and age-related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16(Ink4a)-positive senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age-related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age-related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells.

Figure 1

Three distinct origins of senescent cells. Cells that have reached their Hayflick limits have lost their ability to proliferate further; this is termed “replicative senescence.” In cellular senescence, a variety of stimuli also cause an irreversible cell cycle arrest before cells lose their proliferative capacity. Emerging evidence suggests that there is a third path to the formation of senescent cells, one in which terminally differentiated, nonproliferative cells acquire key features of senescent cells, including a SASP. We have termed these cells SAD (senescence after differentiation) cells. SASP, senescence-associated secretory phenotype.

Figure 2

Germline deletion of p16^Ink4a in BubR1 progeroid animals dramatically impacts overt age-associated phenotypes and delays cellular senescence. Representative images of 5-month-old mice are shown. The inset images are SA-β-Gal-stained fat depots, demonstrating the dramatic attenuation of cellular senescence. SA-β-Gal, senescence-associated-β-galactosidase.

Figure 3

Proposed mechanism through which removal of senescent cells from aged tissues benefits tissue function. Senescent cells, through their SASP, disrupt the functionality of neighboring cells. When the senescent cells are selectively cleared, tissue function improves. The aged cells present retain whatever intrinsic damage they had accrued before the removal of the senescent cells, demonstrating that tissues are not likely to revert to a pre-aging condition.

Figure 4

Normal, age-related, nearly universal changes (left) and age-associated diseases (right) that have senescent cells potentially underlying their incidence, progression, and/or severity. For further details, see individual sections within the text. COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis.

Figure 5

Proposed contribution of senescent cells to tumorigenesis and cancer therapy–induced side effects. Senescent cells stimulate tumor cell growth via various growth factors, and tissue disorganization via the components that they secrete. Once a tumor is removed by systemic radiation or chemotherapy, senescence is triggered in a variety of other organs, leading to long-term ramifications for the patient.