Cell senescence: role in aging and age-related diseases

Abstract

Cell senescence is one of the major paradigms of aging research. It started with the demonstration by L. Hayflick of the limited number of divisions by normal, nontransformed cells, not shown by transformed malignant cells, this processes being largely regulated by the telomere-telomerase system. A complete renewal of this discipline came from the demonstration that cells can enter senescence at any time by an anti-oncogene-triggered pathway, enabling them to escape malignancy. The senescent cell became a major actor of the aging process, among others, by the acquisition of the senescence-associated secretory phenotype. This chapter is devoted to the regulatory process involved in the acquisition of the senescent cell phenotype and its role in organismal aging.

Fig. 1

Age of the donor versus average population doublings of the respective skin fibroblasts, derived from a human embryo (964 S) and from patients with benign tumors (●) or breast cancers (○). The straight line is the regression fitting the plot corresponding to the fibroblasts originating from donors with benign lesions. The correlation coefficient is indicated on the chart. [reproduced with permission from ref [4)]

Fig. 2

Diagrammatic representation of the history of cell strains and the phenomenon of cell alteration. Phase I.: the primary culture terminates with the formation of the first confluent sheet. Phase II. is characterized by luxuriant growth necessitating many sub-cultivations. Cells in this phase are termed “cell strains”. An alteration may occur at any time, giving rise to a “cell line” whose potential life is infinite. Conversely, cell strains characteristically enter Phase III. and are lost after a finite period of time. (reproduced with permission from ref [3])

Fig. 3

Microscopic picture of early passage (“young”) fibroblasts (left) and fibroblasts at the end of their replicative potential. (Photos by L. Hayflick, reproduced with permission)

Fig. 4

Regulation of senescence growth arrest and 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 p16^INK4a tumor suppressor. Stress that does not entail direct genomic or epigenomic damage can also induce p16^INK4a expression and in some cases can indirectly trigger a DDR (dashed line). p16^INK4a activates the pBR tumor suppressor, which silences certain pro-proliferative genes by hetero-chromatinization, thereby instituting a stringent arrest of cell proliferation. Persistent DDR signaling also induces 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.

Fig. 5

Increase with time in culture (4 days and 7 days) and with increasing passages (abscissa) of the expression of SA-β-Gal, a marker of senescent cells in human skin fibroblasts at sequential passages, determined by the SaβGal procedure [12]. Sequential cultures were started after 4 days in culture (lower curve) or after 7 days in culture (upper curve).(reproduced with permission from ref ([3])

Fig. 6

The numerous activities of the senescence-associated secretory phenotype (SASP). The many factors that compose the SASP have several biological activities, all highly dependent upon the physiological context. These activities include stimulation of angiogenesis, stimulation or inhibition of cell proliferation, creation of a chemoresistant niche during cancer chemotherapy, stimulation of an epithelial-to-mesenchymal transition, chronic inflammation, alterations of stem cell renewal and/or differentiation, and optimization of tissue repair. Hexagons represent SASP factors that act within and outside the senescent cell. (reproduced with permission from ref [11])