Cellular senescence is a program activated by normal cells in response to various types of stress. These include telomere uncapping, DNA damage, oxidative stress, oncogene activity and others. Senescence can occur following a period of cellular proliferation or in a rapid manner in response to acute stress. Once cells have entered senescence, they cease to divide and undergo a series of dramatic morphologic and metabolic changes. The hallmark of cellular senescence is an inability to progress through the cell cycle. Senescent cells arrest growth, usually with a DNA content that is typical of G1 phase, yet they remain metabolically active. Once arrested, they fail to initiate DNA replication despite adequate growth conditions. This replication failure is primarily caused by the expression of dominant cellcycle inhibitors. Resistance to apoptosis might partly explain why senescent cells are so stable in culture. This attribute might also explain why the number of senescent cells increases with age.
The two paradigmatic tumor suppressor proteins, p53 and Rb, have been shown to play critical roles in the induction of senescence. Both p53 and Rb are activated upon the entry into senescence. The p53 protein is stabilized and proceeds to activate its transcriptional targets, such as p21CIP1/WAF1. Rb is found at senescence in its active, hypophosphorylated form, in which it binds to the E2F protein family members to repress their transcriptional targets. Dysfunctional telomeres trigger a classical DNAdamage response. The DDR enables cells to sense damaged DNA, particularly double-strand breaks (DSBs), and to respond by arresting cell-cycle progression and repairing the damage if possible. Both damage- and telomere-initiated senescence depend strongly on p53 and are usually accompanied by expression of p21. Sustained signalling by certain anti-proliferative cytokines, such as interferon-β, also causes senescence. Acute interferon-β stimulation reversibly arrests cell growth, but chronic stimulation increases intracellular oxygen radicals and elicits a p53-dependent DDR and senescence.
Several markers can identify senescent cells in culture and in vivo. An obvious marker for senescent cells is the lack of DNA replication, which is typically detected by the incorporation of 5-bromodeoxyuridine or 3 Hthymidine, or by immunostaining for proteins such as PCNA and Ki-67. The first marker to be used for the more specific identification of senescent cells was the senescence-associated βgalactosidase (SA-βgal). Some senescent cells can also be identified by the cytological markers of SAHFs and senescence associated DNA-damage foci (SDFs). SAHFs are detected by the preferential binding of DNA dyes, such as 4′,6-diamidino-2-phenylindole (DAPI), and the presence of certain heterochromatin-associated histone modifications (for example, H3 Lys9 methylation) and proteins (for example, heterochromatin protein-1 (HP1)). SAHFs also contain E2F target genes, which SAHFs are thought to silence.
The association between cellular senescence and organismal aging is highly suggestive of a causal link between these two processes, although establishing a direct causative relationship is challenging. senescence may impact on aging through two nonexclusive and possibly concomitant mechanisms. First, accumulation of senescent cells in tissues may reach a point that compromises functionality, and, second, senescence may limit the regenerative potential of adult stem cells (a limitation that may be produced as well by quiescence or apoptosis of stem cells). In one extreme, aging could be produced by the net accumulation of senescent cells; in the other extreme, the accumulation of senescent cells per se could be harmless, and aging could result primarily from the exhaustion of the regenerative potential of stem cells. Finally, and in relation to the above, it remains to be determined whether adult stem cells undergo senescence, quiescence, or apoptosis upon exhaustion of their proliferative potential.