p53 in Cellular Senescence
Cellular senescence is one of the contributing causes of aging, in the sense that senescent cells accumulate in old tissues. Even when only a tiny fraction of all cells are senescent, their signaling causes chronic inflammation and disruption of tissue function. Senescence is, however, a helpful program when these cells exist only temporarily and are promptly destroyed. The signaling that is so harmful when maintained over the long term aids in wound healing and suppression of cancer when present for a short time only. Since the comparatively recent acceptance of senescent cells as an important cause of aging, the research community has spent a great deal of effort in better understanding the biochemistry of cellular senescence. The open access paper here is a representative example of the output of these scientific initiatives.
The classical depiction of senescence as a static, uniform, and irreversible cellular state has been progressively reconsidered, and senescence is now envisioned as a dynamic and multistep process. During the initiation of the senescence, which is also called as "primary senescence", the stressed cells may be still able to repair and/or eliminate the cause of the damage and then can escape from cell cycle arrest. For example, it was demonstrated that a small proportion of senescent embryonic fibroblasts were capable of reentering the cell cycle when p53 expression was suppressed through RNA interference.
However, these rare cases are considered to take place only in the early stage of senescence establishment. Moreover, persistent exposure to a damaging environment leads the cells to the next stage of senescence, known as "developing senescence", where cells are poised to demonstrate full-featured senescence. Nevertheless, if senescent conditions continue for extended periods of time, as it happens, for instance, in the aging process, the cells enter a third phase of senescence, known as "late senescence", in which they may be characterized by heterogeneous phenotypes such as flattened and enlarged cell shape, expanded lysosomal compartment and vacuoles, increased metabolic rate and reactive oxygen species (ROS) production, senescence-associated secretory phenotype (SASP) secretion.
In most of the models studying senescent cells, p53 (as well as the DNA damage response proteins) seems to be involved in the earlier stages, and the time factor plays an important role in the entire process. p53 activity decreases with time, and this is consistent with the idea of p53 (and p21cip1) being a crucial factor for the induction of the senescence and a gate to an early phase and still reversible senescence. On the other hand, the subsequent increase of p16 activity would be responsible for a late senescent state characterized by a distinct and permanent senescence phenotype, which is no longer reversible through p53 inhibition.