Cells become senescent in response to reaching the Hayflick limit on replication, suffering molecular damage, or in an environment of tissue injury. A senescent cell ceases replication and begins to secrete an inflammatory mix of cytokines and growth factors, the senescence-associated secretory phenotype (SASP), rousing the immune system and provoking changes in surrounding cell behavior. Near all senescent cells are quickly destroyed, but with age these cells linger. The signaling that is useful in the short term for cancer suppression (by removing damaged and potentially damaged cells in the earliest stages of cancer) or regeneration from injury (by provoking greater cell activity) becomes very harmful when sustained for the long-term. Senescent cell accumulation is an important contributing cause of aging and age-related disease.
Cellular senescence is a phenomenon that has been known about for a long time. During recent years, it has gained growing interest as its causal involvement in the aging process has been corroborated by several experimental findings. Because of this, several groups and companies are developing senolytic approaches that aim to remove senescent cells from aged animals in the hope of achieving a rejuvenation and life extension effect. However, at the same time, cellular senescence is also seen as an anti-cancer strategy, which raises the question why interfering with an anti-cancer mechanism should increase life span?
The argument that antagonistic pleiotropy explains the anti-tumorigenic as well as the pro-tumorigenic and inflammatory properties of senescent cells is problematic, since there are multiple ways imaginable to break the link between positive and negative effects. In this paper, we discussed an alternative idea for the evolution of cellular senescence that focuses on the involvement of senescent cells in the repair of cell and tissue damage. From such a viewpoint, many properties of the SASP make much more sense and are actually beneficial. Additionally, the recent finding that also post-mitotic cells can display characteristics of cellular senescence, agrees well with this idea. While post-mitotic cells benefit from triggering a healing and repair mechanism, they do not profit from an anti-cancer process.
According to our interpretation, the negative effects of cellular senescence only emerge because the clearance of senescent cells by the immune system, once the repair process has finished, is imperfect. Senescent cells represent a very heterogeneous population, depending on the original cell type and on how senescence was triggered. We therefore proposed that there is a continuum of turnover rates, since the immune system is more or less capable of recognizing this range of subtypes. A mathematical model, which for simplicity only uses two types of senescent cells (removable and non-removable), achieves an excellent fit to experimental data. Interestingly, our model also predicts a slowdown of senescent cell turnover with age, in our case explained by an accumulation of non-removable senescent cells relative to removable ones.
For obvious reasons, there are high hurdles for the destruction of body cells. We propose that for this reason, the optimal strategy is for the immune system to accept a small fraction of false negatives, leading to the slow accumulation of senescent cells in the body. This, in turn, then leads to life-threatening consequences like chronic inflammation (inflammaging), degenerative diseases, and cancer. In this interpretation of cellular senescence, there needs to be a balance between beneficial effects (i.e., wound healing and tissue repair) and negative consequences (i.e., accumulation of senescent cells with inflammation and diseases).
To see how this differs from the idea that cellular senescence is an anti-cancer strategy, we have to return to the questions that we posed earlier. Why did evolution not break the connection of the antagonistic effects and why do organisms not rely exclusively on apoptosis as anti-cancer strategy? The discussed proposal makes it more difficult to break the antagonistic effects, since there is always a trade-off between overlooking too many senescent cells (false negatives) and killing too many healthy body cells (false positives). However, the situation can be improved quantitatively by somehow enabling the immune system to better recognize senescent cells. Indeed, it may be that this has already happened during the evolution of long-lived species, which accumulate senescent cells at a slower pace than short-lived species.
If this outline of the evolution of cellular senescence is correct, it also follows that the removal of accumulated senescent cells is a good strategy, as long as it does not interfere with the primary function of this process. Thus, a brief senolytic treatment would be suitable, while a chronically administered drug might be problematic.