The accumulation of senescent cells with advancing age is harmful. Selectively destroying those cells, even as few as a third of them, and even just once in later life, produces significant benefits to health and life span in mice. Cells become senescent in response to molecular damage, or to the signaling of nearby senescent cells, or on reaching the Hayflick limit on cell replication, or in response to tissue injury. In youth, senescent cells are rapidly clearly by the immune system and programmed cell death, but in later life the balance of creation and destruction is tipped towards an ever-increasing number of such cells.
Senescent cells serve useful functions prior to running awry in old age. They help to coordinate regeneration and suppress the incidence cancer. They secrete signals that attract the attention of the immune system, spur growth, and provoke the short-term inflammation needed to resolve issues of damage in the body. Thus we might suspect that a blanket and continual removal of senescent cells could be harmful in some ways. In fact, mice do live longer when all senescent cells are continually removed, but that may only mean that the beneficial outcomes outweigh the negative outcomes, rather than there being no meaningful negative outcomes.
The present consensus is that periodic removal of senescent cells, which does produce rejuvenation and extend life span in mice, likely has no meaningful downside. It would clear out the problem lingering cells during short treatments, while at all other times allowing for the temporary formation of new senescent cells as needed, such as in response to injury. This consensus may or may not reflect reality, we shall see as ever more data accumulates. In today's open access paper, researchers hypothesize on the question of why senolytic treatments to clear senescent cells extend median life span to a greater degree than they extend maximum life span in mice. Does that outcome result due to harmful effects that arise in later life to counterbalance the benefits?
This seems a question that is hard to answer, involving the need for a much greater understanding of the relative contributions of different mechanisms of aging at different ages. It is quite possible that any one given mechanism of aging, such as cellular senescence, is more or less influential on mortality in middle age versus extreme old age. That may not require any great difference in the details of cellular senescence in an aging body, but rather arise because another mechanism becomes more important in late life, for reasons that have little to do with cellular senescence, outweighing gains due to a reduced burden of senescent cells. Without intervening in these other mechanisms, it is challenging to say anything about their importance. We only know that senescent cell clearance is exciting as a basis for rejuvenation because it was successfully attempted. Prior to that point, there was no good way to assign a relative importance to the role of cellular senescence in degenerative aging.
Whilst work continues to explore the possible therapeutic benefits of senolysis, we recently suggested that it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence. Entry into the senescent state appears to be regulated, presenting questions about why such a response should have evolved. It seems a priori unlikely that a purely negative action would be favoured by natural selection. In terms of potential benefits, cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. Furthermore, other studies have shown that cellular senescence is beneficially involved in wound healing, development, and tissue repair.
We recently brought these findings and ideas together and concluded that evolutionary logic strongly supports the idea that the latter positive contributions are the main reason for the evolution of cellular senescence. We further suggested that, since the immune system appears to play a role in clearing senescent cells once they have performed their temporary functions, the observed age-related accumulations of senescent cells might arise simply because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).
The importance of understanding the role of senescent cells is further indicated by recent senolysis studies in mice, where it was found that treatment with senolytics resulted in a substantial increase in mean and median survival times. However, in each of the studies there was much less increase in the maximum survival time. Such an outcome is only possible if, following senolytic treatments, the deaths that are postponed to produce the increased mean / median lifespans become concentrated in the interval prior to the relatively unaltered maximum lifespan. Such a phenomenon constitutes a 'compression of mortality', which needs to be explained
We developed computer simulations of three possible mechanistic scenarios in order to gain a better understanding of possible modes of action of senolytic treatments. Scenario A, which supposes simply that senescent cells are all-important in ageing, was shown to be incompatible with experimental findings. Scenario B, which allows for other forms of damage to be involved and which also allows for senescent cells to drive these other forms of damage to some degree, was also found not to explain the data, although it does generate some interesting behaviours. In contrast, Scenario C proved to have the potential to explain the experimental findings. Scenario C includes the idea that the immune system plays an important role in removing senescent cells and related damage, but that this 'repair capacity' of the immune system is also negatively affected by senolytic drugs. In the case of a single senolytic treatment the repair capacity can recover, but if the treatment is given continuously (as in all the experimental studies), the repair capacity is chronically reduced. This leads to an accelerated accumulation of damage, causing a faster increase of mortality.