Cellular senescence is one of the causes of degenerative aging. Normal somatic cells in adults become senescent at the end of their replicative life span, when they reach the Hayflick limit on cell divisions, or in response to damage or a toxic environment. Most such cells self-destruct or are destroyed by the immune system, but some linger to cause problems, ever more of them over the years. A senescent cell generates a mix of signals known as the senescence-associated secretory phenotype (SASP) that promotes inflammation, damages surrounding tissue structures, and alters the behavior of nearby cells for the worse. Senescence isn't all bad, however: in limited doses, it helps to lower the risk of cancer by shutting down those cells most at risk. It also occurs during wound healing and embryonic development, and plays necessary roles in both of those processes. Nonetheless, cellular senescence helps to kill us as we age, and as more of these cells accumulate in tissues, their presence speeds the progression of many age-related diseases.

Researchers are taking two broad approaches to cellular senescence at the present time. The first is to build therapies that can selectively destroy senescent cells, following the SENS rejuvenation model of periodic removal of damage. If the number of senescent cells is managed so as to keep that count low, then they will not cause further harm. This has the advantage of being straightforward and requiring little further research to put into practice. A range of demonstrated treatments and potential treatments already exist - gene therapies, immunotherapies, senolytic drugs, and so forth - and companies such as Oisin Biotechnologies and UNITY Biotechnology are bringing some of these technologies to the clinic. The second approach is nowhere near as far along, and involves altering the behavior of senescent cells to make the SASP less harmful. There is a long way to go yet in order to produce a decent therapy on this front, and it isn't clear how much potential there is in the present avenues of investigation, or how much more research is required to make meaningful progress. Such a therapy wouldn't remove senescent cells, and therefore would have to be a continual rather than periodic treatment.

There is a third potential approach, however, which is to revert senescent cells back to a normal state of operation. In the ordinary course of events, senescence is thought to be an irreversible state, though there is a substantial grey area here, as nothing is black and white in biochemistry. There may well be different degrees and types of senescence, similar outcomes produced by different balances of the same varied collection of processes and triggers. I think it highly unlikely that the switch for senescence boils down to one controlling protein and one configuration. That said, cells are state machines and substantial reprogramming of that state has already been demonstrated, such as for induced pluripotency. Given sufficient understanding of the machinery and the signals involved, it should be possible to turn a senescent cell into a perfectly normal cell. There is the caveat that it will probably just turn right back again if the stimulus or damage that provoked the change in the first place is still around, however. Thus any practical approach to revert senescence is likely only useful if accompanied by other forms of repair or alteration, such as lengthening of telomeres to push the cell back from the Hayflick limit. It is an open question as to whether or not this sort of approach would cause further problems by putting damaged and older cells back into circulation, but to a certain extent that question is in the process of being answered by work on telomerase gene therapies and first generation stem cell therapies, both of which appear to produce that outcome to some degree. This is all highly speculative, however - there is a lot of work left to be accomplished to turn arguments and evidence into solid facts.

From my point of view none of this is really worth the effort for therapeutic development given that senescent cells can be destroyed to produce benefits, and anything other than destroying them is going to be much harder to achieve. It is of course useful from a pure science perspective; it adds to the map of metabolism and the way in which cellular biochemistry interacts with aging. With that in mind, the paper linked below is an example of researchers investigating some of the machinery that forms the switches and triggers that determine whether or not a cell adopts a senescent state. At this point the cutting edge of cellular biochemistry has moved well past simpler considerations of genes and proteins and is delving into the highly complex interactions that take place inside the processes of gene expression, wherein the genetic blueprint is converted into one or more proteins. This has numerous stages, and at every stage there is a dance of various regulatory molecules also produced from DNA. The closer that researchers look, the more there is to be mapped.

Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1