The SENS Research Foundation should need no introduction to this audience, but, just in case, this is one of the few non-profit organizations dedicated to advancing the state of the art in rejuvenation research and development. The focus of the SENS Research Foundation staff is on unblocking lines of research that are presently moving too slowly, rather than on reinforcing success. The co-founder, Aubrey de Grey, assembled the Strategies for Engineered Negligible Senescence (SENS) going on twenty years ago. It was, and is, a synthesis of what is known in the research community regarding the root causes of aging. In the SENS model, a cause of aging is a form of damage that occurs and accumulates as a result of the normal operation of cellular metabolism.
Among these causes of aging is the accumulation of senescent cells, cells that should be destroyed, but linger to cause harm via their inflammatory signaling. It took more than a decade for the suggestion in the SENS proposals that senescent cells should be targeted for destruction to emerge as a well supported line of research, and that required a great deal of advocacy and bootstrapping behind the scenes. The field has advanced considerably since then, and at an accelerating pace. Today, numerous biotech companies are developing what have come to be known as senolytic therapies, capable of selectively destroying senescent cells. There is overwhelming evidence from animal studies for senolytics to be beneficial - to extend healthy life, and more importantly to significantly turn back age-related disease and dysfunction at a late stage. This year, the first clinical trials provided initial data to show that senolytic therapies should function in the same way in humans.
On occasion, the SENS Research Foundation staff publish answers to questions from the community. This month, the topic is clearance of senescent cells, and whether not it is an unalloyed benefit. Is there any reason we should hold back from periodically clearing all lingering senescent cells in old tissues? The animal data so far suggests few caveats; the downsides remain largely theoretical rather than actual, while the upsides are self-evident. The essay is well supported by references; you should read it all, not just the excerpt shown here.
This month's question from the community: when senolytic drugs cause senescent cells to die, other (younger) cells need to divide and take the place of the dead cells. This cell division causes telomere shortening, thus possibly creating new senescent cells. How is it that the process of killing senescent cells is not self-defeating if new senescent cells are being created?
There are a couple of ways to come at this question. The first is to just look at the astonishing beneficial effects of senolytic drugs or gene therapies in aging mice and mouse models of age-related disease. In these studies, senolytic drugs have restored exercise capacity and capacity to form new blood and immune precursor cells in aging mice to near youthful norms, while preventing age-related lung hypofunction, fatty infiltration into the liver, weakening or failure of the heart, osteoporosis, and hair loss. These treatments have also prevented or treated mouse models of diseases of aging like osteoarthritis, fibrotic lung disease, nonalcoholic fatty liver disease, atherosclerosis, cancer and the side-effects of conventional chemotherapy, as well as neurodegenerative diseases of aging like Parkinson's and Alzheimer's diseases ... and on and on! So whatever collateral damage might ensue from ablating senescent cells, it's pretty clear that senolytic treatments are doing a lot more good than harm.
But let's drill down on the underlying reasoning of the question a little more. Suppose (as the question posits) that every time you destroy a senescent cell, a progenitor cell (one of the partly-specialized tissue-specific cells that repopulate a tissue with mature cells specific to that tissue) replicates to create a new cell to take its place. In fact, studies do show that when senescent cells are killed in a tissue, the progenitor cells begin to multiply and/or to function better as stem cells. This benefit is not due to the progenitor cells automatically replicating themselves and taking the place of the senescent cell, but because the baleful secretions spewed out of senescent cells inhibit the progenitor cells' regenerative function, such that destroying senescent cells allows the progenitor cells to begin working properly again. This is observed in blood-cell-forming cells, cardiac progenitor cells, bone-forming cells, and the cells that form new fat cells - in both mice and now (in a small, short-term clinical trial) even in humans!
So does this support the worry behind the question? Not really. It just takes a moment's thought to realize that just one such replication can't possibly be enough to drive a stem/progenitor cell into senescence. Still, even if a single round of senolytics isn't enough to drive your stem cells senescent, what if you turn one tissue stem cell senescent for every two times they are triggered to proliferate by senolytic therapy - or every three, or four, or ten? Might a single round of senolytic drugs be a net benefit, whereas repeated treatments over a lifetime would deplete tissue stem cells step by step, eventually riddling the body with senescent cells and leaving the patient (murine or human) worse off over the long term? Fortunately, we have long-term studies to address that question - and they tell us again that the answer is "no."