Senolytics – a problem or a solution?

Question of the Month: Senolytics – Solution or Self-Defeating for Senescent Cells?

Michael Rae, SENS Research Foundation
Translated by Ariel Finerman, Habr
See references in the text of the translation or (including the list of references) in the original article.

When senolytics cause the death of senescent cells, other (younger) cells are required to replicate and take the place of the killed cells. This cell replication causes telomere shortening, which can lead to the formation of new senescent cells. How is it that the process of destroying senescent cells is not self-destructive if new senescent cells are created?

There are several ways to answer this question. First, just take a look at the amazing effects of senolytic drugs or gene therapy in old mice and mouse models of age-related diseases. In these experiments, senolytic drugs restored physical activity and the ability to form new progenitor blood and immune cells at the level of young mice, while preventing age-related hypofunction of the lungs, fatty infiltration into the liver, weakening or cardiac arrest, osteoporosis and baldness. They also prevented or cured mouse models of aging diseases such as osteoarthritis, fibrotic lung diseases, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, cancer and side effects of conventional chemotherapy, as well as neurodegenerative diseases such as Parkinson's and Alzheimer's diseases and many others! Thus, whatever collateral damage may occur when killing senescent cells, it is quite clear that senolytic treatment brings much more benefits.

But let's take a better look at the root cause of the issue. Suppose (according to the question) that every time you destroy a senescent cell, a progenitor cell (one of the partially specialized tissue-specific cells that populate the tissue with mature cells specific to that tissue) replicates to create a new cell. And experiments show that when senescent cells die in the tissue, progenitor cells begin to multiply and/or function better. But the reasons are not that the progenitor cells automatically replicate and replace the senescent cell, but that the inflammatory factors released from the senescent cells suppress their regenerative function, so that the destruction of senescent cells allows them to start working normally again. This is observed in bone marrow cells, in progenitor cells of the heart muscle, in bone–forming cells, and in cells forming new fat cells - both in mice and (in a small clinical trial) in humans!

Well, are the questioners right? Actually, no. It takes only a moment's thought to realize that such replication alone may not be enough to lead a stem/progenitor cell to senescence: if this were the case, of course, senolytic therapy would not be able to reduce the total number of senescent cells. But experiments clearly show that the use of senolytics reduces the total number of senescent cells in tissues.

In addition, if these drugs did not kill more senescent cells than they generated indirectly, you would not have received these phenomenal effects – and, of course, you have received them in many tissues and many models of aging and age-related diseases.

Returning to the question

However, even if one course of senolytics is not enough to cause stem cell aging, what if you trigger the aging of stem cells in tissues every two courses – or every three, or four, or ten? Can one course of senolytic drugs bring net benefits, while cyclical treatment throughout life will gradually deplete the tissue stem cell pools, and eventually saturating the body with senescent cells and leaving the patient (mouse or human) worse off in the long run?

Fortunately, we have research on this question – and they tell us again that the answer is "no".

In an experiment that played a crucial role in launching a revolution in senolytic therapies, mice were designed with a genetic mechanism of apoptosis embedded in all their cells, which did not function until activated by a two-part instruction: expression of the p16 gene, which is characteristic of senescent cells; and an activating drug that scientists could use to control the rate of senolytic activity. The scientists then waited until the animals were 12 months old (by human standards, this is similar to a person aged 40) before administering the drug for the first time. They then continued to administer the drug every two weeks for the next six months, and in total the animals received 13 cycles of senolytic therapy and were roughly similar to humans at the age of 50.

Experiments have clearly shown that animals have benefited from senolytic therapy even after many continuous cycles during their natural middle and early old age. For example, animals whose mechanism of self-destruction of senescent cells was triggered preserved kidney function better, and fewer of them died in middle and early old age.

Scientists studied the effect of several courses of senolytic therapy on the total number of senescent cells, as well as whether they significantly depleted the reserves of functional progenitor cells in animals. To do this, scientists studied the effect of therapy on preadipocytes (cells that form fat cells (adipocytes)) in the adipose tissue of animals, it is a convenient place to search, because it is easy to find, and it accumulates a considerable number of senescent cells.

After about 13 cycles of senolytic therapy, the animals had only 1/8 of the number of senescent preadipocytes compared to the control (Fig. 1 (a)) – a very significant obvious decrease. But even in this case, the animals had functional progenitor cells as in the control. (Fig. 1 (b)).

Activation of senolytic genes of "self-destruction" throughout life reduces the number of senescent cells (a), practically without affecting the number of progenitor cells (b) in adipose tissue. The columns in (b) with the # icon show statistically significant differences.

In another study, scientists injected physetin – a plant senolytic substance – into mice every day, starting from the moment when they were already in early old age (and thus already had both a large number of senescent cells and a dwindling number of progenitor cells) and continued until their death. This treatment reduced the number of senescent cells in most tissues by about 50%. In addition, the animals lived much longer, and age-related changes were less pronounced in their tissues than in control animals.

We remove the old and implant the new

And yet, it is important to have many functional cells to take advantage of all the benefits of senolytic therapy. This was illustrated in an experiment using senolytic drugs or "self-destruct" genes in the treatment of animal models of osteoarthritis. When joint disease was initiated by trauma in young animals, it led to chronic joint damage and the accumulation of senescent cells in the synovium (the membrane surrounding the joint in which cells live that produce a special fluid that lubricates the joint). The destruction of senescent cells reduced inflammation in the joint, prevented its destruction and relieved pain in animals.

But the senolytic treatment was much less effective when scientists repeated the experiment on old animals, and the reasons shed some light on our original question. Compared to young animals, older animals accumulated much more senescent cells after their joints were damaged, and these cells were located in deeper layers of tissue, which was accompanied by more severe osteoarthritis. Perhaps this is due to the fact that in older animals, more cells have already received considerable damage from aging and were much easier to turn into senescent. And when senolytic treatment was administered to the old animals, the remaining healthy cells also did not respond: the burden of zombie cells decreased, and the old animals still received some pain relief, but the genes that helped the young animals repair their damaged joints were not activated, and their cartilage did not improve. Scientists believe that this may be due to a decrease in the number or function of progenitor cartilage-forming cells caused by aging processes.

Similarly, the destruction of senescent cells in old mice reduced the excessive number of osteoclasts (bone-destroying cells) accumulating in aging bone, but did not restore the decreasing stock of bone-forming osteoblasts, a small number of which undoubtedly limited the rejuvenating effects of treatment.

In both cases, the absence of an increase in the number or activity of young cells was not the result of damage to senolytic treatment: a decrease in their number had already occurred before the start of treatment. Thus, the problem is not that senolytic therapy stops working or becomes destructive over time: rather, it focuses on only one type of damage, while aging causes diseases due to the accumulation of many types of cellular and molecular damage in our tissues. The solution is to combine the destruction of senescent cells with injections of fresh new functional cells using cell therapy. (Our analysis of past work on senolytic therapy in Parkinson's disease models for clinical use in combination therapy).

And if we go back to the initial question, it will also turn out to be a solution if it suddenly turns out that many cycles of senolytic therapy will lead to the aging of too many stem cells. But, as we have seen, all the evidence suggests that this will not be a problem during our current life.

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