Fight Aging!

Today I thought I'd point out publicity materials for recent research from yet another group involved in the search for senolytic drugs to clear senescent cells from the body. The position taken is conservative - at least in part - but that is the style of the formal scientific community. Excitement in print is not the done thing. Nonetheless, it is becoming something of a challenge to hold a very conservative position on clearance of senescent cells as one of the foundations for rejuvenation therapies at the present point in time. It takes some rigor to stand up and say that this may still all go nowhere, and much more needs to be done to prove utility. The evidence in animal studies is robust and compelling, and growing more so with every passing month: extended life spans in mice, slowed and reversed mechanisms for age-related diseases, and measures of tissue aging turned back in specific organs. Behind the animal studies lies decades of evidence to support the role of senescent cells in aging and age-related disease in humans.

Maintaining a strongly conservative position until the very last moment is very much a part of the culture of science in our era. No-one is crucified quite so extensively as the scientist who makes bold predictions that then prove incorrect, or even just not entirely correct. The entire scientific community is haunted by the spirits of Pons and Fleischmann, now and for a time yet, but that is merely the easiest of many examples to reach for. The scientist who remains exceptionally and overly conservative, on the other hand, to the point of holding back his or her field, is only pilloried decades down the line, far too late to offer any threat to career and livelihood. People can and should do as they will, following inquiry and progress, but where such incentives exist, it is wise to note their existence while listening to the output of the scientific community. The aging research community in particular was until very recently one in which a great deal of informal policing took place, guiding researchers away from work and public pronouncements on the prospects for the treatment of aging as a medical condition. Who knows how much further along we might have been absent the decades of that stifling culture, thankfully now done away with.

In any case, below find a conservative view for the present state of research and development in the cellular senescence field - which is to say nowhere near as conservative as it would have been a few years ago, or were the author not planning to found a company to develop a senolytic treatment. But a little cold water never hurts for those of us who are enthusiastic about the prospects for this line of research in the near future. There is, after all, still work to be done before the public can travel to overseas clinics to obtain the first therapies with the confidence that comes with initial human trials: the dose-response curve in mice and humans needs fleshing out to set expectations; we'd like to see better alternative senolytic drugs, those that are not chemotherapeutics with interesting side-effects at higher doses; a variety of service companies need to mature and collaborate. All of this will take a few years to settle down into a treatment with known outcomes (measured in terms of proportion of senescent cells removed and short-term side-effects), a low enough cost for the public at large, and that is available via medical tourism in at least a few clinics.

Anti-aging therapies targeting senescent cells: Facts and fiction

It's an exciting time to be an elderly mouse. Researchers believe that by removing senescent cells (cells with a persistent damage response), which naturally accumulate with age, senior rodents can regrow hair, run faster, and improve organ function. This strategy may bring us one step closer to the "fountain of youth," but it's important to be cautious and not hype. The removal of senescent cells, first discovered in the 1960s, received renewed interest in the 2010s as a therapeutic option to combat some aspects of aging. Researchers noticed that these permanently arrested cells accumulate in mature tissue and that some of them secrete factors that are harmful to tissue function and impair their neighboring cells. To explain what causes this noise in the system, a new paper proposes a "senescence-stem lock model" in which the chronic secretion of pro-inflammatory factors by these senescent cells keeps neighboring cells in a permanent stem-like state and thereby prevents proper tissue renewal.

There are three milestones for realistic translation of an anti-senescence approach. Firstly, the proof of concept. Several studies have already addressed whether senescence is a cause of aging and whether its elimination stalls this process. By taking out senescent cells, naturally aging mice lived 25% longer, which is evidence that it could be possible. Secondly, the development of safe therapeutics. Anti-senescent drugs are already being tested, but none of them have yet to be deemed safe because they also target pathways expressed by non-senescent cells. It is likely that this marker will be passed in the near future. Thirdly, reversal of aging. Researchers will need to identify whether clearance of senescence can also be applied retrospectively to counteract features of natural aging that have already manifested. Although aging does seem like it can be stalled through therapeutic compounds, it remains unclear whether age-related diseases can be completely deterred.

"When bringing in a defective car for repairs it is insufficient to remove the rust and broken parts; you also want to replace these. A perfect anti-senescence therapy would not only clear senescent cells, but also kick-start tissue rejuvenation by stimulating differentiation of nearby stem cells. This may be complementary with, for instance, the exciting approaches recently made in the field of transient expression of stem cell factors. I would also advise caution for claiming too much, too soon about the benefits of the fast-growing list of therapeutic compounds that are being discovered. That being said, these are clearly very exciting times, and I am confident we will find applicable anti-senescence treatments that can counteract age-related pathologies."

The Fountain of Youth by Targeting Senescent Cells?

The potential to reverse aging has long been a tantalizing thought, but has equally been considered mere utopia. Recently, the spotlights have turned to senescent cells as being a culprit for aging. Can these cells be therapeutically eliminated? When so? And is this even safe? Recent developments in the tool box to study senescence have made it possible to begin addressing these questions. It will be especially relevant to identify how senescence impairs tissue rejuvenation and to prospectively design compounds that can both target senescence and stimulate rejuvenation in a safe manner.

Given the recent high-profile reports on this topic, the idea of fighting the effects of aging by targeting senescence is at least plausible. However, it is surprising that in decades of modern research, and the roughly half a century in which senescence has been known, nobody has discovered compounds that are beneficial to health by influencing senescence. It is therefore important to separate fact from speculation and temper unrealistic expectations. Targeting senescence may simply not lead to the fountain of youth. That being said, with anti-senescence therapies we are the furthest we have ever been on the path to healthspan extension and restoration of the loss of health experienced during aging.

From ongoing research, it will become clear to what extent senescent cells can indeed inflict a permanent lock in the stemlike state of their surrounding cells and whether targeting senescence may influence tissue repair and rejuvenation. Targeting senescence and stimulating rejuvenation might at least potentially counter individual age-related diseases and in doing so, we might be getting closer to achieving the goal of developing a 'therapy' against aging. Coming years will undoubtedly see exciting developments to come.

Abstract 2843: TASC1, a selective anti-senescence therapeutic which potently and selectively counteract resistance to chemo- and radiotherapy

Cellular senescence, induced by chemotherapy and radiotherapy, can drive therapy resistance in vivo. Senescence is a tumor suppressive mechanism, but senescent cells can secrete a range of proteins that ironically promote tumor growth, migration and metastazation and therapy resistance. Recent evidence has shown that genetic removal of senescent cells indeed causes a strong reduction in tumor growth and metastasis formation. Unfortunately however, therapeutic options to remove senescent cells are currently lacking. Here, we show the development and optimization of a biochemical compound, TASC1, that potently and selectively kills senescent cells in vitro and in vivo and lowers organ toxicity in a mouse model employed to address the off-target effects of cancer therapy.