This is an informative article from one of the Major Mouse Testing Project principals, covering at a high level the development of senolytic therapies, those capable of removing some fraction of the senescent cells that accumulate with age. Since senescent cells are one of the root causes of aging and age-related disease, removing them qualifies as a narrow form of rejuvenation therapy, one of the first to reach the point of clinical development. Work on senolytics reached its tipping point a couple of years ago, and progress has been rapid and promising since then, with the first study to show extension of life in mice via clearance of senescent cells published last year, and startup companies Oisin Biotechnologies and UNITY Biotechnology working on bringing treatments to the clinic.
As your body ages increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful chemical signals, these encourage other nearby cells to also enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer. Senescent cells normally destroy themselves via a programmed process called apoptosis and they are also removed by the immune system, however the immune system weakens with age and increasing numbers of these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc further driving the aging process.
The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene and later experiments showed the same could be achieved using small molecules. Senolytics are a relatively new class of drugs that focuses on the removal of senescent cells. Senescent cells comprise a small number of total cells in the body but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together form the senescence-associated secretory phenotype or SASP. The resulting SASP is thought to significantly contribute to aging and cancer, and thus senolytics and removal of SASP is a potential strategy for promoting health and longevity.
It was discovered that senescent cells have increased expression of pro-survival genes, consistent with their resistance to apoptosis. Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were dasatinib and quercetin which were both able to remove senescent cells but were better in differing tissue types. However it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types. In other studies whilst only removing thirty percent of senescent cells there were improvements to age related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of aging and promoting healthy longevity.
Even more recently a further study demonstrated the benefits of senolytics for certain aspects of vascular aging. This is the first study to confirm that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, and could be a viable therapeutic to reduce morbidity and mortality from cardiovascular diseases. Dasatinib and quercetin are already approved for use by humans too so the application of these drugs or improved drugs based on them could be developed relatively quickly. However to date the combination of dasatinib and quercetin has yet to be tested in relation to its potential to increase maximum healthy lifespan. Current senolytic studies have focused only on health improvements rather than the long term effects (either bad or good) of this type of approach. The Major Mouse Testing Project aims to address this missing and vitally important question, can these senolytics promote healthy longevity?