Senolytics: A new class of drugs

Senlyotics are a new class of drugs that help remove stubborn senescent cells that refuse to enter apopotosis (programmed cell death) and instead remain in the body sending out toxic signals which have a range of negative consequences. Senescent cells should be removed by the immune system or by their own self-destruction programs, however over time they escape this process and accumulate where they are not wanted, such as in the joints. Senescent cells degrade the surrounding tissue integrity and also release harmful signals that raise the odds of nearby cells becoming senescent, this harmful signalling is known as the senescence-associated secretory phenotype or SASP for short. This research article which includes Judith Campisi, one of the better known researchers in senescent cell biology, may be of interest to those wishing to learn more about SASP and its effects.

This year it was demonstrated in a landmark study that these cells could be removed by the use of Dasatinib (a cancer drug also known as Sprycell) combined with quercetin a common flavonol found in many foods and available as a dietary supplement. What was particularly interesting was the synergy these two compounds created when used together with the resulting removed cells being considerably greater than each compound used in isolation. The MMTP is proposing to test these very same compounds and apply them to lifespan studies to track long term as well as short term effects on health and longevity. The research abstract is below and we encourage those with a scientific interest to follow the link and read about the research, the implications of this new class of drugs are very important.

Abstract: The Achilles’ heel of senescent cells

from transcriptome to senolytic drugs The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

The full research paper is here if you wish to read more about how science is finding ways to remove senescent cells.