New senolytic drugs eliminate senescent cells and improve cardiovascular function and improve healthspan in mice

A research team from The Scripps Research Institute (TSRI), Mayo Clinic and other institutions has identified a new class of drugs called “senolytics” that in animal models dramatically slows the aging process—alleviating symptoms of frailty, improving cardiac function and extending a healthy lifespan.

“We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” said TSRI Professor Paul Robbins, PhD, who with Associate Professor Laura Niedernhofer, MD, PhD, led the research efforts for the paper at Scripps Florida. “When senolytic agents, like the combination we identified, are used clinically, the results could be transformative.”

the team homed in on two available compounds—the cancer drug dasatinib (sold under the trade name Sprycel®) and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory.

Further testing in cell culture showed these compounds do indeed selectively induce death of senescent cells. The two compounds had different strong points. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall

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Remarkable Results

Next, the team looked at how these drugs affected health and aging in mice.

“In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan,” said Niedernhofer, whose animal models of accelerated aging were used extensively in the study. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”

In old mice, cardiovascular function was improved within five days of a single dose of the drugs. A single dose of a combination of the drugs led to improved exercise capacity in animals weakened by radiation therapy used for cancer. The effect lasted for at least seven months following treatment with the drugs. Periodic drug administration of mice with accelerated aging extended the healthspan in the animals, delaying age-related symptoms, spine degeneration and osteoporosis.

The authors caution that more testing is needed before use in humans. They also note both drugs in the study have possible side effects, at least with long-term treatment.

The researchers, however, remain upbeat about their findings’ potential. “Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds,” Robbins said. “Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects.”

Abstract

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 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 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-/∆ mice, delaying age-related symptoms and pathology, osteoporosis and loss of intervertebral disc proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.