Drugs that dramatically increase healthy lifespan discovered by Scripps Research, Mayo Clinic

March 10, 2015

Sprycel (credit: Bristol-Myers Squibb)

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

They found two drugs — the cancer drug dasatinib (sold under the trade name Sprycel) and quercetin, a natural compound found in many fruits, vegetables, leaves and grains and also sold as a supplement that acts as an antihistamine and anti-inflammatory — can kill senescent cells. These are cells that have stopped dividing and accumulate with age, accelerating the aging process.

The scientists coined the term “senolytics for this new class of drugs.

“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 prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging,” said Mayo Clinic Professor James Kirkland, MD, PhD, senior author of the new study. “It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time.”

Finding the target

Since the “healthspan” (time free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that finding treatments that accomplish this in humans could have tremendous potential. The challenge was how to identify and target senescent cells without damaging other cells.

Using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of “pro-survival networks” that help them resist apoptosis or programmed cell death.

But when they tested dasatinib and quercetin in cell culture, these compounds were able to selectively induce death of senescent cells. 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.

Effects on health and aging

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.

However, Robbins noted that senescence is involved in a number of diseases and pathologies, so there could be any number of applications for these and similar compounds. “Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects.”

Researchers at The University of Texas Health Science Center and the Oklahoma Medical Research Foundation where also involved in the open-access research, which was published March 9 online ahead of print by the journal Aging Cell.

The work was supported by the National Institutes of Health, the Glenn Foundation, and the Clinical & Translational Science Awards.


Abstract of 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 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 inErcc1-/∆ 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.