NEW CLASS OF DRUGS DRAMATICALLY INCREASES HEALTHY LIFESPAN
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.
The new research was
published March 9 online ahead of print by the journal Aging Cell.
The scientists coined
the term "senolytics" for the 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
Senescent cells --
cells that have stopped dividing -- accumulate with age and accelerate the
aging process. 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 scientists were
faced with the question, though, of how to identify and target senescent cells
without damaging other cells.
The team suspected
that senescent cells' resistance to death by stress and damage could provide a
clue. Indeed, 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. This
finding provided key criteria to search for potential drug candidates.
Using these criteria,
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.
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."
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