Senolytic drugs reverse damage caused by senescent cells in mice

July 9, 2018, National Institutes of Health

Injecting senescent cells into young mice results in a loss of health and function but treating the mice with a combination of two existing drugs cleared the senescent cells from tissues and restored physical function. The drugs also extended both life span and health span in naturally aging mice, according to a new study in Nature Medicine, published on July 9, 2018. The research was supported primarily by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH).

A research team led by James L. Kirkland, M.D., Ph.D., of the Mayo Clinic in Rochester, Minnesota, found that injecting even a small number of senescent cells into young, healthy mice causes damage that can result in physical dysfunction. The researchers also found that treatment with a combination of dasatinib and quercetin could prevent cell damage, delay physical dysfunction, and, when used in naturally aging mice, extend their life span.

"This study provides compelling evidence that targeting a fundamental aging process—in this case, cell senescence in mice—can delay age-related conditions, resulting in better health and longer life," said NIA Director Richard J. Hodes, M.D. "This study also shows the value of investigating biological mechanisms which may lead to better understanding of the aging process."

Many normal cells continuously grow, die, and replicate. Cell senescence is a process in which cells lose function, including the ability to divide and replicate, but are resistant to cell death. Such cells have been shown to affect neighboring ones because they secrete several pro-inflammatory and tissue remodeling molecules. Senescent cells increase in many tissues with aging; they also occur in organs associated with many chronic diseases and after radiation or chemotherapy.

Senolytics are a class of drugs that selectively eliminate senescent cells. In this study, Kirkland's team used a combination of dasatinib and quercetin (D+Q) to test whether this senolytic combination could slow physical dysfunction caused by senescent cells. Dasatinib is used to treat some forms of leukemia; quercetin is a plant flavanol found in some fruits and vegetables.

To determine whether senescent cells caused physical dysfunction, the researchers first injected young (four-month-old) mice with either senescent (SEN) cells or non-senescent control (CON) cells. As early as two weeks after transplantation, the SEN mice showed impaired physical function as determined by maximum walking speed, muscle strength, physical endurance, daily activity, food intake, and body weight. In addition, the researchers saw increased numbers of senescent cells, beyond what was injected, suggesting a propagation of the senescence effect into neighboring cells.

To then analyze whether a senolytic compound could stop or delay physical dysfunction, researchers treated both SEN and CON mice for three days with the D+Q compound mix. They found that D+Q selectively killed and slowed the deterioration in walking speed, endurance, and grip strength in the SEN mice.

In addition to young mice injected with , the researchers also tested older (20-month-old), non-transplanted mice with D+Q intermittently for 4 months. D+Q alleviated normal age-related physical dysfunction, resulting in higher walking speed, treadmill endurance, grip strength, and daily activity.

Finally, the researchers found that treating very old (24- to 27-month-old) mice with D+Q biweekly led to a 36 percent higher average post-treatment life span and lower mortality hazard than control mice. This indicates that senolytics can reduce risk of death in old mice.

"This is exciting research," said Felipe Sierra, Ph.D., director of NIA's Division of Aging Biology. "This study clearly demonstrates that senolytics can relieve physical dysfunction in . Additional research will be necessary to determine if compounds, like the one used in this study, are safe and effective in clinical trials with people."

The researchers noted that current and future preclinical studies may show that senolytics could be used to enhance life span not only in older people, but also in cancer survivors treated with senescence-inducing radiation or chemotherapy and people with a range of senescence-associated chronic diseases.

Explore further: Researchers uncover new agents

More information: Senolytics improve physical function and increase lifespan in old age, Nature Medicine (2018). DOI: 10.1038/s41591-018-0092-9 , https://www.nature.com/articles/s41591-018-0092-9

Related Stories

Researchers uncover new agents

March 9, 2017
Mayo Clinic researchers have uncovered three new agents to add to the emerging repertoire of drugs that aim to delay the onset of aging by targeting senescent cells - cells that contribute to frailty and other age-related ...

Link between cells associated with aging and bone loss

August 21, 2017
Mayo Clinic researchers have reported a causal link between senescent cells - the cells associated with aging and age-related disease - and bone loss in mice. Targeting these cells led to an increase in bone mass and strength. ...

Elimination of senescent cells improves lung function in mice

August 4, 2016
Most cells can divide only a limited number of times and eventually undergo permanent cell cycle arrest, a state known as cellular senescence. Cellular senescence is mediated by activation of specific cellular signaling pathways ...

Another piece to the puzzle in naked mole rats' long, cancer-free life

February 6, 2018
With their large buck teeth and wrinkled, hairless bodies, naked mole rats won't be winning any awards for cutest rodent. But their long life span—they can live up to 30 years, the longest of any rodent—and remarkable ...

Long-term benefits of 'senolytic' drugs on vascular health in mice

February 11, 2016
Building on previous studies, Mayo Clinic researchers have demonstrated significant health improvements in the vascular system of mice following repeated treatments to remove senescent cells. They say this is the first study ...

Researchers reduce stem cell dysfunction and metabolic disease in aged mice

January 4, 2016
Mayo Clinic researchers have taken what they hope will be the first step toward preventing and reversing age-related stem cell dysfunction and metabolic disease. That includes diabetes, which affects 12.2 million Americans ...

Recommended for you

3-D bioPen: A hydrogel injection to regenerate cartilage

September 25, 2018
Highly specialized cartilage is characteristically avascular and non-neural in composition with low cell numbers in an aliphatic environment. Despite its apparent simplicity, bioengineering regenerative hyaline cartilage ...

Skin wounds in older mice are less likely to scar

September 25, 2018
Researchers have discovered a rare example in which the mammalian body functions better in old age. A team at the University of Pennsylvania found that, in skin wounds in mice, being older increased tissue regeneration and ...

Study finds that enzymes 'partner up' to accelerate cancer, aging diseases

September 25, 2018
A new study from molecular biologists at Indiana University has identified cellular processes that appear to supercharge both the growth and shrinkage of the chemical "caps" on chromosomes associated with aging, called telomeres.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy

September 25, 2018
Massachusetts General Hospital (MGH) researchers have found that extracellular RNA (exRNA) in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about ...

Evidence that addictive behaviors have strong links with ancient retroviral infection

September 24, 2018
New research from an international team led by Oxford University's Department of Zoology and the National-Kapodistrian University of Athens, published today in Proceedings of the National Academy of Sciences (PNAS), shows ...

Taking a catnap? Mouse mutation shown to increase need for sleep

September 24, 2018
Sleep is vital for adequate functioning across the animal kingdom, but little is known about the physiological mechanisms that regulate it, or the reasons for natural variation in people's sleep patterns.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

dirk_bruere
not rated yet Jul 09, 2018
This drug combination was reported more than 2 years ago

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.