Senescent cells increase in many tissues with aging and are often associated with inflammation, tissue damage, and age-related diseases. Senolytics are a class of drugs that selectively eliminate these cells. In a study published this week in the journal Nature Medicine, a team of researchers found that treatment with a combination of two senolytic drugs — dasatinib plus quercetin — could prevent cell damage, delay physical dysfunction and extend lifespan in naturally aging mice. The team also found that injecting even a small number of senescent cells into young, healthy mice causes damage that can result in physical dysfunction.
Microscopic image of senescence on mouse embryonic fibroblast cells; blue-green areas indicate the expression of senescence-associated beta-galactosidase. Image credit: Y. Tambe / CC BY-SA 3.0.
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.
In the current study, Mayo Clinic researcher Dr. James L. Kirkland and co-authors used a combination of dasatinib and quercetin (dasatinib is used to treat some forms of leukemia; quercetin is a plant flavanol found in some fruits and vegetables) to test whether this senolytic combination could slow physical dysfunction caused by senescent cells.
To determine whether these cells caused physical dysfunction, they first injected young mice with either senescent cells or non-senescent control cells.
As early as two weeks after transplantation, the senescent 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 scientists 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, they treated both senescent and control mice for three days with the senolytic cocktail.
They found that dasatinib plus quercetin selectively killed senescent cells and slowed the deterioration in walking speed, endurance, and grip strength in the senescent mice.
In addition to young mice injected with senescent cells, the study authors also tested older, non-transplanted mice with two senolytic drugs intermittently for 4 months.
The senolytic cocktail alleviated normal age-related physical dysfunction, resulting in higher walking speed, treadmill endurance, grip strength, and daily activity.
Finally, the team found that treating very old mice with the compound mix biweekly led to a 36% higher average post-treatment lifespan and lower mortality hazard than control mice. This indicates that senolytics can reduce risk of death in old mice.
“Current and future preclinical studies may show that senolytics could be used to enhance lifespan 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,” the researchers said.
“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 Dr. Richard J. Hodes, Director of the National Institute on Aging (NIA), who wasn’t involved with the study.
“The study also shows the value of investigating biological mechanisms which may lead to better understanding of the aging process.”
“This is exciting research. This study clearly demonstrates that senolytics can relieve physical dysfunction in mice,” added Dr. Felipe Sierra, Director of NIA’s Division of Aging Biology.
“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.”
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Ming Xu et al. Senolytics improve physical function and increase lifespan in old age. Nature Medicine, published online July 9, 2018; doi: 10.1038/s41591-018-0092-9
