Senolytic drugs reverse damage caused by senescent cells in mice

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 lifespan.

Senolytic drugs reverse damage caused by senescent cells in mice. Image credit: National Institutes of Health

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 which selectively eliminate senescent cells. In this study, the 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 senescent cells and slowed the deterioration in walking speed, endurance, and grip strength in the SEN mice.

In addition to young mice injected with senescent cells, 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.

The researchers noted that current and future pre-clinical 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. (National Institutes of Health)

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