A paper published in GeroScience has reported that older mice taking the well-known senolytic combination of dasatinib and quercetin (D+Q) are able to build muscle more like young mice.
Senescent cells harm muscle development
In this paper, the researchers cite their prior research showing that the SASP, in conjunction with its known inflammatory effects, harms the ability of muscle progenitor cells to proliferate, thus depleting the ability of muscle to regenerate . That paper showed that removing senescent cells through the senolytic combination of dasatinib and quercetin (D+Q) allowed for muscle regeneration in old mice, although it did not benefit old mice.
In this new research, the research sought to determine whether this also applied to muscle hypertrophy: that is, whether senolytics can help older organisms to build muscle through resistance training.
Resistance training for mice
Unfortunately, it isn’t possible to get mice to the gym. Therefore, the researchers used an established technique of removing “synergistic” muscle tissue (in this case, of the soleus and the gastrocnemius) in order to spur the development of the targeted muscle (in this case, the plantaris) . Sham surgeries, in which no tissue was actually removed, were performed on a control group.
The plantaris muscles of both young (5 to 6 months) and old (23 to 24 months) mice increased slightly compared to their respective control groups, although young mice had significantly more muscle mass both before and afterwards, and while older mice stopped growing plantaris muscle tissue after a week, younger mice continued to grow it for two weeks.
As expected, senescent cells, which increase in muscle tissue after exercise, were found in substantially greater numbers in the older mice, especially after 14 days. While their numbers varied wildly from mouse to mouse, older mice had substantially and significantly more senescent cells than younger animals did, according to tests for the known senescent biomarkers p21 and SA-ß-gal.
The effects of senolytics
The effects of D+Q on senescent cells were significant, in line with previous murine studies. Cells expressing SA-ß-gal were decreased to a third of their previous level, while cells expressing p21 were approximately halved.
The researchers’ main hypothesis, that D+Q would increase muscle mass upon resistance training, was shown to be correct: older mice given this senolytic combination and the surgery had greater plantaris muscle mass and superior fiber characteristics to the older mice given only the surgery. However, this comes with an important caveat. Older mice that received D+Q but only received the sham surgery, which did not impart resistance effects on their plantaris muscles, actually had muscles that were weaker or equal to the mice that did not receive D+Q at all.
In other words, in the absence of resistance training, senolytics were not shown to be of any benefit and may have even have caused harm below the level of statistical significance.
Senescent cells in human volunteers
Fortunately, it is possible to get people to the gym. In a cohort of human volunteers between 20 and 39 years old, nearly no senescent cells were found in muscle tissue; however, after resistance exercise, p21 and SA-ß-gal tests found the presence of these senescent cell biomarkers, although their numbers varied wildly as they did in mice. This data suggests that the results found in mice may apply to human beings, although this was not a human trial.
The finding that senolytics may only have value in building muscle when combined with resistance exercise is a very important one that will certainly guide future trial design. If the results found in mice are recapitulated in human beings, a senolytic and exercise combination may be prescribed in the near future in order to give older people back some of their mobility and fight back against frailty.
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 Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., … & Peterson, C. A. (2022). Deletion of SA ß-Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, e13528.
 Kirby, T. J., McCarthy, J. J., Peterson, C. A., & Fry, C. S. (2016). Synergist ablation as a rodent model to study satellite cell dynamics in adult skeletal muscle. In Skeletal Muscle Regeneration in the Mouse (pp. 43-52). Springer, New York, NY.
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