Skin & Muscle

Latest Mayo Clinic Study Shows Senolytic Combo Counters Age-Related Muscle Weakness 

Mayo Clinic researchers show that the senolytics dasatinib plus quercetin (D+Q) — drugs that eliminate senescent cells — strengthen the muscles of older mice.

By Daniel R. Miranda, Ph.D.

Key Points: 

  • D + Q lowers senescent cell (aged cell) burden and increases grip strength in older mice.
  • Senescent cells are elevated in older individuals and associated with reduced muscle strength. 

For older individuals, muscle weakness can make it difficult to get up from a chair, or even walk, let alone catch oneself in a fall. Sarcopenia, the rapid decline in muscle mass and strength associated with aging, is an obvious hazard to the elderly, yet there is no obvious treatment. However, the most recent aging science suggests that senescent cells — growth-arrested cells that accumulate with aging — may contribute to age-related losses in muscle strength. 

Mayo Clinic scientists report in Nature Aging that the senolytics D + Q enhance muscle strength in old mice. Zhang and colleagues confirm the senolytic — senescent cell killing — action of D + Q by showing that the combo reduces markers of senescence in muscle from older mice. Furthermore, it is shown that markers of senescence are elevated in the muscle of older individuals and correlated with decreased muscle strength. 

Senolytic Combo Counters Muscle Weakness in Older Mice  

To test whether senescent cells contribute to skeletal muscle aging, Zhang and colleagues administered D + Q to 20-month-old (equivalent to about 65 human years) mice. They found that D + Q countered the age-associated increase in multiple senescence-related genes. While muscle size was not changed by D + Q treatment, grip strength was increased, suggesting that age-related muscle weakness can be mitigated by eliminating senescent cells. 

(Zhang et al., 2022 | Nature Aging) Age-Related Deficits in Grip Strength Countered by D + Q. Old mice fed D + Q (Old-DQ) exhibited greater grip strength than untreated old mice (Old-Veh).

Senescence Associated with Reduced Muscle Strength in Elderly Individuals 

Zhang and colleagues next reanalyzed data from a clinical trial (NCT01477164) studying the effects of aerobic and resistance exercise in older adults. They found that the muscle of older adults had increased signs of senescent cells. In the clinical trial, the older adults performed a one rep max leg exercise to assess strength. The Mayo Clinic investigators found that a lower one rep max was correlated with increased markers of senescent cells, suggesting that senescent cells contribute to muscle weakness in older adults.

(Zhang et al., 2022 | Nature Aging) Elevated Senescent Cells in Muscle of Older Adults. A marker for senescence (P16) was observed at higher levels in the nuclei of muscle cells from older adults compared to younger adults.  

The findings of Zhang and colleagues suggest that senescent cells contribute to the muscle weakness associated with sarcopenia. Muscle cells go into a state of senescence in response to stress and are usually eliminated by our immune system. However, with aging our immune system is unable to get rid of senescent cells, and they build up. Since senolytics like D + Q can bypass the immune system and get rid of senescent cells, they can potentially treat some of the muscle weaknesses associated with sarcopenia.

Senolytics for Reversing Muscle Aging & Increasing Lifespan  

With senolytics on the frontier of aging science, there have been limited human studies concerning the effect of senolytics on sarcopenia and frailty — resilience to stress. However, a recent study showed that 10 mg/day of quercetin was associated with reduced odds of frailty in middle-aged and older adults. Additionally, several animal studies have shown that senolytics, including rapamycin and 25c can potentially reverse sarcopenia. D + Q, specifically, could improve muscle regeneration and muscle-building potential in old age. Therefore, senolytics could possibly prevent or reverse signs of muscle aging. 

The importance of maintaining muscle mass and strength cannot be understated, as reduced grip strength is associated with an increased risk of mortality. Several studies, including one out of the United Kingdom (U.K.) and one out of China, have shown an association between reduced grip strength and increased risk of death. The U.K. study also showed an increased risk of dementia with reduced grip strength. Additionally, a recent study revealed that low grip strength is associated with an increased risk of death from various types of cancer. Thus, maintaining grip strength, whether it be by muscle or mind, may also be important for living a long life. 

Model & Dosage

Model: C57BL/6 mice

Dosage (oral): 5 mg/kg dasatinib and 50 mg/kg querecetin

Source

Zhang, X., Habiballa, L., Aversa, Z. et al. Characterization of cellular senescence in aging skeletal muscle. Nat Aging 2, 601–615 (2022). https://doi.org/10.1038/s43587-022-00250-8

References

Englund DA, Zhang X, Aversa Z, LeBrasseur NK. Skeletal muscle aging, cellular senescence, and senotherapeutics: Current knowledge and future directions. Mech Ageing Dev. 2021 Dec;200:111595. doi: 10.1016/j.mad.2021.111595. Epub 2021 Nov 3. PMID: 34742751; PMCID: PMC8627455.

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