New Study Shows Rejuvenated Stem Cells Prolong Lifespan and Increase Muscle Fitness

Spanish scientists find that drug-induced stem cell rejuvenation improves muscle strength and size while significantly increasing the lifespan of mice.

Key Points:

Treating aged muscle stem cells with a cell-cycle protein inhibitor called CASIN increases stem cell function and enhances balance, grip strength, and muscle cell size.
CASIN treatment rejuvenates — increases functional capacity to regenerate tissue — aged blood stem cells.
Transplanting blood stem cells from CASIN-treated mice into aged mice with impaired immune systems (immunocompromised) extends median lifespan by about 25% and maximum lifespan by about 34%.

Aging inevitably compromises the regenerative potential of stem cells, leading to impaired tissue healing and muscle atrophy. Thus, identifying treatments that rejuvenate aged stem cells is vital to thwarting age-related conditions linked to poor stem cell function. Researchers have pinpointed a cell-cycle protein called Cdc42, the activity of which increases with aging and exacerbates stem cell dysfunction.

Now, in a new study published in Regenerative Medicine, researchers explore the effects of a Cdc42 inhibitor (CASIN) on aged mouse stem Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice | npj Regenerative Medicinecells. Florian and colleagues show that deactivating Cdc42 with CASIN in aged mouse muscle stem cells enhances their regenerative capacity and overall function, which increases muscle fitness in treated mice. Furthermore, the investigators show that CASIN treatment rejuvenates aged blood stem cells, which, when transplanted to aged mice with impaired immune systems, contributes to increased lifespan.

CASIN Enhances Muscle Fitness and Growth

The self-renewal properties of muscle stem cells play a key role in regenerating muscle tissue after exercise, which contributes to improved muscle strength and fitness. However, muscle stem cell function declines with aging, increasing susceptibility to age-related diseases like sarcopenia- characterized by the progressive loss of muscle tissue and strength. With this in mind, Florian and colleagues wanted to see if inhibiting Cdc42 could improve muscle stem cell function and enhance the muscle fitness of aged mice.

The investigators found that treating the muscle stem cells of aged mice with CASIN led to them having significantly larger muscle fibers than untreated aged mice, indicating that Cdc42 inhibition increases the regenerative potential of muscle stem cells. Furthermore, the mice with increased muscle stem cell function exhibited superior muscle fitness over untreated aged mice, demonstrated by increased grip strength and improved endurance. Taken together, the findings demonstrate that inhibiting Cdc42 boosts muscle fitness and overall health through enhanced muscle stem cell function.

(Florian et al., 2022 | *Regenerative Medicine*) **CASIN treatment increases muscle fitness and enhances muscle growth.** (Left) CASIN-treated mice (blue) took longer to fall off the rotarod, showing better endurance than untreated mice (grey). CASIN-treated mice also exhibit greater grip strength (middle) and larger muscle fibers (right), as indicated by cross-sectional area (CSA).

Transplanting CASIN-Exposed Cells Prolongs Lifespan

Previous studies have shown that CASIN treatment successfully prolongs the lifespan of aged mice. Therefore, the investigators examined whether transplanting stem cells from CASIN-treated aged mice could induce similar effects in immunocompromised aged mice. Florian and colleagues chose blood stem cells for transplantation due to their well-established rejuvenation capabilities, which were improved following treatment with CASIN.

The results showed that transplanting CASIN-treated blood stem cells from aged mice significantly extends the median and maximum lifespan of aged immunocompromised mice. These findings reveal that the rejuvenation of blood stem cells may be key to longevity. Overall, the findings highlight the potential of utilizing drugs like CASIN to increase stem cell function (tissue regeneration), thereby mitigating the tissue-degenerating effects of aging.

(Florian et al., 2022 | *Regenerative Medicine*) **Transplanting blood stem cells increases lifespan**. Immunocompromised mice transplanted with CASIN-treated blood stem cells (NSGW HSC_CASIN) live significantly longer than mice transplanted with untreated stem cells (NSGW HSC_Aged) and mice that didn’t undergo transplantation (NSGW_Control (not Tx)).

Drugs that Target Stem Cells: A Future Anti-Aging Therapy?

Studies continue demonstrating stem cell therapy’s effectiveness in mitigating aging features, including muscle decline and poor skin health. That being said, research surrounding stem cell rejuvenation upon aging is still in its infancy. Given that stem cell exhaustion is a primary driver of tissue decline, its important to develop novel therapies that can revitalize stem cells.

Florian and colleagues show that CASIN can directly target muscle and blood stem cells to restore their regenerative capacity. This means that we can potentially rejuvenate our stem cells without the need for invasive stem cell therapy. If CASIN or similar compounds are found not to have off-target deleterious effects, it could lead the way for the development of stem cell rejuvenation supplements or drugs in the future.