Key Points:
- A new study suggests niclosamide alleviates frailty and prevents the loss of endurance and strength in aged mice.
- Research suggests that mTOR becomes overactivated in cells to drive aging, and niclosamide suppresses it, similar to rapamycin, a drug repurposed to counteract aging.
- The study’s data suggest that niclosamide also revamps the cellular process of autophagy—a mechanism that eliminates and recycles dysfunctional cellular components.
As published in the Journal of Advanced Research, Jung and colleagues from the Korea University of Science and Technology showed that niclosamide alleviated frailty and prevented the loss of endurance and strength in old mice. Moreover, in muscle cells, niclosamide reduced factors linked to the hyperactivation of mTOR, which researchers have tied to driving aging. Furthermore, the study’s data support that niclosamide improved the functional capacity of cellular autophagy within muscle cells of old mice. These findings suggest that niclosamide may be repurposed from use against tapeworms to alleviate age-related frailty and that it works by inhibiting mTOR and activating autophagy, similar to rapamycin.
Autophagy breaks down malfunctioning cellular components to maintain cell function, and its declining operational capacity has been linked to aging. Interestingly, research has shown that niclosamide, a drug approved by the FDA for human use against tapeworms in 1982, activates autophagy in human cells and a mouse model.
Moreover, the drug rapamycin, approved by the FDA to alleviate organ rejection in transplant recipients, is also a well-known mTOR inhibitor and autophagy activator and has been repurposed to counteract aging. Yet, no research before this study had tested whether niclosamide confers effects against aging and whether it could be repurposed in a way similar to rapamycin.
Niclosamide Reduces Age-Related Frailty, Suppresses mTOR, and Activates Autophagy
To identify autophagy-regulating drugs that may work similarly to rapamycin, Jung and colleagues first assessed 97 compounds’ effects on worm lifespan. Among these compounds, the researchers identified niclosamide as the most effective and readily accessible since it extended worm lifespan an impressive 21.67% at the highest dose tested. Because these experiments pinpointed niclosamide as an autophagy regulator that extends worm lifespan, Jung and colleagues moved on to find whether it works against aging in mammals, specifically, mice.
Jung and colleagues subsequently treated mice with niclosamide beginning in the middle stages of their lives (12 months; roughly equivalent to age 44 in humans). Because frailty entails the age-related decline in multiple physiological systems, and its severity increases the probability of death, Jung and colleagues assessed niclosamide’s effects on mouse frailty. The researchers used the frailty index—an evaluation that quantifies mice’s vulnerability to an age-related decline in physical function—with higher scores representing increased aging-associated health vulnerabilities. Interestingly, Jung and colleagues found that the highest dose of niclosamide tested significantly reduced the frailty index in aged mice that were 21 months old (roughly equivalent to 63-year-old humans). This finding supports that niclosamide alleviates age-related frailty, especially when administration begins during the middle stages of life.
Additionally, Jung and colleagues assessed endurance and strength in aged mice treated with niclosamide to confirm the drug’s effects against frailty. Interestingly, the highest dose of niclosamide tested increased the distances that old mice ran on a rodent treadmill before exhaustion and increased their grip strength. These results provide data confirming that niclosamide either prevents the progression of or reverses frailty in old mice when administration begins in the middle stages of life.
Next, seeking confirmation that niclosamide’s mechanism of action resembles the mTOR inhibitor rapamycin, Jung and colleagues measured levels of three protein markers of mTOR activation. The researchers honed in on the levels of these proteins in the leg muscles of aged mice. Compared to young mice, levels of these three proteins each approximately doubled in old mice’s leg muscles. However, niclosamide lowered levels of these proteins in old mice nearly to those seen in young mice at the highest niclosamide doses tested. These findings suggest that niclosamide suppresses mTOR in aged mouse muscle, similarly to rapamycin.
Previous research suggests that overactivation of the mTOR protein complex suppresses cellular autophagy, so Jung and colleagues surmised that inhibiting mTOR with niclosamide may improve autophagy during aging. The researchers found that, indeed, treating aged mice with niclosamide increased levels of proteins associated with the cellular process of autophagy in muscles. This finding supports that niclosamide suppresses mTOR to boost cellular autophagy in muscles, which may rejuvenate muscle cells and cumulatively counteract frailty.
“We advocate that [niclosamide] is a promising anti-aging agent, similar to rapamycin,” said Jung and colleagues in their publication.
Repurposing Compounds Like Niclosamide to Counteract Aging
In their attempt to identify autophagy activators that may work against aging in mammals, similar to rapamycin, Jung and colleagues identified the FDA-approved compound niclosamide. Their study’s data suggest that niclosamide alleviates age-related frailty in mice; however, the possibility that it also extends lifespan in mice remains unexplored. Future testing of niclosamide’s effects against aging should test whether it extends mouse lifespan in addition to alleviating frailty. Since the study’s data support that niclosamide suppresses mTOR and activates autophagy, just as rapamycin does, the compound could very well extend mouse lifespan as demonstrated with rapamycin.
As far as available products that may confer effects somewhat similar to niclosamide, Restorin contains mTOR inhibitors and autophagy activators. In that sense, niclosamide’s reported mTOR suppression and autophagy activation may work similarly to Restorin’s mTOR inhibition and autophagy activation technologies.
Restorin is roughly based on Seragon’s drug SRN-901, which extended aged mouse lifespan by an impressive 33%. Also, SRN-901 was shown to significantly counteract frailty in aged mice, in a way similar to niclosamide. Therefore, while researchers still need to perform human trials on Restorin and niclosamide to confirm their potential to alleviate age-related frailty, the preclinical evidence on both suggests they do counteract frailty. Thus, since niclosamide requires a doctor’s prescription to obtain, the product Resotrin, which also inhibits mTOR and activates autophagy, may potentially serve as an alternative to confer similar effects against frailty.
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