In recent years there has been considerable interest in the inhibition of mTOR signaling as a mechanism to upregulate autophagy, a form of calorie restriction mimetic strategy for drug development. While there are a number of safe, low cost, off-patent small molecules that achieve this goal, rapamycin being the most well studied of these options, interest in a mechanism will ensure that researchers eventually work their way through the entire portfolio of approved drugs and drug candidate libraries in search of more options. Even if two small molecules ostensible target the same mechanism, there will always be differences in tissue specificity, side-effects, cost-effectiveness, and so forth. Here find one example of this sort of work, in which researchers add to the body of knowledge regarding the ability of niclosamide to inhibit mTOR signaling.
Niclosamide (NIC) is a medication that has been included in the World Health Organization’s list of essential medicines since the 1960s, and is used to treat tapeworm infection. The mechanism of action of NIC involves uncoupling oxidative phosphorylation in the mitochondria, which disrupts the tapeworm’s ability to survive. NIC has also been shown to affect various signal transduction pathways, such as Wnt/β-catenin, mammalian target of rapamycin (mTOR), STAT3, NFκB, and Notch pathways. Recent studies have also explored the potential of NIC as a therapeutic agent against cancer, bacterial or viral infections, and metabolic diseases. Studies have shown that NIC promotes autophagy in both small-cell lung carcinoma cells and mouse model, by inducing tumor cell death through the activation of autophagy and apoptosis via the AMPK/AKT/mTOR pathway. Furthermore, NIC improves insulin and glucose homeostasis by activating autophagy in metabolic disease cells and mouse models.
Despite these promising results, no study has focused on its effects on aging. Therefore, in this study, we aimed to evaluate the effects of NIC on natural aging models. We report that NIC promotes healthy aging in C. elegans and mice. NIC increases physical function and mitochondrial function in skeletal muscles, which are reduced with aging. We found that NIC inhibited the expression of muscle atrophy-related genes by suppressing hyperactivated mTORC1 and enhancing autophagic flux, thereby improving age-related decline. Our results demonstrate a new function of the NIC in contributing to healthy aging, particularly skeletal muscle health.
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