CALORIC RESTRICTION MIMETICS (CRM)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133883/

CALORIC RESTRICTION MIMETICS

Although the beneficial effects of caloric restriction on lifespan and health have been clearly demonstrated, it is difficult to implement such restrictions in our lives. To overcome these difficulties, gerontologists and biologists are attempting to develop drugs to mimic the beneficial effects of caloric restriction without the need for diet limitations. Such medicines are known as caloric restriction mimetics (CRM).

Resveratrol

Resveratrol is a polyphenol compound isolated from the skins of red grapes. Resveratrol is currently the most thoroughly studied CRM. As a CRM, resveratrol was first identified by Sinclair through screening of small molecular libraries for compounds that activate Sirtuin and extend lifespan in a yeast model (56). In that study, they demonstrated that resveratrol can mimic the benefits associated with caloric restriction, and that caloric restriction did not further extend the lifespan of yeast grown in resveratrol supplemented medium. Resveratrol was subsequently shown to extend longevity in worms, flies, fish, and obese mice (57,58). However, a recent study showed that resveratrol had no effect on the longevity of mice fed a normal diet (59). Although the longevity extension effect of resveratrol is not yet certain, it is accepted that resveratrol can improve health and prevent age-related diseases. Further investigations and clarifications are required to verify whether resveratrol is a true CRM.

Rapamycin

Rapamycin, an antibiotic, immune-suppressor drug, is another proposed CRM that has shown a longevity benefit. After studies showing the extension of replicative lifespan of yeast via inhibition of the TOR signaling in response to rapamycin treatment (60), it was reported that rapamycin extends the median and maximum lifespan of 20-month-old mice accompanied with a decrease in TOR activity (61). Since then, many studies have been conducted to ascertain the function of rapamycin as a CRM. However, it is important to note that there is evidence showing adverse side-effects of rapamycin such as an increase in the incidence of diabetes (62).

Metformine

Metformin is another CRM of interest to gerontologists. Metformin is a biguanide used as a drug for treatment of type-2 diabetes that increases insulin sensitivity and activates AMPK. Metformin received a great deal of attention after it was identified in a screening assay of drugs showing similar transcriptional profiles to that of caloric restriction in mice (63). Moreover, metformin was shown to have a caloric restriction-related longevity benefit mediated by the activation of AMPK in C. elegans (64). Metformin also has a beneficial effect on other aspects of the aging process such as a decrease in age-related disease incidence. However, the longevity benefit of metformin was not observed in a Drosophila model in a recent study (65), or in the non-disease rodent model (66). The appearance of evidence showing that metformin is ineffective on longevity in some species has led to uncertainty as to whether metformin is a true CRM.

CONCLUSIONS

As the number of elderly people who cannot undergo physical activities has increased, anti-aging has become one of the ultimate goals of gerontologists. Although it has been 75 years since the beneficial effects of caloric restriction on animal health were first reported, the underlying mechanism of longevity extension in response to food restriction has still not been identified. Further organized and global investigations encompassing various research fields using well-developed genetic model animals and well-controlled practical human studies will enable the aging process to be controlled, thus allowing humans to live healthier and happier lives in the near future.