4.3.3 Effect of rapamycin on cancer
In 2002, rapamycin was first reported to have antineoplastic properties in mice by suppressing cancer metastasis and angiogenesis159. Since then, overwhelming in vivo andin vitro studies have reported that rapamycin and its derivatives have the potential of ameliorating cancer onset and development90, 150. So far, rapalogs have been approved for treating multiple cancers, including renal cell carcinoma, hepatocellular carcinoma and mantle cell lymphoma 160, 161. Moreover, hundreds of clinical trials have been conducted to test either monotherapy of rapamycin or combination therapy with other drugs in treating various cancers such as breast cancer and endometrial cancer13. However, the actual clinical benefits of rapamycin in treating cancer have been modest 162, 163.
Importantly, rapamycin has also been tested for its potential to prevent cancer. For example, administrating rapamycin to transgenic HER-2/neu cancer-prone mice has been reported not only to extend the lifespan of the mice, but also to result in a delay in the spontaneous tumor onset90, 164. However, the same study found that rapamycin fails to extend the lifespan of the mice with established tumors. In addition, rapamycin has been shown to inhibit the development and progression of tobacco-induced lung cancer. Granville et al. exposed mice with the tobacco carcinogen NNK before administering rapamycin to these mice. The results showed that both phenotypic progression of the tumor as well as tumor size underwent a dramatic decrease. These findings point to the possibility that rapamycin might be used as a cancer prevention agent for those smokers who are at high risk of lung cancer 165.
Discussion
Despite the promising effects that metformin and rapamycin have shown against aging, intensive work is still required to explain several outstanding questions. On the basic level, the full extent of metformin and rapamycin’s effects have not been fully understood. Recently, researchers have attributed growth differentiating factor 15 (GDF15), which interacts with the GFRAL receptor in the central nervous system to suppress appetite, to the weight loss effect of metformin through a mechanism independent from insulin sensitization and glucose lowering mechanisms 166, 167. Furthermore, metformin and rapamycin have been shown gender-specific difference, suggesting the need to investigate the drug-hormones interactions 151, 168 .
Safety of long-term is another concern. Although metformin has been used safely in diabetic patients for a long time, the chronic use of metformin has been associated with the dose-dependent Vitamin B12 deficiency, which is a cause of anemia and neuropathy169, 170. To maximize the safe use of metformin, an assessment of the serum level of Vitamin B12 may be needed before prescribing metformin. In addition, the response to metformin also varies from person to person. From the results of genome-wide association study, a locus on chromosome 11 (rs11212617) is associated with the glycemic response 171. Although this association remains disputable, it may be helpful to develop an approach to predict the response of metformin treatment in clinical settings.
The issue of drug safety also stifles the progress of repurposing rapamycin to anti-aging use - the common side effects of using rapamycin such as diarrhea and nausea have been reported in over a third of rapamycin users, resulting around 5% of treatment discontinuation172. Recent results suggest that designed dosage could be effective in easing the incidence of side effects. A small RCT suggests that the short-term use of rapamycin (8 weeks) to be a relatively safe approach 173. In a mice study, the intermittent use of rapamycin (administrating 2mg/kg rapamycin every 5 days) has also been shown to reduce the incidence of side effects174. However, these results are still at the preliminary stage and should be validated by in substantial basic and clinical studies. Tweaking the chemical structure of rapamycin by developing rapalogs without compromising the anti-aging effect and engineering controlled release of rapamycin from biodegradable biomaterial scaffolds are also prospective directions.
Another concern is whether the positive results obtained from animal and clinical studies can be fully translated to humans. Current model animals have large physiological and genetic differences from human. Although many studies that have obtained positive results, the dosage of metformin used in these studies exceeded the limit for humans175, 176. Thus, the results obtained from mice, yeast, and fruit flies will require further effort to validate.
The anti-aging effects of metformin and rapamycin studies in human have been inconsistent and varied in their strength of evidence, and many of these epidemiological studies are at high risk of bias. This has generated heterogeneous associations, and further studies are required to determine the genuine extent of their anti-aging effects177. It is hoped that the results of the large ongoing study—TAME trial—will shed more light on the anti-aging effect of metformin 178.
Conclusion
Although efforts have been made to ease the progression of diseases from a disease-centric level, less has been done to elucidate the shared mechanisms of aging and the broad effects on a host of diseases. Here, we have discussed two repositioned drugs, metformin and rapamycin, which have had encouraging results both in animal and in human studies in counteracting aging and age-related diseases. Nonetheless, these two drugs still have a long way to go from becoming the ultimate solution to age-related diseases, but the hope will be that they will succeed in helping to extend the healthspan of humans.