Date Published: March 22, 2018
Publisher: Impact Journals
Author(s): Roxanne Weiss, Elizabeth Fernandez, Yuhong Liu, Randy Strong, Adam B. Salmon.
The use of rapamycin to extend lifespan and delay age-related disease in mice is well-established despite its potential to impair glucose metabolism which is driven partially due to increased hepatic gluconeogenesis. We tested whether a combination therapeutic approach using rapamycin and metformin could diminish some of the known metabolic defects caused by rapamycin treatment in mice. In genetically heterogeneous HET3 mice, we found that chronic administration of encapsulated rapamycin by diet caused a measurable defect in glucose metabolism in both male and female mice as early as 1 month after treatment. In female mice, this defect was alleviated over time by simultaneous treatment with metformin, also by diet, such that females treated with both drugs where indistinguishable from control mice during glucose tolerance tests. While rapamycin-mediated glucose intolerance was unaffected by metformin in males, we found metformin prevented rapamycin-mediated reduction in insulin and leptin concentrations following 9 months of co-treatment. Recently, the Interventions Testing Program showed that mice treated with metformin and rapamycin live at least as long as those treated with rapamycin alone. Together, our data provide compelling evidence that the pro-longevity effects of rapamycin can be uncoupled from its detrimental effects on metabolism through combined therapeutic approaches.
Pharmaceutical inhibition of the mechanistic target of rapamycin (mTOR) is now well established as a valuable tool to better understand ways by which the aging process can be delayed in mammals. In multiple studies, chronic treatment with the mTOR inhibitor rapamycin significantly extends mouse lifespan in both males and females even when begun late in life [1-5]. Moreover, rapamycin delays the progression of several age-related pathologies and may be capable of revitalizing age-related declines in some tissues [5-9]. At the same time, chronic administration of rapamycin is known to have side-effects such as increased incidence of metabolic dysfunction, including glucose intolerance and insulin resistance, likely hindering its use in human populations as an anti-aging treatment. There is emerging evidence that these metabolic defects caused by rapamycin might be alleviated by adjusting treatment protocols, including use of an intermittent treatment schedule or drug-free holidays [10-12]. It is still unclear whether these alternative treatment regimens fully recapitulate the effects of chronic rapamycin on longevity or healthy aging, though there is growing evidence that at least some of these effects are likely to be maintained [13-15],
Four month old male and female HET3 mice were randomly assigned to one of four groups fed the following diets based on LabDiet 5LG6: diet only (Control), 14 ppm encapsulated rapamycin (eRapa), 0.1% metformin (Met), or both 14 ppm encapsulated rapamycin and 0.1% metformin (eRapa+Met). For the duration of the experiment, mice were given access to diet and water ad libitum.
Our main finding here is that a multi-drug approach utilizing metformin can alleviate common metabolic deficits associated with chronic rapamycin treatment as a pro-longevity therapeutic. Moreover our data are in line with recent studies suggesting the metabolic dysfunction of rapamycin can be dissociated from its molecular effects on inhibition of mTOR either pharmaceutically or through alternative pharmaceutical regimens [10,16]. This has been an ambiguous question since the initial report of the pro-longevity effect of rapamycin administration in mice by the ITP in 2009 . One interpretation of this seemingly paradoxical outcome is that rapamycin promotes long life despite also developing glucose intolerance, insulin resistance and/or decline in insulin production and that preventing these metabolic defects may extend lifespan further still. While glucose impairments promote clear health deficits in humans, one potential confound of this interpretation for mouse studies is that their lifespan is typically thought to be due to the development of cancer rather glucose metabolic dysfunction. However, such metabolic impairments have been associated with the acceleration of cancer progression and even the development of certain types of cancer in mouse models suggesting that glucose metabolism could impact mouse mortality at least indirectly [35,36]. The ITP has recently reported the lifespan of eRapa+Met mice is at least as long, if not longer than historical data for mice treated with eRapa alone . Together, our data provide modest evidence for this interpretation, but leave open questions regarding the next steps in research pursuit. While both young and old mice are susceptible to rapamycin-mediated glucose intolerance , it is unknown whether metformin would have the same benefit in aged mice. More testing will be required to address whether metformin can alleviate the greater degree of glucose intolerance caused by higher doses of rapamycin than the 14 ppm dose used here .