 Rapamycin and Metformin are viewed by many as the two most promising anti-aging drugs, but now scientists have found that these drugs can work hand in hand, boosting each other's effectiveness and blocking side effects. At least, that's what we've seen in mice. Both Metformin and Rapamycin have been in use for decades and have decent safety profiles. However, there are reports of some notable side effects. We've already done an episode on a possible link between Metformin use and birth defects, and have discussed how it can limit exercise gains and VO2 max. But Rapamycin also has some concerning effects of its own. For instance, it is known to promote hyperglycemia in some patients, probably by increasing insulin resistance and decreasing pancreatic response to glucose. Some previous studies have already shown that Metformin, a diabetes drug, can alleviate this rapamycin-induced resistance, but there is high variability in the results. When tested by the Intervention Testing Program, Metformin failed to show much increase in lifespan in mice. However, in combination with rapamycin, it worked synergistically, leading to a drastic increase in median and maximal lifespan. In this new study, the researchers put the combination hypothesis to the test. They used male mice of a common pre-diabetes model, which received either rapamycin, metformin, or a combination from 12 to 30 weeks of age. Being pre-diabetic, these mice usually gain a lot of weight with age. Metformin treatment did not alleviate this trend, but both the rapamycin and combination treatments allowed the mice to maintain normal weight through the end of the experiment. The mice used in this experiment are of a variety known to develop fatty liver. While metformin alone had only a modest effect, fatty liver was completely prevented by rapamycin, both alone and in combination with metformin. Plasma insulin levels, a measurement of insulin resistance, typically rise in these mice with age. Both metformin and rapamycin were able to decrease these levels, but the combination was again superior to the single drug treatments. Somewhat paradoxically, plasma glucose levels became elevated in all treatment groups early into the experiment. In the rapamycin group, the glucose levels remained high, while in the metformin group, and especially in the combination group, the levels gradually decreased down to those observed in healthy mice not prone to diabetes. These mice also started exhibiting a sign of diminished insulin storage quite early in life. Rapamycin treatment exacerbated this symptom, metformin somewhat attenuated it, and the combination treatment resulted in levels similar to those of controls. While generally considered safe, metformin is suspected to be toxic to kidneys. In this new study, metformin treatment substantially elevated kidney inflammation levels and the albumin creatinine ratio, a measurement of kidney damage. Rapamycin did exactly the opposite, and the combined treatment was just as good as rapamycin alone in preserving kidney function. The researchers gathered their results in a table that illustrates the effects of the combination treatment. In every case in which one or both drugs had a beneficial effect, this effect was fully preserved. In one case, metformin enhanced rapamycin-induced insulin sensitivity despite having no effect on its own. In three cases, rapamycin-induced deleterious effects were alleviated or blocked by metformin, and in two cases, rapamycin's benefits were maintained in the combination treatment despite metformin independently working in the opposite direction. Both metformin and rapamycin are viewed by many as promising anti-aging drugs, and despite this study's limitations, such as using only diabetes-prone male mice, it demonstrates an intriguing synergy between the two molecules. Ultimately, combination treatments may be the way to go. When there's more to share, we'll have it for you here, so please subscribe so you don't miss out. I'm Ryan O'Shea and we'll see you next time on Lifespan News.