Shorter Period of Rapamycin Treatment in Mice Produces Greater Slowing of Aging

Rapamycin, an immunosuppressant and MTOR inhibitor, is known to slow aging in mice - though it has been debated whether this extension of life span is actually a slowing of aging versus a lower rate of cancer. Researchers here try a variety of different treatment regimens and find that a comparatively short period of rapamycin treatment in mouse middle age produces better effects than the longer term dosage that has been standard in studies. The publicity materials emphasize the high points and the outliers in the mouse data; I'd recommend reading the paper for a more responsible and overall view of the outcomes.

Even with improved results and possibly a new longevity record for this mouse species, I don't think the improved outcomes much alter the overall picture for trying to slow the processes of aging in this way, by altering metabolism towards the sort of changes known to occur in response to calorie restriction. It is, however, interesting to consider what must be going on in mouse biochemistry to allow a shorter intervention to have a larger effect than a longer intervention. One possibility is that the longer intervention does in fact have all of the beneficial effects, but that the unpleasant side-effects of rapamycin begin to outweigh those benefits greatly as the mice get older. Regardless, keep in mind that mice have very plastic life spans - interventions such as calorie restriction and growth hormone receptor knockout that extend life in mice by 40-70% are known not to have large effects on longevity in humans, and we should expect that to be the case for the beneficial side of rapamycin as well.

Rapamycin, approved by the FDA for certain organ transplant recipients, is already known to extend life in mice and delay some age-related problems in rodents and humans. Still, many questions prevail about when, how much and how long to administer rapamycin, what its mechanisms of action are in promoting healthy aging, and ways to avoid serious side effects. Researchers showed that a transient dose of rapamycin in middle age was enough to increase life expectancy and improve measures of healthy aging. The scientists treated mice with rapamycin for 90 days starting at 20 months of age, approximately the mouse equivalent of a 60 year old person. The control and rapamycin-treated mice were maintained identically both before and after the treatment period. Remarkably, the rapamycin treated mice lived up to 60 percent longer after the treatment was stopped, compared to the animals that received a mock control treatment.

This, the researchers said, seems to be the biggest increase in life expectancy ever reported in normal mice from a medication. "It's quite striking that short-term rapamycin treatment had such a lasting impact on health and survival after the treatment was stopped." The reasons behind this outcome aren't completely clear, according to the researchers, but one interpretation might be that the animals were, to some degree, rejuvenated by the treatment and became biologically younger than their actual age. The most-senior mouse in the study was Ike, the namesake of a relative of one of the researchers. The mouse Ike lived 1400 days. For a person, that would be like hailing a 140th year birthday. "To our amazement, considering the relatively small size of the group of mice we studied, Ike might have been one of the longest lived mice of his kind." Ike was a wild-type C57BL/6, a designation for the one of the most common sub-strains of mice.

On the other hand, some of the side effects observed during the study were less than celebratory. The cautionary findings, the researchers noted, illustrate the need to better understanding the relationship between the dose of rapamycin and its beneficial as well as detrimental effects. The researchers saw a gender difference when higher doses of rapamycin were given: males outlived the females. At lower doses, both male and female mice had longer lives, compared to untreated mice. Higher doses can make female mice more susceptible to aggressive cancers of blood-forming cells and tissue. At the same time, middle-aged female mice receiving high-doses of rapamycin were less likely to develop other types of cancer. The transient rapamycin treatment also changed the composition of the microbiome - the collection of bacteria and other microbes - in the guts of the mice. They had more segmented, filamentous bacteria of a type not usually present in high numbers in aged mice. While these bacteria are not invasive, they adhere tightly to the cells of the intestinal wall and may encourage the formation of immune cells in the mouse. Otherwise, the influence of this gut microbiome change from rapamycin on the health of an animal, for good or bad, and whether the same thing happens in humans, has not been determined.

Link: http://hsnewsbeat.uw.edu/story/brief-rapamycin-therapy-middle-aged-mice-extends-lives

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