Finding a way to promote longevity without promoting harmful side effects is a key goal of longevity proponents and researchers, but new work on aging in mice points to the challenge ahead.
Finding a way to promote longevity without promoting harmful side effects is a key goal of longevity proponents and researchers. New work on aging in mice points to the challenge ahead.
Researchers found that mice genetically modified to produce less of a protein involved in a wide variety of cell functions — including protein synthesis and gene expression, energy production and metabolism, cell motility and survival, and immune system regulation — lived 16% longer than mice with normal levels of the protein. They did so, however, with decreased bone density and increased infections in the mouth, eye and skin, indicating decreased immune function.
The results show that “some interventions that slow aging may also have unintended, negative tissue-specific side effects,” write the authors in their paper, published in Cell Reports.
The protein, mammalian target of the drug rapamycin, mTOR, is so important that knocking it out altogether in mice causes them to die while still embryos. Scientists collaborating within several divisions of the National Institutes of Health used mice with the level of mTOR reduced to just 25% of normal. That allowed researchers to keep the mice alive long enough to determine the effect of the protein on aging, both for the mouse as a whole and for individual tissues and organs in the mouse.
Reducing mTOR levels not only allowed the mice to live longer, they were also more coordinated, had better balance and had less of a cognitive decline relative to age-matched mice with normal mTOR levels. The latter was tested by determining how long it took the mice to find an escape hole in a maze and marking how that time decreased over the course of five days — a test of spatial learning and memory.
Not only was protection against the typical age-dependent decline in cognitive function observed, significant reductions in biomarkers of aging in the liver and brain tissue were also seen. So, while therapeutics that reduce mTOR might initially appear to be good candidates for therapeutics targeting Alzheimer’s disease and other age-related senilities, it’s not that simple.
Targeting “single genetic pathways that extend lifespan will likely have non-uniform effects” on aging in different tissues, write the authors. In fact, mice with reduced mTOR had a greater percent of cataracts compared to normal mice. They also had a significantly higher rate of needing to be euthanized because of severe superficial infections.
Mammalian target of rapamycin was originally identified as a key regulator of the immune system, so decreased immune function was not a surprising finding. This is not necessarily a bad thing; there are times when decreased immune function is beneficial.
Mice with reduced mTOR had decreased number of tumors, emphasizing the connection scientists know to exist between aging and tumor formation. Some of the same cellular mechanisms that promote aging also promote spontaneous tumors—tumors with no genetic cause—and when those pathways are modified to shift the equilibrium towards longevity a beneficial side effect of reduced tumor formation is seen. Of the mice with normal amounts of mTOR, 39% had tumors, while only 21% of those with reduced mTOR had tumors.
“While the high extension in lifespan is noteworthy, this study reinforces an important facet of aging; it is not uniform,” says Toren Finkel, senior author of the paper.
While not a surprising conclusion, it underscores the idea that increased longevity will not be easily attained or even healthfully achieved.
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