Decreased mTOR Expression Provides 20% Mean Life Span Extension in Mice

Posted: September 1, 2013 at 2:49 am

Mammalian (or mechanistic, depending on who you ask) target of rapamycin (mTOR) is the most likely candidate for the next round of billion-dollar research funding devoted to the search for drugs that can slow aging. It will be a repeat of the overhyped and ultimately largely futile interest in sirtuin research, which generated knowledge but nothing of real practical application, except that this time there is far more compelling evidence that manipulation of mTOR actually extends life in laboratory animals. Though as always, there are those who believe that this is not in fact the case - that mTOR alteration only reduces cancer risk, rather than impacting the processes of aging per se. Just as resveratrol and resveratrol-derivatives are the compounds of choice for those investigating sirtuin biology, so rapamycin and rapamycin-derivatives are the compounds of choice for research groups focused on manipulating mTOR and its related signaling networks. I would imagine that we're in for another decade or so of overhyped claims and public and research community interest in what is in fact an inefficient, expensive, and time-consuming path towards only slightly extending healthy life.

Drugs to slow aging through alterations to metabolism are not the path to radical life extension. Slowing aging does nothing for people already old. The research community should focus instead on rejuvenation through therapies that repair and remove the cellular damage that causes aging, an approach that can actually meaningfully help the aged when realized. For all that rejuvenation is the obviously superior research strategy, however, it's taking time to convince the world of that truth. Time spent on trying to slow aging is little different in outcome to time spent investigating the details of aging but choosing to do nothing about it: a few years here and there, and nothing that is as effective as simple exercise and calorie restriction. There's no such thing as useless knowledge in the long term, but we already know enough to work effectively on human rejuvenation.

The new study quoted below will no doubt bolster the prospects of those groups presently raising funds for attempts to slow aging or further develop drug candidates derived from rapamycin. While looking at the results, however, you might compare them with plain old calorie restriction in mice, something that can produce twice the extension of healthy life shown here.

Mutant Mice Live Longer

MTOR is a kinase involved in myriad cellular processes, from autophagy to protein synthesis. Genetic studies of TOR in other organisms, such as yeast and flies, have implicated a role for the enzyme in lifespan. In mammals, however, mTOR is required for survival, making a knockout mouse model unfeasible. So the National Heart, Lung and Blood Institute's Toren Finkel and his colleagues decided to use a mouse in which transcription was only partially disrupted, reducing the levels of mTOR to about 25 percent of the normal amount.

All else being equal, the researchers found that normal mice typically lived 26 months, while those with less mTOR survived around 30 months. Finkel said the increase in lifespan was greater than other researchers have seen using the immunosuppressant rapamycin to inhibit mTOR. It's possible that having mTOR reduced beginning in the womb, rather than at middle age, could explain the disparity. Additionally, this new mutant affected the levels of both forms of mTOR - mTORC1 and mTORC2 complexes - rather than preferentially impacting one, as rapamycin would.

The paper on this research is open access, so head on over and take a look. I think you'll find it interesting. In particular note the author's cautions regarding the size of the life extension effect and the life span of the control mice in the discussion section: the number of mice used isn't large, and it's possible that the controls were just randomly a slightly short-lived group.

Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTOR?/?) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTOR?/? mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTOR?/? mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTOR?/? mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.

Source:
https://www.fightaging.org/archives/2013/08/decreased-mtor-expression-provides-20-mean-life-span-extension-in-mice.php

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