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Reduced Levels of Myc Extend Healthy Lifespans in Mice

The transcription factor myc has shown up in cancer research over the past decade, and it is possible that reducing its abundance can turn off rapid cellular proliferation in many cancers. Researchers can't get rid of myc entirely, however, as its presence is necessary for a range of fundamental cell processes. Myc is also important in modern stem cell research, as it is one of the factors used in reprogramming somatic cells to become induced pluripotent stem cells, a potentially important source of customized cells for research and therapies. This is one of many examples that illustrate cancer and regeneration to be opposite sides of the same coin from a mechanistic point of view: the same proteins show up in similar roles on both sides of the fence.

Researchers investigating the role of myc in cancer recently stumbled upon an unexpected finding, demonstrating that reduced levels of myc caused improvements in health and longevity in laboratory mice. This was not the result they were looking for at all, but arguably it is far better for everyone involved for their project to be derailed in this fashion:

Benefits of Missing MYC

Compared to wild-type mice, those missing one copy of Myc live longer and suffer less severe aging-associated problems. The mice that we created are long-lived, but they are incredibly normal, and they are incredibly healthy." Myc's apparent broad role in aging comes as a surprise to those who study the gene. "We've been so focused on [MYC's] normal function and its cancer function. I don't think any of us really thought about what happens in terms of longevity."

At first, researchers genetically engineered mice to lack a copy of Myc because they thought this might increase cellular senescence, an aging-associated process in which cells cease to divide. To the researchers' surprise, the mice did not show increased cell senescence but rather increased longevity compared with wild-type animals. As expected given MYC's role in cancer, the loss of one copy appeared to slow progress of the disease. But loss of a Myc copy also reduced hardening of heart muscle, osteoporosis, and age-related decline in immune function. Mice with reduced MYC displayed better motor function, showed reduced age-related changes in cholesterol than control mice. The engineered mice showed reduced levels of insulin growth factor-1. Reduction of this growth factor has also previously been shown to be associated with increased lifespan.

"It's pretty clear that the [Myc-mutant] mice live longer for a variety of reasons, or at least if you look at their overall health, you see effects in a bunch of different organs." Because the Myc-mutant mice were smaller than average, the researchers wondered whether the engineered animals were eating less than the control mice, as caloric restriction has been shown to slow aging. But the researchers found that the engineered mice were in fact eating more than the control animals.

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/-) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism.

Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/- mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

It would be interesting for researchers to now try this in conjunction with some of the other longevity-enhancing genetic alterations that are thought to work through alterations to quality control and repair systems: do they stack? By the sound of it reduced levels of myc work to extend life via many of the same mechanisms as produce the health and longevity benefits of calorie restriction, so there again it would be interesting to see what the outcome is for calorie restriction myc-reduced mice. If there is no or little additive effect there, then perhaps carefully designed drugs capable of suppressing myc levels might prove to be a form of calorie restriction mimetic.

Comments

A quick web search shows that, in certain tissues, myc-expression is reduced by salicylates, curcumin, EGCG, and some tetracycline derivatives.

Posted by: Lou Pagnucco at January 22nd, 2015 9:10 PM

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