Reducing Myc gene activity extends healthy lifespan in mice

No bones about it Young mice have good bone density whether they have two copies (top row; +/+) or one copy (bottom row; +/-) of the Myc gene. As they age, researchers found, mice with just one copy maintain better bone density and stay healthy longer. Sedivy lab/Brown University

Mice with one rather than the normal two copies of the gene Myc (also found in humans) lived 15 percent longer and had considerably healthier lives than normal mice, according to a new Brown University-led study in Cell.

PROVIDENCE, R.I. [Brown University] — A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice, the first such finding regarding this gene in a mammalian species.

Myc is found in the genomes of all animals, ranging from ancestral single-celled organisms to humans. It is a major topic of biomedical research and has been shown to be a central regulator of cell proliferation, growth, and death. It is of such widespread and fundamental importance that animals cannot live without it. But in humans and mice, too much expression of the protein that Myc encodes has been closely linked to cancer, making it a well-known but elusive target of drug developers.

In a new study in the journal Cell, the scientists report that when they bred laboratory mice to have only one copy of the gene, instead of the normal two, thus reducing the expression of the encoded protein, those mice lived 15 percent longer on average — 20 percent longer for females and 10 percent longer among males — than normal mice. Moreover, the experimental mice showed many signs of better health into old age.

The experimental — “heterozygous” — mice grew to be about 15 percent smaller than the normal mice (a probable disadvantage in the wild) but that was the only discernable downside found to date for lacking a second copy of the gene, said senior author John Sedivy, the Hermon C. Bumpus Professor of Biology and professor of medical science at Brown.

“The animals are definitely aging slower,” he said. “They are maintaining the function of their organs and tissues for longer periods of time.”

Physiological differences

That assessment is based on detailed studies of the physiology — down to the molecular level — of the heterozygous and normal mice. The researchers conducted these experiments to try to understand the longevity difference between the two groups.

John Sedivy “The animals are definitely aging slower [and[ they are maintaining the function of their organs and tissues for longer periods of time.”

Co-lead author Jeffrey Hoffman, a medical and doctoral student, led the studies of the health of the mice, including various bodily systems. In many cases they were just like their normal counterparts. They reproduced just as well, for example.

“These mice are incredibly normal, yet they are really long-lived,” Sedivy said. “The reason why we were struck by that is because in many other longevity models like caloric restriction or treatment with rapamycin, the animals live longer but they also have some health issues.”

Instead the Myc heterozygous mice simply experienced fewer problems of aging. They did not develop osteoporosis, they maintained a healthier balance of immune system T cells, had less cardiac fibrosis, were more active, experienced less age-related slowing of their metabolic rate, produced less cholesterol, and exhibited better coordination.

Graduate student and co-lead author Xiaoai Zhao, meanwhile, led the molecular analysis of several pathways known to be involved in regulating longevity to find out how they might be different. Sure enough, heterozygous mice exhibited changes in IGF-1 signaling and nutrient and energy-sensing pathways, but how Myc engages those mechanisms is still not clear. Of particular interest, heterozygous mice showed less protein synthesis in several tissues. Regulation of this process is known to be under direct Myc control, and its reduction by a variety of means is known to extend lifespan in diverse species from yeast to mammals.

Genome-wide patterns of gene expression showed that Myc heterozygotes had significant differences in pathways related to metabolism and the immune system. Those patterns, however, only overlapped somewhat with patterns seen in other lifespan extending interventions.

Zhao and Hoffman’s studies also argue against a role for Myc in an oft-cited paradigm of greater longevity: upregulation of a variety of stress defense mechanisms. Their experimental mice seemed to suffer from as much stress and consequences of stress as normal mice.

The different benefits of Myc reduction compared to other laboratory longevity extenders shows that just as there are many ways the body can break down with aging, Sedivy said, there may be many ways to forestall that.

“There is more than one way to become long-lived,” Sedivy said.

Help for humans?

In the long term, Sedivy said he is optimistic that the findings about Myc could prove to matter to human health.

Finding the right target for a drug in one of Myc’s key metabolic or immune system pathways may or may not extend human lifespan, he said, but it might help people stay healthier as they age — for example, if it can reduce osteoporosis in people the way it does in mice. In particular, Sedivy said, it emphasizes the importance of the process of protein synthesis as a target of interventions that are likely to have widespread benefits on many organ systems.

And the study also offers encouragement to companies seeking to develop cancer drugs that block Myc overexpression. As important as normal Myc expression is to physiology, it appears that at least in mice there were many substantial benefits in reducing it by, say, half. Thus, Sedivy said, any drug that can target Myc directly is likely to find many applications beyond cancer.

In addition to Sedivy, Hoffman, and Zhao, the paper’s other authors are Marco De Cecco, Abigail Peterson, Luca Paglilaroli, Jayameenakshi Manivannan Bin Feng, Thomas Serre, Kevin Bath, Haiyan Xu, and Nicola Neretti of Brown; Gene Hubbard, Wenbo Qi, and Holly Van Remmen of the University of Texas; Yongqing Zhang and Rafael de Cabo of the National Institute on Aging; and Richard Miller of the University of Michigan.

The National Institutes of Health (grants R37AG016694, F30AG035592), the Ellison Medical Foundation, and the Glenn Award for Research on the Biological Mechanism of Aging supported the research. Some experiments were conducted in the Brown University molecular pathology and genomics cores.

Not just a longer life, but a healthier, stronger body “Do you think she might be a Myc hypomorph?” Drawing: Emma Sedivy

Source: Brown University

Hunter-gatherer past shows our fragile bones result from inactivity since invention of farming

Hunter-gatherer bone mass compared to agriculturalist bone mass. Credit: Timothy Ryan

New research across thousands of years of human evolution shows that our skeletons have become much lighter and more fragile since the invention of agriculture -- a result of our increasingly sedentary lifestyles as we shifted from foraging to farming.

The new study, published today in the journal PNAS, shows that, while human hunter-gatherers from around 7,000 years ago had bones comparable in strength to modern orangutans, farmers from the same area over 6,000 years later had significantly lighter and weaker bones that would have been more susceptible to breaking.

Bone mass was around 20% higher in the foragers -- the equivalent to what an average person would lose after three months of weightlessness in space.

After ruling out diet differences and changes in body size as possible causes, researchers have concluded that reductions in physical activity are the root cause of degradation in human bone strength across millennia. It is a trend that is reaching dangerous levels, they say, as people do less with their bodies today than ever before.

Researchers believe the findings support the idea that exercise rather than diet is the key to preventing heightened fracture risk and conditions such as osteoporosis in later life: more exercise in early life results in a higher peak of bone strength around the age of 30, meaning the inevitable weakening of bones with age is less detrimental.

There is, in fact, no anatomical reason why a person born today could not achieve the bone strength of an orangutan or early human forager, say researchers; but even the most physically active people alive are unlikely to be loading bones with enough frequent and intense stress to allow for the increased bone strength seen in the 'peak point' of traditional hunter-gatherers and non-human primate bones.

"Contemporary humans live in a cultural and technological milieu incompatible with our evolutionary adaptations. There's seven million years of hominid evolution geared towards action and physical activity for survival, but it's only in the last say 50 to 100 years that we've been so sedentary -- dangerously so," said co-author Dr Colin Shaw from the University of Cambridge's Phenotypic Adaptability, Variation and Evolution (PAVE) Research Group.

"Sitting in a car or in front of a desk is not what we have evolved to do."

The researchers x-rayed samples of human femur bones from the archaeological record, along with femora from other primate species, focusing on the inside of the femoral head: the ball at the top of the femur which fits into the pelvis to form the hip joint, one of the most load-bearing bone connections in the body.

Two types of tissue form bone: the cortical or 'hard' bone shell coating the outside, and the trabecular or 'spongy' bone: the honeycomb-like mesh encased within cortical shell that allows flexibility but is also vulnerable to fracture.

The researchers analysed the trabecular bone from the femoral head of four distinct archaeological human populations representing mobile hunter-gatherers and sedentary agriculturalists, all found in the same area of the US state of Illinois (and likely to be genetically similar as a consequence).

The trabecular structure is very similar in all populations, with one notable exception: within the mesh, hunter-gatherers have a much higher amount of actual bone relative to air.

"Trabecular bone has much greater plasticity than other bone, changing shape and direction depending on the loads imposed on it; it can change structure from being pin or rod-like to much thicker, almost plate-like. In the hunter-gatherer bones, everything was thickened," said Shaw.

This thickening is the result of constant loading on the bone from physical activity as hunter-gatherers roamed the landscape seeking sustenance. This fierce exertion would result in minor damage that caused the bone mesh to grow back ever stronger and thicker throughout life -- building to a 'peak point' of bone strength which counter-balanced the deterioration of bones with age.

Shaw believes there are valuable lessons to be learnt from the skeletons of our prehistoric predecessors. "You can absolutely morph even your bones so that they deal with stress and strain more effectively. Hip fractures, for example, don't have to happen simply because you get older if you build your bone strength up earlier in life, so that as you age it never drops below that level where fractures can easily occur."

Other theories for humans evolving a lighter, more fragile skeleton include changes in diet or selection for a more efficient, lighter skeleton, which was never reversed.

While the initial switch to farming did cause a dip in human health due to monoculture diets that lacked variety, the populations tested were unaffected by this window in history. "Of course we need a level of calcium to maintain bone heath, but beyond that level excess calcium isn't necessary," said Shaw.

The research also counters the theory that, at some point in human evolution, our bones just became lighter -- perhaps because there wasn't enough food to support a denser skeleton. "If that was true, human skeletons would be entirely distinct from other living primates. We've shown that hunter-gatherers fall right in line with primates of a similar body size. Modern human skeletons are not systemically fragile; we are not constrained by our anatomy."

"The fact is, we're human, we can be as strong as an orangutan -- we're just not, because we are not challenging our bones with enough loading, predisposing us to have weaker bones so that, as we age, situations arise where bones are breaking when, previously, they would not have" Shaw said.

While the 7,000-year-old foragers had vastly stronger bones than the 700-year-old farmers, Shaw says that neither competes with even earlier hominids from around 150,000 years ago. 

"Something is going on in the distant past to create bone strength that outguns anything in the last 10,000 years."

The next step for Shaw's research team will be to look at how different types of loading and mobility shape bodies and bones by cross-referencing archaeological records with testing on modern ultra-marathon runners, who cover punishing distances over a range of terrains -- from the Himalayas to the Namibian desert. He hopes this future work will provide insight into the kind of mobility that gave our ancient ancestors such powerful physical strength.

Source: University of Cambridge