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

Back pain killing your sex life? Study reveals best positions to save your spine

Contrary to popular belief, spooning is not always the best sex position for those with a bad back, according to new research from the University of Waterloo. For the first time ever, scientists have successfully documented the way the spine moves during sex and discovered exactly why certain positions are better than others when it comes to avoiding back pain. The pioneering study combined infrared and electromagnetic motion capture systems to track how ten couples' spines moved when attempting five common sex positions. The findings were used to create an atlas, or set of guidelines, that recommends different sex positions and thrusting techniques based on what movements trigger a patient's pain. Pictured: Professor Stuart McGill demonstrates the motion of the spine during sex.  
Credit: University of Waterloo

Contrary to popular belief, spooning is not always the best sex position for those with a bad back, according to new research from the University of Waterloo.

For the first time ever, scientists have successfully documented the way the spine moves during sex and discovered exactly why certain positions are better than others when it comes to avoiding back pain.

"Any family doctor will tell you that couples often ask them how to manage their back pain during and after sex. Many couples will remain celibate because one night of love-making can lead to months of back agony," said Professor Stuart McGill, of Waterloo's Faculty of Applied Health Sciences. "Until now, doctors have never had any hard science to base their recommendations upon."

The pioneering study combined infrared and electromagnetic motion capture systems -- like those used in the creation of video games -- to track how 10 couples' spines moved when attempting five common sex positions. The findings were used to create an atlas, or set of guidelines, that recommends different sex positions and thrusting techniques based on what movements trigger a patient's pain.

"Before now, spooning was often recommended by physicians as the one position that fit all. But as we've discovered, that is not the case," said Natalie Sidorkewicz, a PhD candidate at Waterloo and lead author on the paper. "Sex positions that are suitable for one type of back pain aren't appropriate for another kind of pain."

The atlas recommends that men who are flexion-intolerant -- meaning those whose back pain is made worse by touching their toes or sitting for long periods of time, for example -- replace spooning with doggy-style sex. The guide recommends that these men use a hip-hinging motion rather than thrusting with their spines.

"For the first time ever, we now have very solid science to guide clinicians on their recommendations for patients who suffer debilitating back pain, but still want to be intimate," said Sidorkewicz. "This has the potential to improve quality of life -- and love-life -- for many couples."

According to Statistics Canada, four of every five people will experience at least one episode of disabling low back pain in their lifetime. Up to 84 per cent of men with low back pain and 73 per cent of women report a significant decrease in the frequency of intercourse when suffering back pain.

The study also shed light for the first time on the mechanics of the male orgasm. Electrodes hooked up to the male participants' muscles revealed that it is abdominal and buttock, not back muscles, that are most active during orgasm. Spine motion, on the other hand, varied with the individual. For some males, a drastic increase in flexion or extension was seen, while for others spine motion did not change much at all.

"Many of the back pain patients that we see have told us that they experience elevated levels of pain during orgasm, to the point where they will avoid having one during sex with their partner," said Sidorkewicz. "These initial findings help us to begin to understand what might be provoking their pain during the moment of climax."

A paper documenting male spine movement was published in the journal Spine. Female findings are expected to be published in the coming months. The next phase of the study will involve recruiting patients with hip pain and additional categories of back pain to further develop the guidelines.

Source: University of Waterloo

Software to automatically outline bones in x-rays

An image from the Bone Finder software. Credit: Image courtesy of Manchester University

Research into disorders such as arthritis is to be helped by new software developed at the University of Manchester which automatically outlines bones -- saving thousands of hours of manual work.

Amidst a national shortage of radiographers in the UK and an increasing requirement for researchers to work with large databases of radiograph images, the software which is being funded by the Engineering and Physical Sciences Research Council, is being designed to automatically pick out the shapes of bones in the images, rather than relying on individual researchers.

The system can already identify hips, but the researchers from the University's Institute of Population Health will now adapt it to map out knees and hands and to be able to learn to identify other bones and structures within the body.

The funding will allow further development to ensure the system is accurate enough that it can be used in hospitals to help provide faster diagnosis of problems in patients.

Professor of Computer Vision, Tim Cootes said: "Mapping the outlines of bones from radiographs is hard work that takes time and skill. When researchers into conditions like arthritis are working with hundreds of images, it's a very inefficient way of obtaining data.

"The idea of this software is to take the routine tasks out of human hands, so scientists can 

focus on drawing conclusions and developing treatments."

The funding of £300,000 lasts for three years and builds on earlier work which developed software, called Bonefinder, to identify problems and find the outlines of hips. This free software has been adopted by a number of research groups, including some based in Oxford and California.

Professor Cootes added: "We have a growing problem with arthritis which affects more than 30% of over 65s and costs around £30 billion to the UK economy year.

"Ultimately we want to get this technology into hospitals where it can save time and resources for the benefit of patients."

Source: Manchester University

New natural supplement relieves canine arthritis

Portrait old dog

Arthritis pain in dogs can be relieved, with no side effects, by a new product based on medicinal plants and dietary supplements that was developed at the University of Montreal's Faculty of Veterinary Medicine. "While acupuncture and electrical stimulation are two approaches that have been shown to have positive effects on dogs, until now a few studies have investigated a plant-based approach to therapy," explained Professor Éric Troncy, senior author of the study. His findings were published in Research in Veterinary Science.

Troncy and his team worked with 32 dogs (and their owners!) who had been diagnosed with arthritis by X-ray and orthopaedic exam, and who all weighed more than 20 kilograms. By drawing on existing rodent studies and working with Pierre Haddad of the university's Department of Pharmacology, Troncy developed two formulas for his trial. These formulas are not currently commercially available.

The first formula, composed of curcumin, devil's claw, black current, Indian frankincense (Salai), willow bark, pineapple bromelaine and camomile, was developed to treat arthritis-induced inflammation. The second included the same ingredients, plus dietary supplements such as omega 3, chondroitin sulfate and glutamine, and was formulated in the hope that it would promote the regeneration of articulations.

Half the dogs received the first formula for four weeks and then the second formula for another four weeks. The other half, acting as the control, received a placebo. The outcomes were tested using three methods. Firstly, the dogs were filmed as they walked at a consistent speed over a special platform that captures the strength of each paw. Secondly, a special electronic collar recorded the dogs' daily activities. And finally, the owners were asked to provide their own evaluations of their dog's behaviour.

The researchers were able to identify an improvement by the fourth week of the trial. "After the eight week course, on average, the strength of the dogs receiving treatment had improved to the equivalent of a kilo of extra strength per paw, which is moreover. None of these dogs saw their health decline, unlike 35.8% of the dogs who were given the placebo," said Maxim Moreau, who was first author of the study.

The improvements were also reflected in the dogs' daily lives. The collars revealed that the dogs receiving treatment maintained their physical activity, and in fact the group average increased from six hours of daily activity to eight. Meanwhile, the dogs receiving the placebo were progressively less active. "In some cases, we recorded the dogs to ensure that the collar was recording actual physical activity rather than movements such as scratching," Troncy explained.

Nonetheless, the ratings from the owners were more mixed. "This third evaluation was more subjective and the contrast between the test group and the control group less stark," Troncy said. "We suspect that the owner may have forgotten what the animal's behaviour was like before it developed arthritis."

The findings raise the possibility of offering a new form of treatment to human beings. "The model of evaluation that we have used is the best for predicting the efficacy of anti-arthritis treatments. We can therefore consider that clinical trials on humans would have a good chance of having positive outcomes," Troncy said.

About this study: This study was funded in part by a grant from ArthroLab Inc., an ongoing New Opportunities Fund grant (#9483) and a Leader Opportunity Fund grant (#24601) from the Canada Foundation for Innovation for the pain/function equipment, a Discovery Grant (#327158-2008; #441651-2013) from the Natural Sciences and Engineering Research Council of Canada for the bio-analyses and salaries, and by the Osteoarthritis Chair of the University of Montreal Hospital Centre, Université de Montréal. Maxim Moreau received a doctoral scholarship from the Canadian Institutes of Health Research (TGF-53914) -- Strategic Training Initiative in Health Research program (MENTOR) and a doctoral scholarship from the Fonds de recherche du Québec-Santé.

Source: Universite de Montreal

High milk intake linked with higher fractures and mortality, research suggests

Women who drank more than three glasses of milk a day had a higher risk of death than women who drank less than one glass of milk a day. Credit: © Africa Studio / Fotolia

A high milk intake in women and men is not accompanied by a lower risk of fracture and instead may be associated with a higher rate of death, suggests observational research published in The BMJ this week.

This may be explained by the high levels of lactose and galactose (types of sugar) in milk, that have been shown to increase oxidative stress and chronic inflammation in animal studies, say the researchers.

However, they point out that their study can only show an association and cannot prove cause and effect. They say the results "should be interpreted cautiously" and further studies are needed before any firm conclusions or dietary recommendations can be made.

A diet rich in milk products is promoted to reduce the likelihood of osteoporotic fractures, but previous research looking at the importance of milk for the prevention of fractures and the influence on mortality rates show conflicting results.

So a research team in Sweden, led by Professor Karl Michaëlsson, set out to examine whether high milk intake may increase oxidative stress, which, in turn, affects the risk of mortality and fracture.

Two large groups of 61,433 women (aged 39-74 years in 1987-1990) and 45,339 men (aged 45-79 years in 1997) in Sweden completed food frequency questionnaires for 96 common foods including milk, yoghurt and cheese.

Lifestyle information, weight and height were collated and factors such as education level and marital status were also taken into account. National registers were used to track fracture and mortality rates.

Women were tracked for an average of 20 years, during which time 15,541 died and 17,252 had a fracture, of whom 4,259 had a hip fracture.

In women, no reduction in fracture risk with higher milk consumption was observed. Furthermore, women who drank more than three glasses of milk a day (average 680 ml) had a higher risk of death than women who drank less than one glass of milk a day (average 60 ml).

Men were tracked for an average of 11 years, during which time 10,112 died and 5,066 had a fracture, with 1,166 hip fracture cases. Men also had a higher risk of death with higher milk consumption, although this was less pronounced than in women.

Further analysis showed a positive association between milk intake and biomarkers of oxidative stress and inflammation.

In contrast, a high intake of fermented milk products with a low lactose content (including yoghurt and cheese) was associated with reduced rates of mortality and fracture, particularly in women.

They conclude that a higher consumption of milk in women and men is not accompanied by a lower risk of fracture and instead may be associated with a higher rate of death. 

Consequently, there may be a link between the lactose and galactose content of milk and risk, although causality needs be tested.

"Our results may question the validity of recommendations to consume high amounts of milk to prevent fragility fractures," they write. "The results should, however, be interpreted cautiously given the observational design of our study. The findings merit independent replication before they can be used for dietary recommendations."

Michaëlsson and colleagues raise a fascinating possibility about the potential harms of milk, says Professor Mary Schooling at City University of New York in an accompanying editorial. However, she stresses that diet is difficult to assess precisely and she reinforces the message that these findings should be interpreted cautiously.

"As milk consumption may rise globally with economic development and increasing consumption of animal source foods, the role of milk and mortality needs to be established definitively now," she concludes.

Source: BMJ-British Medical Journal

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