Posts Tagged ‘ageing’

by Lindsey Valich

Explorers have dreamt for centuries of a Fountain of Youth, with healing waters that rejuvenate the old and extend life indefinitely.

Researchers at the University of Rochester, however, have uncovered more evidence that the key to longevity resides instead in a gene.

In a new paper published in the journal Cell, the researchers—including Vera Gorbunova and Andrei Seluanov, professors of biology; Dirk Bohmann, professor of biomedical genetics; and their team of students and postdoctoral researchers—found that the gene sirtuin 6 (SIRT6) is responsible for more efficient DNA repair in species with longer lifespans. The research illuminates new targets for anti-aging interventions and could help prevent age-related diseases.

Inevitable double-strand breaks

As humans and other mammals grow older, their DNA is increasingly prone to breaks, which can lead to gene rearrangements and mutations—hallmarks of cancer and aging. For that reason, researchers have long hypothesized that DNA repair plays an important role in determining an organism’s lifespan. While behaviors like smoking can exacerbate double-strand breaks (DSBs) in DNA, the breaks themselves are unavoidable. “They are always going to be there, even if you’re super healthy,” says Bohmann. “One of the main causes of DSBs is oxidative damage and, since we need oxygen to breathe, the breaks are inevitable.”

Organisms like mice have a smaller chance of accumulating double-strand breaks in their comparatively short lives, versus organisms with longer lifespans, Bohmann says. “But, if you want to live for 50 years or so, there’s more of a need to put a system into place to fix these breaks.”

The longevity gene

SIRT6 is often called the “longevity gene” because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. The researchers hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?

To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). They found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes—the SIRT6 proteins—are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer. “The SIRT6 protein seems to be the dominant determinant of lifespan,” Bohmann says. “We show that at the cell level, the DNA repair works better, and at the organism level, there is an extended lifespan.”

The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein “more active in repairing DNA and better at enzyme functions,” Gorbunova says. When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6.

Species with even more robust SIRT6?

Although it appears that human SIRT6 is already optimized to function, “we have other species that are even longer lived than humans,” Seluanov says. Next steps in the research involve analyzing whether species that have longer lifespans than humans—like the bowhead whale, which can live more than 200 years—have evolved even more robust SIRT6 genes.

The ultimate goal is to prevent age-related diseases in humans, Gorbunova says. “If diseases happen because of DNA that becomes disorganized with age, we can use research like this to target interventions that can delay cancer and other degenerative diseases.”

https://phys.org/news/2019-04-longevity-gene-responsible-efficient-dna.html

Beauty might only be skin deep, but for those wondering how to keep that skin young, scientists may have found an answer in the form of a protein that encourages cell competition.

The prosaically named COL17A1 might not sound like a fountain of youth, but the new study suggests it does the heavy lifting when it comes to keeping skin intact and unimpaired.

The protein works by encouraging cell competition, a key process to maintain tissue fitness. That effectively “drives out” weaker cells while encouraging replication of stronger ones.

“Damaged or stressed stem cells can be selectively eliminated by intact stem cells every day in our skin,” said Emi Nishimura, a professor at the Tokyo Medical and Dental University’s Stem Cell Biology department, who led the research.

But ageing results in a depletion of COL17A1, as do familiar enemies of youthful skin, like UV radiation and other stress factors.

And when that happens, weaker cells replicate, leaving the skin thinner, more prone to damage and slower to heal.

The research published Thursday in the journal Nature is based on investigations using mice tails, which share many of the same characteristics as human skin.

After confirming the importance of COL17A1, the team decided to investigate whether they could stimulate the protein once it was depleted—effectively looking for compounds that could kickstart the anti-ageing process in skin.

They isolated two chemical compounds—Y27632 and apocynin—and tested both on skin cells, with positive results.

“Application of these drugs to full-thickness skin wounds significantly promoted wound repair,” the study said.

The two compounds point to ways of “facilitating skin regeneration and reducing skin ageing,” the study added.

In a review of the study commissioned by Nature, two professors from the University of Colorado said cell competition had previously only been studied extensively in fruit flies.

The research “provides evidence that healthy cells in mammals can also efficiently repopulate adult tissues, replacing unfit or damaged cells,” wrote professors Ganna Bilousova and James DeGregori.

And they said the research offered “proof-of-principle” that the two chemical compounds could combat ageing.

“Future studies are needed to determine the mechanisms of cell competition in other tissues, and to identify compounds capable of reversing ageing in other organs,” they said.

Nishimura told AFP that the work could eventually lead to products like creams or tablets that could stop skin deterioration and promote repair.

“We are going to collaborate with pharmaceutical or cosmetic companies for the clinical use of the chemicals,” she said.

She said additional research would investigate whether the same process might also be at work in other parts of the body that have so-called epithelial cells like skin does.

“We are working on other epithelial organs as well to find out (whether) similar competition may underlie long-term tissue maintenance as well as organ ageing,” she said.

https://medicalxpress.com/news/2019-04-young-uncovers-protein-skin-youthful.html

Estimated age based on exercise stress testing performance may be a better predictor of mortality than chronological age, according to a study published online Feb. 13 in the European Journal of Preventive Cardiology.

Serge C. Harb, M.D., from the Cleveland Clinic, and colleagues evaluated whether age based on stress testing exercise performance (A-BEST) would be a better predictor of mortality than chronological age among 126,356 consecutive patients (mean age, 53.5 years) referred for exercise (electrocardiography, echocardiography, or myocardial perfusion imaging) stress testing between Jan. 1, 1991, and Feb. 27, 2015. Exercise capacity (number of peak estimated metabolic equivalents of task), chronotropic reserve index, and heart rate recovery were used to compute estimated age taking into account patient’s gender and medications that affect heart rate.

The researchers found that after adjustment for clinical comorbidities, improved survival was associated with higher metabolic equivalents of task (adjusted hazard ratio [aHR] for mortality, 0.71) and higher chronotropic reserve index (aHR for mortality, 0.97). Higher mortality was associated with abnormal heart rate recovery (aHR for mortality, 1.53) and higher A-BEST (aHR for mortality, 1.05). There was a significant increase in the area under the curve when A-BEST rather than chronological age was used in prediction models (0.82 versus 0.79). The overall net reclassification improvement was significant.

“For the first time we can quantify the impact of your performance level on a treadmill test in adding or subtracting years from your actual age,” Harb said in a statement.

https://www.physiciansbriefing.com/cardiology-2/age-health-news-7/stress-test-based-physiological-age-may-be-superior-mortality-predictor-742824.html

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Even the occasional drink is harmful to health, according to the largest and most detailed research carried out on the effects of alcohol, which suggests governments should think of advising people to abstain completely.

The uncompromising message comes from the authors of the Global Burden of Diseases study, a rolling project based at the University of Washington, in Seattle, which produces the most comprehensive data on the causes of illness and death in the world.

Alcohol, says their report published in the Lancet medical journal, led to 2.8 million deaths in 2016. It was the leading risk factor for premature mortality and disability in the 15 to 49 age group, accounting for 20% of deaths.

Current alcohol drinking habits pose “dire ramifications for future population health in the absence of policy action today”, says the paper. “Alcohol use contributes to health loss from many causes and exacts its toll across the lifespan, particularly among men.”

Most national guidelines suggest there are health benefits to one or two glasses of wine or beer a day, they say. “Our results show that the safest level of drinking is none.”

The study was carried out by researchers at the Institute of Health Metrics and Evaluation (IHME), who investigated levels of alcohol consumption and health effects in 195 countries between 1990 to 2016. They used data from 694 studies to work out how common drinking was and from 592 studies including 28 million people worldwide to work out the health risks.

Moderate drinking has been condoned for years on the assumption that there are some health benefits. A glass of red wine a day has long been said to be good for the heart. But although the researchers did find low levels of drinking offered some protection from heart disease, and possibly from diabetes and stroke, the benefits were far outweighed by alcohol’s harmful effects, they said.

Drinking alcohol was a big cause of cancer in the over-50s, particularly in women. Previous research has shown that one in 13 breast cancers in the UK were alcohol-related. The study found that globally, 27.1% of cancer deaths in women and 18.9% in men over 50 were linked to their drinking habits.

In younger people globally the biggest causes of death linked to alcohol were tuberculosis (1.4% of deaths), road injuries (1.2%), and self-harm (1.1%).

In the UK, the chief medical officer Sally Davies has said there is no safe level of drinking, but the guidance suggests that drinkers consume no more than 14 units a week to keep the risks low. Half a pint of average-strength lager contains one unit and a 125ml glass of wine contains around 1.5 units.

While the study shows that the increased risk of alcohol-related harm in younger people who have one drink a day is small (0.5%), it goes up incrementally with heavier drinking: to 7% among those who have two drinks a day (in line with UK guidance) and 37% for those who have five.

One in three, or 2.4 billion people around the world, drink alcohol, the study shows. A quarter of women and 39% of men drink. Denmark has the most drinkers (95.3% of women, and 97.1% of men). Pakistan has the fewest male drinkers (0.8%) and Bangladesh the fewest women (0.3%). Men in Romania and women in Ukraine drink the most (8.2 and 4.2 drinks a day respectively), while women in the UK take the eighth highest place in the female drinking league, with an average of three drinks a day.

“Alcohol poses dire ramifications for future population health in the absence of policy action today. Our results indicate that alcohol use and its harmful effects on health could become a growing challenge as countries become more developed, and enacting or maintaining strong alcohol control policies will be vital,” said the report’s senior author, Prof Emmanuela Gakidou.

“Worldwide we need to revisit alcohol control policies and health programmes, and to consider recommendations for abstaining from alcohol. These include excise taxes on alcohol, controlling the physical availability of alcohol and the hours of sale, and controlling alcohol advertising. Any of these policy actions would contribute to reductions in population-level consumption, a vital step toward decreasing the health loss associated with alcohol use.”

Dr Robyn Burton, of King’s College London, said in a commentary in the Lancet that the conclusions of the study were clear and unambiguous. “Alcohol is a colossal global health issue and small reductions in health-related harms at low levels of alcohol intake are outweighed by the increased risk of other health-related harms, including cancer,” she wrote.

“There is strong support here for the guideline published by the Chief Medical Officer of the UK who found that there is ‘no safe level of alcohol consumption’.”

Public health policy should be to prioritise measures to reduce the numbers who drink through price increases, taxation, or setting the price according to the strength of the drink (minimum unit pricing), followed by curbs on marketing and restricting the places where people can buy alcohol.

“These approaches should come as no surprise because these are also the most effective measures for curbing tobacco-related harms, another commercially mediated disease, with an increasing body of evidence showing that controlling obesity will require the same measures,” she wrote.

Ben Butler, a Drinkaware spokesperson, said: “This new study supports existing evidence about the harms associated with alcohol. Our research shows that over a quarter of UK adults typically exceed the low risk drinking guidelines and are running the risk of serious long term illnesses.”

But David Spiegelhalter, Winton professor for the public understanding of risk at the University of Cambridge, said the data showed only a very low level of harm in moderate drinkers and suggested UK guidelines were very low risk.

“Given the pleasure presumably associated with moderate drinking, claiming there is no ‘safe’ level does not seem an argument for abstention,” he said. “There is no safe level of driving, but government do not recommend that people avoid driving. Come to think of it, there is no safe level of living, but nobody would recommend abstention.”

https://www.theguardian.com/society/2018/aug/23/no-healthy-level-of-alcohol-consumption-says-major-study

20120917-restriction

Instead of survival of the fittest, evolution might actually be about survival of the laziest.

That’s according to a new study published Tuesday in the journal The Royal Society. Researchers from the University of Kansas studied fossils of ancient mollusks and gastropods, and found that organisms with higher metabolic rates were more likely to go extinct.

Animals that required less energy to power their daily lives and maintain their bodily functions were more likely to win in the long run, the results showed.

While metabolism isn’t the only factor that determines whether a species goes extinct, the researchers suggest that it’s a very important component of long-term survival.

That new finding adds to a growing body of evidence that links lower metabolism with longevity. (Naked mole rats, for example, are the longest living rodents thanks to a quirk in their metabolism.)

Rozalyn Anderson, an associate professor at the University of Wisconsin’s School of Medicine and Public Health, told Business Insider that her work in monkeys also suggests metabolism is at the center of the aging process.

“I think it’s all about energy: energy use, energy storage and the type of pathways that are being engaged to derive energy,” she said.

Restricting calories in monkeys
Anderson’s most recent research has been on the impacts of restricting caloric intake in Rhesus monkeys.

In a study of 76 monkeys published in the journal Science in 2009, Anderson and her colleagues found that restricting how many calories the animals consumed by 25% over a span of 20 years made them age differently, compared to a group of control monkeys that ate however much they wanted.

The monkeys who ate less were 2.5 times less likely to have an age-related disease like cancer or heart disease.

“The calorically restricted animals age differently,” Anderson said. “They don’t age slower, they age differently, and the way they age is associated with less disease risk. And that difference is in terms of their metabolism.”

She added that restricting a body’s caloric intake — the fuel it takes in — alters how the body produces and consumes energy, making it more energetically efficient.

Anderson also noted that the monkeys that underwent caloric restriction maintained their level of physical activity as they aged, whereas the control animals’ physical activity levels decreased. She explained at a conference in 2014 that for calorically restricted animals, there’s a lower metabolic cost associated with movement — more “bang for your buck” when it comes to trading nutrients for usable energy units.

When humans restrict their calories, researchers have seen similar outcomes. A two-year-long, NIH-supported study published in The Journals of Gerontology in 2015 found that participants who restricted their calories by 12% on average saw decreases in risk factors that contribute to age-related heart disease and diabetes. The experiment did not significantly alter their metabolism, though.

Connecting the dots between factors in the aging process
Anderson said that in her various studies of different facets of aging, she’s most fascinated when her research uncovers pathways that converge and overlap. This is happening more and more in the field of aging, and it’s helping her piece together why caloric restriction seems to alter parts of the aging process.

“I think it’s all completely connected, and these are just different ways of looking at the same phenomenon, which is the things that change with age that makes older people more vulnerable to disease than young people,” Anderson said. “How could you imagine a machine as complicated as a person or a monkey or a mouse, and not have it massively interconnected?”

For example, she found that a specific group of microRNAs — molecules that control gene expression — that she studied in relation to aging a while back plays an active role in the body’s response to caloric restriction. Anderson also found links between caloric restriction and her previous studies on NAD, a molecule that’s tied to energy metabolism and mitochondria. Putting these cellular-level studies into a bigger picture allows Anderson to gauge how all the moving parts come together when calories are limited.

“There’s this idea that the constellation of cells in a tissue are performing different tasks and different ones are creating vulnerability in different ways,” Anderson said. “It’s becoming more nuanced, for sure, it’s becoming more complicated. But it’s also making more sense. Which is why I think it’s kind of cool.”

Aging is inevitable, Anderson said, but her work is suggesting that how you age is flexible and manipulatable.

Understanding the relationship between metabolism and aging will allow scientists to better design studies on longevity. And as more research reveals how and why animals with lower metabolisms live longer and survive better, scientists may be able to figure out ways to mimic those effects in humans.

https://www.thisisinsider.com/restricting-calories-could-protect-against-aging-2018-8

Psychologists at the University of Sussex have found a link between depression and an acceleration of the rate at which the brain ages. Although scientists have previously reported that people with depression or anxiety have an increased risk of dementia in later life, this is the first study that provides comprehensive evidence for the effect of depression on decline in overall cognitive function (also referred to as cognitive state), in a general population.

For the study, published today, Thursday 24 May 2018, in the journal Psychological Medicine, researchers conducted a robust systematic review of 34 longitudinal studies, with the focus on the link between depression or anxiety and decline in cognitive function over time. Evidence from more than 71,000 participants was combined and reviewed. Including people who presented with symptoms of depression as well as those that were diagnosed as clinically depressed, the study looked at the rate of decline of overall cognitive state – encompassing memory loss, executive function (such as decision making) and information processing speed – in older adults.

Importantly, any studies of participants who were diagnosed with dementia at the start of study were excluded from the analysis. This was done in order to assess more broadly the impact of depression on cognitive ageing in the general population. The study found that people with depression experienced a greater decline in cognitive state in older adulthood than those without depression. As there is a long pre-clinical period of several decades before dementia may be diagnosed, the findings are important for early interventions as currently there is no cure for the disease.

Lead authors of the paper, Dr Darya Gaysina and Amber John from the EDGE (Environment, Development, Genetics and Epigenetics in Psychology and Psychiatry) Lab at the University of Sussex, are calling for greater awareness of the importance of supporting mental health to protect brain health in later life.

Dr Gaysina, a Lecturer in Psychology and EDGE Lab Lead, comments: “This study is of great importance – our populations are ageing at a rapid rate and the number of people living with decreasing cognitive abilities and dementia is expected to grow substantially over the next thirty years.

“Our findings should give the government even more reason to take mental health issues seriously and to ensure that health provisions are properly resourced. We need to protect the mental wellbeing of our older adults and to provide robust support services to those experiencing depression and anxiety in order to safeguard brain function in later life.”

Researcher Amber John, who carried out this research for her PhD at the University of Sussex adds: “Depression is a common mental health problem – each year, at least 1 in 5 people in the UK experience symptoms. But people living with depression shouldn’t despair – it’s not inevitable that you will see a greater decline in cognitive abilities and taking preventative measures such as exercising, practicing mindfulness and undertaking recommended therapeutic treatments, such as Cognitive Behaviour Therapy, have all been shown to be helpful in supporting wellbeing, which in turn may help to protect cognitive health in older age.”

The research paper, ‘Affective problems and decline in cognitive state in older adults’ will be available at: https:// doi.org/10.1017/S0033291718001137 from Thursday 24 May 2018.

http://www.sussex.ac.uk/broadcast/read/44977

A research team at University of Copenhagen including a researcher from the Faculty of Health and Medical Sciences has discovered a circuit in the brains of mice connecting circadian rhythm to aggressive behaviour. The discovery is particularly interesting to Alzheimer’s patients who experience increased aggression at night. The researchers have developed special protein tools capable of turning off the cells in the brain causing the behaviour.

Each year around 8,000 Danes are diagnosed with a form of dementia. Alzheimer’s disease is one of them. The disease manifests itself in memory difficulties in particular, but can also result in personality changes and mood swings.

When the sun sets 20 per cent of all Alzheimer’s patients experience increased bewilderment, anxiety, unease, disorientation, irritation and aggression. This phenomenon is called ‘sundowning’ or sundown syndrome. At worst, the condition can mean that the patient must be left in professional care, as it can be difficult for family members to handle. The cause of the condition is unknown, but previous research has suggested that it is connected to the circadian rhythm.

A research team including a researcher from the Department of Drug Design and Pharmacology at the University of Copenhagen is now able to confirm this connection. The researchers have identified and mapped a circuit between the part of the brain containing the circadian clock or circadian rhythm and a part of the brain controlling aggression.

’We have shown that the circadian clock in mice is closely linked to an aggression centre in the mouse brain by a cell circuit. The human brain has those same groups of cells that the circuit goes through. With this knowledge, we are now enabled to target this circuit pharmacologically and target cells that make people aggressive at the end of the day’, says Assistant Professor Timothy Lynagh from the Department of Drug Design and Pharmacology at the University of Copenhagen.

Turn off the Aggression
The inner clock or circadian rhythm is located in the part of the brain called suprachiasmatic nucleus. One of the parts of the brain that control aggressive behaviour is called the ventromedial hypothalamus. Researchers have previously observed a connection between the two parts of the brain, though none have had knowledge of the specific circuit connecting them.

Using electrophysiology and microscopy, the researchers measured the activity of the brain cells at main author Clifford Saper’s laboratory in Boston. They also turned off parts of the cell circuit in the brains of mice to map the circuit and to identify the cells connecting the two parts of the brain. To map circuits in the brain you need a protein tool that can turn off the various cells to determine their function. Assistant Professor Timothy Lynagh has designed precisely such a tool.

‘We take a receptor and mutate it, so that it is not sensitive to anything in the brain, but very sensitive to a particular drug. The tool works like an on/off switch. When you put the protein tool in the mouse brain, under normal circumstances, nothing will happen. But when you give the animal the drug, the cells that have the receptor on them will be turned off’, Timothy Lynagh explains.

Using this tool, the researchers can thus in theory turn off the cells that cause people suffering from sundown syndrome to become more aggressive at night.

May Be Used on Humans 20 Years into the Future
The tool can also be used in other contexts than sundown syndrome. In other studies, Tim Lynagh’s tool has been used to turn off cells in rats linked to anxiety and fear.

‘If you can start understanding which cells in the brain lead to which problems, you can then put this tool into any of those parts of the brain. The person who takes the drug will then have the cells causing the problem turned off’, Timothy Lynagh says.

Even though the study was conducted on mice, the tool and the knowledge the research has generated can potentially be used in the treatment of humans.

‘Because of the huge advances that are coming along with CRISPR, I would be tempted to say that based on a recent demonstration of gene therapy for brain disease, potentially, it could be used in the human brain in 20 years’ time. Of course it needs a lot more research’, he says.

Reference:
Todd, W. D., Fenselau, H., Wang, J. L., Zhang, R., Machado, N. L., Venner, A., … & Lowell, B. B. (2018). A hypothalamic circuit for the circadian control of aggression. Nature neuroscience, 1.

http://healthsciences.ku.dk/news/2018/05/researchers-discover-connection-between-circadian-rhythm-and-aggression/