Aging  

A new study has identified what appears to be a molecular switch controlling inflammatory processes involved in conditions ranging from muscle atrophy to Alzheimer’s disease.

A study led by Massachusetts General Hospital (MGH) investigators has identified what appears to be a molecular switch controlling inflammatory processes involved in conditions ranging from muscle atrophy to Alzheimer’s disease.

"Our findings identified nitric oxide-mediated inactivation of SIRT1 – believed to be a longevity gene – as a hub of the inflammatory spiral common to many aging-related diseases, clarifying a new preventive molecular target."

In their report published in Science Signaling, the research team found that the action of the signaling molecule nitric oxide on the regulatory protein SIRT1 is required for the induction of inflammation and cell death in cellular and animal models of several aging-related disorders.

“Since different pathological mechanisms have been identified for diseases like type 2 diabetes, atherosclerosis and Parkinson’s disease, it has been assumed that therapeutic strategies for those conditions should also differ,” says Masao Kaneki, MD, PhD, MGH Department of Anesthesia, Critical Care and Pain Medicine, senior author of the paper. “In contrast, our findings identified nitric oxide-mediated inactivation of SIRT1 – believed to be a longevity gene – as a hub of the inflammatory spiral common to many aging-related diseases, clarifying a new preventive molecular target.”

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Studies have implicated a role for nitric oxide in diabetes, neurodegeneration, atherosclerosis and other aging-related disorders known to involve chronic inflammation. But exactly how nitric oxide exerts those effects – including activation of the inflammatory factor NF-kappaB and the regulatory protein p53, which can induce the death of damaged cells – was not known.

SIRT1 is known to suppress the activity of both NF-kappaB and p53, and since its dysregulation has been associated with models of several aging-related conditions, the research team focused on nitric oxide’s suppression of SIRT1 through a process called S-nitrosylation.

Cellular experiments revealed that S-nitrosylation inactivates SIRT1 by interfering with the protein’s ability to bind zinc, which in turn increases the activation of p53 and of a protein subunit of NF-kappaB. Experiments in mouse models of systemic inflammation, age-related muscle atrophy and Parkinson’s disease found that blocking or knocking out NO synthase – the enzyme that induces nitric oxide generation – prevented the cellular and in the Parkinson’s model behavioral effects of the diseases. Additional experiments pinpointed the S-nitrosylation of SIRT1 as a critical point in the chain of events leading from nitric oxide expression to cellular damage and death.

“Regardless of the original event that set off this process, once turned on by SIRT1 inactivation, the same cascade of enhanced inflammation and cell death leads to many different disorders,” says Kaneki, an associate professor of Anaesthesia at Harvard Medical School.

“While we need to confirm that what we found in rodent models operates in human diseases, I believe this process plays an important role in the pathogenesis of conditions including obesity-related diabetes, atherosclerosis, Alzheimer’s disease and the body’s response to major trauma. We’re now trying to identify small molecules that will specifically inhibit S-nitrosylation of SIRT1 and related proteins and suppress this proinflammatory switch.”



SOURCE  Massachusetts General Hospital

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 Anti-Aging  

Scientists from Harvard and the University of New South Wales say they have discovered how to reverse the ageing process.

Scientists from Harvard and the University of New South Wales in Australia say they have discovered how to reverse the ageing process. The research has focused on mice, but early clinical trials have also been conducted on humans.

The scientists said they switched youthful genes on and older genes off, using naturally occurring proteins and molecules.

Professor of genetics at Harvard and UNSW, David Sinclair, led the research team.

"We've discovered genes that control how the body fights against ageing and these genes, if you turn them on just the right way, they can have very powerful effects, even reversing ageing - at least in mice so far," he said.

Image Source - University of NSW

"We fed them a molecule that's called NMN and this reversed ageing completely within just a week of treatment in the muscle, and now we're looking to reverse all aspects of ageing if possible."

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Professor Sinclair said the breakthroughs could be used to develop drugs to restore youthfulness in human cells.

"We've discovered genes that control how the body fights against ageing and these genes, if you turn them on just the right way, they can have very powerful effects, even reversing ageing - at least in mice so far."

"We've gone from mice into early human studies actually. There have been some clinical trials around the world, and we're hoping in the next few years to know if this will actually work in people as well," he said.

The clinical trials were small studies but showed promising results in humans, he said.

Sinclair claims they have also developed a way to prematurely age mice.  "We have some new results, it's still in progress, but we have what we think is a way to accelerate ageing and that'll allow us to not only use it as a way to find new drugs but to really understand what causes us to age in the first place."

"They show that the molecules that extend lifespan in mice are safe in people; they seem to be anti-inflammatory, so they might be useful against disease's inflammation, like skin redness or even inflammatory bowel disease," he said.

"Eventually we want these molecules to be taken by many people to prevent diseases of ageing and make them live longer, healthier lives."

Professor Sinclair was named by Time Magazine as one of most influential people in the world.

He has been taking the red wine molecule, resveratrol, for a decade. "I've been taking resveratrolfor the last 10 years because it seemed to be very safe," he said.

"I think the risks are, for myself, worth it, though I don't ever promote it.

"But the more research that I see done, and there are now thousands of papers on it, I think that there's a good chance that it'll have some benefit."

Professor Sinclair said the latest discovery could, one day, be seen in the same light as antibiotics.

"Some people say it's like playing God, but if you ask somebody 100 years ago, what about antibiotics? They probably would have said the same thing," he said.

"Some people worry about big advances in technology and medicine, but once it's adapted and it's natural for people to live until they're 90 in a healthy way ... we'll look back at today like we do at the times before antibiotics when people died from an infected splinter."


SOURCE  ABC

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 Biological Clock  

Researchers have discovered a new mechanism that governs how body clocks react to changes in the environment. The discovery could provide a solution for alleviating the detrimental effects of chronic shift work and jet-lag.

Researchers from The University of Manchester have discovered a new mechanism that governs how body clocks react to changes in the environment.

The discovery, which is being published in Current Biology, could provide a solution for alleviating the detrimental effects of chronic shift work and jet lag.

The team’s findings reveal that the enzyme casein kinase 1epsilon (CK1epsilon) controls how easily the body’s clockwork can be adjusted or reset by environmental cues such as light and temperature.

"It is now becoming clear that clock disruption is increasing the incidence and severity of diseases including obesity and diabetes."

Internal biological timers (circadian clocks) are found in almost every species on the planet. In mammals including humans, circadian clocks are found in most cells and tissues of the body, and orchestrate daily rhythms in our physiology, including our sleep/wake patterns and metabolism.

Dr David Bechtold, who led The University of Manchester’s research team, said: “At the heart of these clocks are a complex set of molecules whose interaction provides robust and precise 24 hour timing. Importantly, our clocks are kept in synchrony with the environment by being responsive to light and dark information.”

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The research identifies a new mechanism through which our clocks respond to these light inputs. During the study, mice lacking CK1epsilon, a component of the clock, were able to shift to a new light-dark environment (much like the experience in shift work or long-haul air travel) much faster than normal.

The research team went on to show that drugs that inhibit CK1epsilon were able to speed up shift responses of normal mice, and critically, that faster adaption to the new environment minimised metabolic disturbances caused by the time shift.

Dr Bechtold said: “We already know that modern society poses many challenges to our health and wellbeing - things that are viewed as commonplace, such as shift-work, sleep deprivation, and jet lag disrupt our body’s clocks. It is now becoming clear that clock disruption is increasing the incidence and severity of diseases including obesity and diabetes.

“We are not genetically pre-disposed to quickly adapt to shift-work or long-haul flights, and as so our bodies’ clocks are built to resist such rapid changes. Unfortunately, we must deal with these issues today, and there is very clear evidence that disruption of our body clocks has real and negative consequences for our health.”

He continues: “As this work progresses in clinical terms, we may be able to enhance the clock’s ability to deal with shift work, and importantly understand how maladaptation of the clock contributes to diseases such as diabetes and chronic inflammation.”


SOURCE  University of Manchester

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