Anti-aging  

Researchers have developed a new method for clearing away removing cellular damage that accumulates with age. Their results show that a tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved.

Researchers from Caltech and UCLA have developed a new approach to removing cellular damage that accumulates with age. The technique can potentially help slow or reverse an important cause of aging.

The team developed a technique to remove mutated DNA from mitochondria, the small organelles that produce most of the chemical energy within a cell. A paper describing the research appears in the journal Nature Communications.

"The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes."

There are hundreds to thousands of mitochondria per cell, each of which carries its own small circular DNA genome, called mtDNA, the products of which are required for energy production. Because mtDNA has limited repair abilities, normal and mutant versions of mtDNA are often found in the same cell, a condition known as heteroplasmy. Most people start off life with some level of heteroplasmy, and the levels of mutant mtDNA increase throughout life. When a critical threshold level of mutant mtDNA is passed, cells become nonfunctional or die.

The accumulation of mutant mtDNA over a lifetime is thought to contribute to aging and degenerative diseases of aging such as Alzheimer's, Parkinson's, and sarcopenia—age-related muscle loss and frailty. Inherited defects in mtDNA are also linked to a number of conditions found in children, including autism.

"We know that increased rates of mtDNA mutation cause premature aging," says Hay, Caltech professor of biology and biological engineering. "This, coupled with the fact that mutant mtDNA accumulates in key tissues such as neurons and muscle that lose function as we age, suggests that if we could reduce the amount of mutant mtDNA, we could slow or reverse important aspects of aging."

The team genetically engineered Drosophila, the common fruit fly, so that about 75 percent of the mtDNA in muscles required for flight, one of the most energy demanding tissues in the animal kingdom, underwent mutation in early adulthood.

This model recapitulates aging in young animals. Drosophila grow quickly and most human disease genes have counterparts in the fly, making it an important model in which to study human disease-related processes. The researchers chose to focus on muscle because this tissue undergoes age-dependent decline in all animals, including humans, and it is easy to see the consequences of loss of function.

Related articles

• Is It Humanity's Fate To Be The 'Mitochondria' of Super-Intelligent AIs? 
• Understanding Human Skin Cells Offers a Pathway for New Anti-Aging Treatments 
• Researchers Uncover Structure of Mitochondrial Sub-Architecture 

The team found that when they artificially increased the activity of genes that promote mitophagy, including that of several genes implicated in familial forms of Parkinson's disease, the fraction of mutated mtDNA in the fly muscle cells was dramatically reduced. For example, overexpressing the gene parkin, which is known to specifically promote the removal of dysfunctional mitochondria and is mutated in familial forms of Parkinson's disease, reduced the fraction of mutant mtDNA from 76 percent to 5 percent, while the overexpression of the gene Atg1 reduced the fraction to 4 percent.

"Such a decrease would completely eliminate any metabolic defects in these cells, essentially restoring them to a more youthful, energy-producing state," notes Hay. "The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes."

"Now that we know mtDNA quality control exists and can be enhanced, our goal is to work with Dr. Guo's lab to search for drugs that can achieve the same effects," Hay adds. "Our goal is to create a future in which we can periodically undergo a cellular housecleaning to remove damaged mtDNA from the brain, muscle, and other tissues. This will help us maintain our intellectual abilities, mobility, and support healthy aging more generally."

SOURCE  Caltech

By  33rd Square

Embed

 Aging  

Scientists have effectively reversed aging in human cell lines. They found that, contrary to the mitochondrial theory of aging, epigenetic regulation controls age-associated defects.

Research led by Jun-Ichi Hayashi from the University of Tsukuba in Japan has shown that, in human cell lines at least, aging can be reversed.

The scientists also found that the regulation of two genes involved
with the production of glycine, the smallest and simplest amino acid, is partly responsible
for some of the characteristics of aging.

Professor Hayashi and his team made this exciting discovery while in the process of addressing some controversial issues surrounding a popular theory of aging.

This theory, the mitochondrial theory of aging, proposes that age-associated mitochondrial defects are controlled by the accumulation of mutations in the mitochondrial DNA.

Abnormal mitochondrial function is one of the hallmarks of aging in many species, including humans. This is mostly due to the fact that the mitochondrion is the so-called powerhouse of the cell as it produces energy in a process called cellular respiration. Damage to the mitochondrial DNA results in changes or mutations in the DNA sequence. Accumulation of these changes is associated with a reduced lifespan and early onset of aging-related characteristics such as weight and hair loss, curvature of the spine and osteoporosis.

There is a growing body of conflicting evidence that has raised doubts about the validity of this theory though. The Tsukuba team in particular has performed some compelling research that has led them to propose that age-associated mitochondrial defects are not controlled by the accumulation of mutations in the mitochondrial DNA but by another form of genetic regulation.

The research examined the function of the mitochondria in human fibroblast cell lines derived from young people (ranging in age from a fetus to a 12 year old) and elderly people (ranging in age from 80-97 years old). They compared the mitochondrial respiration and the amount of DNA damage in the mitochondria of the two groups, expecting respiration to be reduced and DNA damage to be increased in the cells from the elderly group. While the elderly group had reduced respiration, in accordance with the current theory, there was, however, no difference in the amount of DNA damage between the elderly and young groups of cells. This led the researchers to propose that another form
of genetic regulation, epigenetic regulation, may be responsible for the age-associated effects seen in the mitochondria.

The work has been published in Nature Scientific Reports.

Related articles Telomeres and the Aging Process  3D Printing Breakthrough With Human Embryonic Stem Cells  Do You Want To Live Forever?

Epigenetic regulation refers to changes, such as the addition of chemical structures or proteins, which alter the physical structure of the DNA, resulting in genes turning on or off. Unlike mutations, these changes do not affect the DNA sequence itself. If this theory is correct, then genetically reprogramming the cells to an embryonic stem cell–like state would remove any epigenetic changes associated with the mitochondrial DNA.

In order to test this theory, the researchers reprogrammed human fibroblast cell lines derived from young and elderly people to an embryonic stem cell-like state. These cells were then turned back into fibroblasts and their mitochondrial respiratory function examined. Incredibly, the age-associated defects had been reversed - all of the fibroblasts had respiration rates comparable to those of the fetal fibroblast cell line, irrespective of whether they were derived from young or elderly people. This indicates that the aging process in the mitochondrion is controlled by epigenetic regulation, not by mutations.

The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects or restore mitochondrial function in the fibroblast cell lines. In a compelling finding, the addition of glycine for 10 days to the culture medium of the 97 year old fibroblast cell line restored its respiratory function. This suggests that glycine treatment can reverse the age-associated respiration defects in the elderly human fibroblasts.

These findings reveal that, contrary to the mitochondrial theory of aging, epigenetic regulation controls age-associated respiration defects in human fibroblast cell lines. Can epigenetic regulation also control aging in humans? That theory remains to be tested, and if proven, could result in glycine supplements giving our older population a new lease of life.



SOURCE  University of Tsukuba via AlphaGalileo

By 33rd Square

Embed

 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."

Related articles David Sinclair Talks About Aging  Breakthrough May Lead To Anti-Aging Drugs In Five Years  Researchers Use Metabolic Reprogramming To Reverse Aging in Mice

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

By 33rd Square

Embed

 Anti-Aging  

Results of a recent study show promise for reversing aging in muscles.  Researchers have a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells.

Researchers at the Stanford University School of Medicine have pinpointed why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury: Over time, stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew.

“In the past, it’s been thought that muscle stem cells themselves don’t change with age, and that any loss of function is primarily due to external factors in the cells’ environment,” said Helen Blau, PhD, the Donald and Delia B. Baxter Foundation Professor.

“However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.”

Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. “Our findings identify a defect inherent to old muscle stem cells,” she said. “Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage.”

Their study has been published in Nature Medicine.

Blau, a professor of microbiology and immunology and director of Stanford’s Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, published online Feb. 16 in Nature Medicine. Postdoctoral scholar Benjamin Cosgrove, PhD, and former postdoctoral scholar Penney Gilbert, PhD, now an assistant professor at the University of Toronto, are the lead authors.

The researchers found that many muscle stem cells isolated from mice that were 2 years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells.

Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage, Blau said.

Related articles Researchers Create Stem Cells In Living Organism for First Time  Heart's Own Stem Cells Point To Future Treatment for Cardiac Disease  Stem Cell Transplant Restores Memory and Learning in Mice

“Aging is a stochastic but cumulative process,” Cosgrove said. “We’ve now shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew.”

The researchers found that, when transplanted back into the animal, the treated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair.

“In mice, we can take cells from an old animal, treat them for seven days — during which time their numbers expand dramatically, as much as 60-fold — and then return them to injured muscles in old animals to facilitate their repair,” Blau said.

The researchers found that targeting the p38 MAP kinase to induce the rapid expansion of the remaining functional stem cells from old mice required the soft hydrogel substrate. “The drug plus hydrogel boosts the small clones so that they undergo a burst of self-renewing divisions,” Gilbert said. Thus, rejuvenation of the population is contingent on the synergy between biophysical and biochemical cues.

Finally, the researchers tested the ability of the rejuvenated old muscle stem cell population to repair muscle injury and restore strength in 2-year-old recipient mice. They teamed up with co-author Scott Delp, PhD, the James H. Clark Professor in the School of Engineering, who has designed a novel way to measure muscle strength in animals that had muscle injuries and then underwent the stem cell therapy.

“We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice,” Cosgrove said. “Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all.”

The researchers plan to continue their research to learn whether this technique could be used in humans. “If we could isolate the stem cells from an elderly person, expose them in culture to the proper conditions to rejuvenate them and transfer them back into a site of muscle injury, we may be able to use the person’s own cells to aid recovery from trauma or to prevent localized muscle atrophy and weakness due to broken bones,” Blau said. “This really opens a whole new avenue to enhance the repair of specific muscles in the elderly, especially after an injury. Our data pave the way for such a stem cell therapy.”


SOURCE  Stanford School of Medicine

By 33rd Square

Subscribe to 33rd Square

 Aging  

Researchers hope an anti-ageing compound could be tested on humans as early as next year, following a key breakthrough that saw the ageing process reversed in mice. The study, led by researcher David Sinclair, discovered a way of restoring the efficiency of cells, completely reversing the ageing process in muscles.

Researchers have discovered a cause of aging in mammals that may be reversible.

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

In tests, two-year-old mice were given a compound over a week, moving back the key indicators of ageing to that of a six-month-old mouse. Researchers said this was the equivalent of making a 60-year-old person feel like a 20-year-old.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The study was published in the journal Cell.

Mitochondria are often referred to as the cell's "powerhouse," generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins.

Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

Image Source - Ana Gomes

Related articles Major Cause of Age-Related Memory Loss Identified  Researchers Discover Protein That Reverses Heart Disease In Older Mice  Researchers Identify The Key to Aging In The Hypothalamus  Breakthrough May Lead To Anti-Aging Drugs In Five Years

“This was at odds with what the literature suggested,” said Gomes. As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome.

Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.

“This particular component of the aging process had never before been described,” said Gomes.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.

When Sirt1 loses its ability to monitor HIF-1, communication between mitochondria and the nucleus breaks down, and aging accelerates. Image by Ana Gomes

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice.

One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.

“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We're starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”

“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.

The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.



SOURCE  Harvard Medical School

By 33rd Square

Subscribe to 33rd Square

 Anti-Aging  

Resveratrol-based drugs that combat aging may be available within five years says the discoverer of the Sirituin activating compounds, David Sinclair. In a recently published paper, the researcher and his team foudn that a whole new class of anti-aging drugs is now viable by targeting the enzyme SIRT1.

According to a prominent Australian researcher, drugs that combat aging may be available within five years, following landmark research.

The study, published in a recent issue of the journal Science, finally proves that a single anti-aging enzyme in the body can be targeted, with the potential to prevent age-related diseases and extend lifespans.

The paper shows all of the 117 drugs tested work on the single enzyme through a common mechanism. This means that a whole new class of anti-aging drugs is now viable, which could ultimately prevent cancer, Alzheimer's disease and type 2 diabetes.

"Ultimately, these drugs would treat one disease, but unlike drugs of today, they would prevent 20 others," says the lead author of the paper, Professor David Sinclair, from UNSW Medicine, who is based at Harvard University. "In effect, they would slow aging."

The target enzyme, Sirtuin 1 (SIRT1), is switched on naturally by caloric restriction and exercise, but it can also be enhanced through activators. The most common naturally-occurring activator is resveratrol, which is found in small quantities in red wine, but synthetic activators with much stronger activity are already being developed.

Professor David Sinclair

Although research surrounding resveratrol has been going for a decade, until now the basic science had been contested. Despite this, there have already been promising results in some trials with implications for cancer, cardiovascular disease and cardiac failure, type 2 diabetes, Alzheimer's and Parkinson's diseases, fatty liver disease, cataracts, osteoporosis, muscle wasting, sleep disorders and inflammatory diseases such as psoriasis, arthritis and colitis (inflammatory bowel disease).

"In the history of pharmaceuticals, there has never been a drug that tweaks an enzyme to make it run faster," says Professor Sinclair, a geneticist with the Department of Pharmacology at UNSW.

The technology was sold to pharmaceutical giant GlaxoSmithKline in 2008 for over $700 million. Four thousand synthetic activators, which are 100 times as potent as a single glass of red wine, have been developed -- the best three are in human trials.

"Our drugs can mimic the benefits of diet and exercise, but there is no impact on weight," says Professor Sinclair, who suggests the first therapeutic to be marketed will be for diabetes.

There have been limited trials in people with type 2 diabetes and the skin inflammatory disease, psoriasis. There were benefits to the metabolism in the first group and a reduction in skin redness in the second.

The drugs can be administered orally, or topically. So far, there have been no drugs developed targeting aging skin, but one major skin care range has developed a crème with resveratrol in it.

While any drug would be strictly prescribed for certain conditions, Professor Sinclair suggests that one day, they could be taken orally as a preventative. This would be in much the same way as statin drugs are commonly prescribed to prevent, instead of simply treating, cardiovascular disease.

In animal models, overweight mice given synthetic resveratrol were able to run twice as far as slim mice and they lived 15 per cent longer.

"Now we are looking at whether there are benefits for those who are already healthy. Things there are also looking promising," says Professor Sinclair, who also heads the Lowy Cancer Research Centre's Laboratory for aging Research at UNSW.

"We're finding that aging isn't the irreversible affliction that we thought it was," he says. "Some of us could live to 150, but we won't get there without more research."

Sinclair is featured in the BBC Horizon episode on reversing aging below:




SOURCE  University of New South Wales

By 33rd Square

Subscribe to 33rd Square