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Researchers have shown they can reverse the aging process for human adult stem cells, which are responsible for helping old or damaged tissues regenerate. The findings could lead to medical treatments that may repair a host of ailments that occur because of tissue damage as people age. A research group led by the Buck Institute for Research on Aging and the Georgia Institute of Technology conducted the study in cell culture, which appears in the September 1, 2011 edition of the journal Cell Cycle.

The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. A research group led by the Buck Institute for Research on Aging in collaboration with the Georgia Institute of Technology, conducted the study that pinpoints what is going wrong with the biological clock underlying the limited division of human adult stem cells as they age.

“We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional ‘genomic junk’,” said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.

Adult stem cells are important because they help keep human tissues healthy by replacing cells that have gotten old or damaged. They’re also multipotent, which means that an adult stem cell can grow and replace any number of body cells in the tissue or organ they belong to. However, just as the cells in the liver, or any other organ, can get damaged over time, adult stem cells undergo age-related damage. And when this happens, the body can’t replace damaged tissue as well as it once could, leading to a host of diseases and conditions. But if scientists can find a way to keep these adult stem cells young, they could possibly use these cells to repair damaged heart tissue after a heart attack; heal wounds; correct metabolic syndromes; produce insulin for patients with type 1 diabetes; cure arthritis and osteoporosis and regenerate bone.

The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. They thought so because body cells are known to experience a shortening of the caps found at the ends of chromosomes, known as telomeres. But adult stem cells are known to maintain their telomeres. Much of the damage in aging is widely thought to be a result of losing telomeres. So there must be different mechanisms at play that are key to explaining how aging occurs in these adult stem cells, they thought.

Researchers used adult stem cells from humans and combined experimental techniques with computational approaches to study the changes in the genome associated with aging. They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups.

“We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons,” said King Jordan, associate professor in the School of Biology at Georgia Tech.

“Retroransposons were previously thought to be non-functional and were even labeled as ‘junk DNA’, but accumulating evidence indicates these elements play an important role in genome regulation,” he added.

While the young adult stem cells were able to suppress transcriptional activity of these genomic elements and deal with the damage to the DNA, older adult stem cells were not able to scavenge this transcription. New discovery suggests that this event is deleterious for the regenerative ability of stem cells and triggers a process known as cellular senescence.

“By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture,” said Lunyak.

“Furthermore, by rewinding the cellular clock in this way, we were not only able to rejuvenate ’aged’ human stem cells, but to our surprise we were able to reset them to an earlier developmental stage, by up-regulating the “pluripotency factors” – the proteins that are critically involved in the self-renewal of undifferentiated embryonic stem cells.” she said.

Next the team plans to use further analysis to validate the extent to which the rejuvenated stem cells may be suitable for clinical tissue regenerative applications.

Source: Georgia Institute of Technology

Protein linked to aging may boost memory and learning ability

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Crystallographic structure

Crystallographic structure of yeast sir2 complexed with ADP and a histone H4 peptide. Credit: MIT

Over the past 20 years, biologists have shown that proteins called sirtuins can slow the aging process in many animal species.

Now an MIT team led by Professor Li-Huei Tsai has revealed that sirtuins can also boost memory and brainpower—a finding that could lead to new drugs for Alzheimer’s disease and other neurological disorders.

Sirtuins’ effects on brain function, including learning and memory, represent a new and somewhat surprising role, says Tsai, the Picower Professor of Neuroscience and an investigator of the Howard Hughes Medical Institute. “When you review the literature, sirtuins are always associated with longevity, metabolic pathways, calorie restriction, genome stability, and so on. It has never been shown to play a role in synaptic plasticity,” she says.

Synaptic plasticity—the ability of neurons to strengthen or weaken their connections in response to new information—is critical to learning and memory. Potential drugs that enhance plasticity by boosting sirtuin activity could help patients with neurological disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, says Tsai.

A protein with many roles
Sirtuins have received much attention in recent years for their life-span-boosting potential, and for their link to resveratrol, a compound found in red wine that has shown beneficial effects against cancer, heart disease and inflammation in animal studies.

MIT Biology Professor Leonard Guarente discovered about 15 years ago that the SIR2 gene regulates longevity in yeast. Later work revealed similar effects in worms, mice and rats.

More recently, studies have shown that one mammalian version of the gene, SIRT1, protects against oxidative stress (the formation of highly reactive molecules that can damage cells) in the heart and maintains genome stability in multiple cell types. SIRT1 is thought to be a key regulator of an evolutionarily conserved pathway that enhances cell survival during times of stress, especially a lack of food.

In 2007, Tsai and her colleagues showed that sirtuins (the proteins produced by SIR or SIRT genes) protect neurons against neurodegeneration caused by disorders such as Alzheimer’s. They also found that sirtuins improved learning and memory, but believed that might be simply a byproduct of the neuron protection.

However, Tsai’s new study, funded by National Institutes of Health, the Simons Foundation, the Swiss National Science Foundation and the Howard Hughes Medical Institute, shows that sirtuins promote learning and memory through a novel pathway, unrelated to their ability to shield neurons from damage. The team demonstrated that sirtuins enhance synaptic plasticity by manipulating tiny snippets of genetic material known as microRNA, which have recently been discovered to play an important role in regulating gene expression.

Specifically, the team showed that sirtuins block the activity of a microRNA called miR-134, which normally halts production of CREB, a protein necessary for plasticity. When miR-134 is inhibited, CREB is free to help the brain adjust its synaptic activity.

Mice with the SIRT1 gene missing in the brain performed poorly on several memory and learning tests, including object-recognition tasks and a water maze.

“Activation of sirtuins can directly enhance cognitive function,” says Tsai. “This really suggests that SIRT1 is a very good drug target, because it can achieve multiple beneficial effects.”

Raul Mostoslavsky, assistant professor of medicine at Harvard Medical School, says the findings do suggest that activating SIRT1 could benefit patients with neurodegenerative diseases. “However, we will need to be very cautious before jumping to conclusions,” he says, “since SIRT1 has (multiple) effects in multiple cells and tissues, and therefore targeting specifically this brain function will be quite challenging.”

Tsai and her colleagues are now studying the mechanism of SIRT1’s actions in more detail, and are also investigating whether sirtuin genes other than SIRT1 influence memory and learning.

SOURCE

 

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Published: November 2, 2011
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In a potentially fundamental advance, researchers have opened up a novel approach to combating the effects of aging with the discovery that a special category of cells, known as senescent cells, are bad actors that promote the aging of the tissues. Cleansing the body of the cells, they hope, could postpone many of the diseases of aging.

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Photographs from The Van Deursen Laboratory

Fat cells of an untreated mouse, at left, where senescent cells remain, are smaller than in a mouse with senescent cells removed.

The findings raise the prospect that any therapy that rids the body of senescent cells would protect it from the ravages of aging. But many more tests will be needed before scientists know if drugs can be developed to help people live longer.

Senescent cells accumulate in aging tissues, like arthritic knees, cataracts and the plaque that may line elderly arteries. The cells secrete agents that stimulate the immune system and cause low-level inflammation. Until now, there has been no way to tell if the presence of the cells is good, bad or indifferent.

The answer turns out to be that the cells hasten aging in the tissues in which they accumulate. In a delicate feat of genetic engineering, a research team led by Darren J. Baker and Jan M. van Deursen at the Mayo Clinic in Rochester, Minn., has generated a strain of mouse in which all the senescent cells can be purged by giving the mice a drug that forces the cells to self-destruct.

Rid of the senescent cells, the Mayo Clinic researchers reported online Wednesday in the journal Nature, the mice’s tissues showed a major improvement in the usual burden of age-related disorders. They did not develop cataracts, avoided the usual wasting of muscle with age, and could exercise much longer on a mouse treadmill. They retained the fat layers in the skin that usually thin out with age and, in people, cause wrinkling.

“I am very excited by the results,” said Dr. Norman E. Sharpless, an expert on aging at the University of North Carolina. “It suggests therapies that might work in real patients,” he said.

Dr. van Deursen’s work is the first to show that removing senescent cells is beneficial. If confirmed, it “will be considered a fundamental advance by our field,” Dr. Sharpless said.

Aging research is a relatively young field because until 20 or so years ago the prospect of defeating age seemed hopeless. Then researchers found that the lifespan of laboratory animals could be extended by manipulating certain genes, setting off a hunt for drugs that might influence the corresponding genes in people. This line of research remains promising but has produced few tangible results so far. The discovery that senescent cells seem to be the cause of tissue degeneration opens out a new direction for researchers on aging to explore.

Judith Campisi, at the Buck Institute for Research on Aging, said the new finding was the first proof that senescent cells can drive the aging process. “So it’s really quite a breakthrough,” she said.

In both mice and people, senescent cells are few in number but have major effects on the body’s tissues. Killing the cells should therefore have large benefits with little downside. The gene-altering approach used on the mice cannot be tried in people, but now that senescent cells appear to be harmful, researchers can devise ways of targeting them.

Drugs already exist to combat some of the inflammatory hormones secreted by senescent cells. The body’s immune system, which probably clears away senescent cells all the time but does so less efficiently with age, could perhaps be trained to attack senescent cells more aggressively. Or researchers could one day develop specific drugs to kill the cells, when the differences between ordinary and senescent cells are better understood.

Dr. van Deursen said he thought it worth trying to eliminate senescent cells after the finding that they reliably switch on a characteristic marker gene known as p16-Ink4a. In his mice, he arranged that the genetic element that switches on the marker gene would also prime a mechanism to make the cell self-destruct. The mechanism fired only when the mice were dosed with a specific drug. The result was that only senescent cells were at risk from the drug, and that they could be purged at any desired time in the mouse’s lifetime.

In a second experiment, the mice were not given the cell-cleaning drug until they were middle-aged. Their cataracts had already developed by then and were irreversible, but aging was delayed in their fat and muscle tissues.

It may be that senescent cells are beneficial in youth but harmful in old age, when the immune system seems to clear them less rapidly from the body. The second mouse experiment suggests that middle age would be an effective time for clinical intervention, assuming humans behave in the same way.

If aging of the tissues is delayed by eliminating senescent cells, the mice should, in principle, have lived longer. Dr. van Deursen said this was not the case in this experiment only because he had chosen a fast-aging strain of mice in order to save himself time. These particular mice succumb to heart attacks at an early age, regardless of the state of their tissues. The Mayo Clinic team plans to repeat its experiment with an ordinary strain of mouse that normally lives three years or more, to see if its life span is extended as expected.

The Mayo Clinic finding “is a really important step forward for the field,” said Dr. Campisi of the Buck Institute.

The purpose of research on aging, she said, is not to let people live a thousand years, as portrayed in science fiction, but to increase health span, the proportion of people’s natural lives that they live in good health.

“People used to see aging as a rusting nail — there’s nothing you can do about it,” Dr. Campisi said. “But we now know that there are processes that are driving aging, and that those processes can be meddled with.”

 

2011 Nov 2;479(7372):232-6. doi: 10.1038/nature10600. [Have paper]

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM.

Source

Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Abstract

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

Comment in

 

2013 Jan;93(1):105-16. doi: 10.1038/clpt.2012.193. Epub 2012 Dec 5.

Senescent cells: a novel therapeutic target for aging and age-related diseases.

Naylor RM, Baker DJ, van Deursen JM.

Source

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells--damaged cells that have lost the ability to divide--drive the deterioration that underlies aging and age-related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16(Ink4a)-positive senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age-related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age-related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells.