Collaborations between Johns Hopkins and National Taiwan University researchers have successfully manipulated the life span of common, single-celled yeast organisms by figuring out how to remove and restore protein functions related to yeast aging.

A chemical variation of a “fuel-gauge” enzyme that senses energy in yeast acts like a life span clock: It is present in young organisms and progressively diminished as yeast cells age.

In a report in the September 16 edition of Cell, the scientists describe their identification of a new level of regulation of this age-related protein variant, showing that when they remove it, the organism’s life span is cut short and when they restore it, life span is dramatically extended.

In the case of yeast, the discovery reveals molecular components of an aging pathway that appears related to one that regulates longevity and lifespan in humans, according to Jef Boeke, Ph.D., professor of molecular biology, genetics and oncology, and director of the HiT Center and Technology Center for Networks and Pathways, Johns Hopkins University School of Medicine.

“This control of longevity is independent of the type described previously in yeast which had to do with calorie restriction,” Boeke says. “We believe that for the first time, we have a biochemical route to youth and aging that has nothing to do with diet.” The chemical variation, known as acetylation because it adds an acetyl group to an existing molecule, is a kind of “decoration” that goes on and off a protein — in this case, the protein Sip2 — much like an ornament can be put on and taken off a Christmas tree, Boeke says. Acetylation can profoundly change protein function in order to help an organism or system adapt quickly to its environment. Until now, acetylation had not been directly implicated in the aging pathway, so this is an all-new role and potential target for prevention or treatment strategies, the researchers say.

The team showed that acetylation of the protein Sip2 affected longevity defined in terms of how many times a yeast cell can divide, or “replicative life span.” The normal replicative lifespan in natural yeast is 25. In the yeast genetically modified by researchers to restore the chemical modification, life span extended to 38, an increase of about 50 percent.

The researchers were able to manipulate the yeast life span by mutating certain chemical residues to mimic the acetylated and deacetylated forms of the protein Sip2. They worked with live yeast in a dish, measuring and comparing the life spans of natural and genetically altered types by removing buds from the yeast every 90 minutes. The average lifespan in normal yeast is about 25 generations, which meant the researchers removed 25 newly budded cells from the mother yeast cell. As yeast cells age, each new generation takes longer to develop, so each round of the experiment lasted two to four weeks.

“We performed anti-aging therapy on yeast,” says the study’s first author, Jin-Ying Lu, M.D., Ph.D., of National Taiwan University. “When we give back this protein acetylation, we rescued the life span shortening in old cells. Our next task is to prove that this phenomenon also happens in mammalian cells.”

The research was supported by the National Science Council, National Taiwan University Hospital, National Taiwan University, Liver Disease Prevention & Treatment Research Foundation of Taiwan, and the NIH Common Fund.

Authors on the paper, in addition to Boeke and Lu, are Yu-Yi Lin, Jin-Chuan Sheu, June-Tai Wu, Fang-Jen Lee, Min-I Lin, Fu-Tien Chian, Tong-Yuan Tai, Keh-Sung Tsai, and Lee-Ming Chuang, all of National Taiwan University; Yue Chen and Yinming Zhao, both of the University of Chicago; and Shelley L. Berger, Wistar Institute.

The above story is reprinted from materials provided by Johns Hopkins Medical Institutions.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

1. Jin-Ying Lu, Yu-Yi Lin, Jin-Chuan Sheu, June-Tai Wu, Fang-Jen Lee, Yue Chen, Min-I Lin, Fu-Tien Chiang, Tong-Yuan Tai, Shelley L. Berger, Yingming Zhao, Keh-Sung Tsai, Heng Zhu, Lee-Ming Chuang, Jef D. Boeke. Acetylation of Yeast AMPK Controls Intrinsic Aging Independently of Caloric Restriction. Cell, 2011; 146 (6): 969 DOI: 10.1016/j.cell.2011.07.044

Scientists have recently succeeded in rejuvenating cells from elderly donors (aged over 100). These old cells were reprogrammed in vitro to induced pluripotent stem cells (iPSC) and to rejuvenated and human embryonic stem cells (hESC): cells of all types can again be differentiated after this genuine “rejuvenation” therapy. The results represent significant progress for research into iPSC cells and a further step forwards for regenerative medicine.

Inserm’s AVENIR “Genomic plasticity and aging” team, directed by Jean-Marc Lemaitre, Inserm researcher at the Functional Genomics Institute (Inserm/CNRS/Université de Montpellier 1 and 2) performed the research. The results were published in Genes & Development on November 1, 2011.

Human embryonic stem cells (hESC) are undifferentiated multiple-function cells. They can divide and form all types of differentiated adult cells in the body (neurons, cardiac cells, skin cells, liver cells, etc.). Since 2007, a handful of research teams across the world have been capable of reprogramming human adult cells into induced pluripotent cells (iPSC), which have similar characteristics and potential to human embryonic stem cells (hESC). This kind of reprogramming makes it possible to reform all human cell types without the ethical restrictions related to using embryonic stem cells.

Until now, research results demonstrated that senescence (the final stage of cellular aging) was an obstacle blocking the use of this technique for therapeutic applications in elderly patients. Today, Inserm researcher Jean-Marc Lemaitre and his team have overcome this obstacle. The researchers have successfully rejuvenated cells from elderly donors, some over 100 years old, thus demonstrating the reversibility of the cellular aging process.

To achieve this, they used an adapted strategy that consisted of reprogramming cells using a specific “cocktail” of six genetic factors, while erasing signs of aging. The researchers proved that the iPSC cells thus obtained then had the capacity to reform all types of human cells. They have the physiological characteristics of “young” cells, both from the perspective of their proliferative capacity and their cellular metabolisms.

A cocktail of six genetic factors…

Researchers first multiplied skin cells (fibroblasts) from a 74 year-old donor to obtain the senescence characterized by the end of cellular proliferation. They then completed the in vitro reprogramming of the cells. In this study, Jean-Marc Lemaitre and his team firstly confirmed that this was not possible using the batch of four genetic factors (OCT4, SOX2, C MYC and KLF4) traditionally used. They then added two additional factors (NANOG and LIN28) that made it possible to overcome this barrier.

Using this new “cocktail” of six factors, the senescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.

In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the “rejuvenated” characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).

“Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity,” explains Jean-Marc Lemaitre who directs the Inserm AVENIR team.

…tested on cells taken from donors over the age of 100

The results obtained led the research team to test the cocktail on even older cells taken from donors of 92, 94 and 96, and even up to 101 years old. “Our strategy worked on cells taken from donors in their 100s. The age of cells is definitely not a reprogramming barrier.” He concluded. “This research paves the way for the therapeutic use of iPS, insofar as an ideal source of adult cells is provided, which are tolerated by the immune system and can repair organs or tissues in elderly patients.” adds the researcher.

The above story is reprinted from materials provided by INSERM (Institut national de la santé et de la recherche médicale).

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

1. L. Lapasset, O. Milhavet, A. Prieur, E. Besnard, A. Babled, N. Ait-Hamou, J. Leschik, F. Pellestor, J.-M. Ramirez, J. De Vos, S. Lehmann, J.-M. Lemaitre. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & Development, 2011; 25 (21): 2248 DOI: 10.1101/gad.173922.111

When the body fights oxidative damage, it calls up a reservist enzyme that protects cells — but only if those cells are relatively young, a study has found. Biologists at USC discovered major declines in the availability of an enzyme, known as the Lon protease, as human cells grow older.

The finding may help explain why humans lose energy with age and could point medicine toward new diets or pharmaceuticals to slow the aging process.

The researchers showed that when oxidative agents attack the power centers of young cells, the cells respond by calling up reinforcements of the enzyme, which breaks up and removes damaged proteins.

As the cells age, they lose the ability to mobilize large numbers of Lon, the researchers reported in The Journals of Gerontology.

Senior author Kelvin J. A. Davies, a professor at the USC Leonard Davis School of Gerontology, used a war analogy to explain that no “standing army” of Lon protease can endure an attack by invading oxidants without calling up reserves.

“Once the war has started, what’s your capacity to keep producing … to protect your vital resources and keep the fight going?” he asked.

Since aging is the longest war, the USC study suggests a more important role for the reservist enzyme than previously known.

Lon protects the mitochondria — tiny organisms in the cell that convert oxygen into energy. The conversion is never perfect: Some oxygen leaks and combines with other elements to create damaging oxidants.

Oxidation is the process behind rust and food spoilage. In the body, oxidation can damage or destroy almost any tissue. Lon removes oxidized proteins from the mitochondria and also plays a vital role in helping to make new mitochondria.

“We know that mitochondrial function declines with age, which is a major limitation to cells. One of the components of that decline is the loss of Lon. The ability of Lon to be induced by [oxidative] stress is a very important component of overall stress resistance,” Davies said.

Davies and his team worked with a line of human lung cells. They exposed the cells to hydrogen peroxide, a powerful oxidant that is a byproduct of energy production and that also can result from metabolism of some drugs, toxins, pesticides and herbicides.

To fight the oxidant, young cells doubled the size of their Lon army within five hours and maintained it for a day. In some experiments, young cells increased their Lon army as much as seven-fold.

Middle-aged cells took a full day to double their Lon army, during which time the cells were exposed to harmful levels of oxidized proteins.

Older cells started with a standing Lon army only half as large and showed no statistically significant increase in Lon levels over 24 hours.

The Davies group, which discovered Lon in 2002, previously had shown that Lon’s standing army gets smaller with age and that the anti-oxidant power of Lon depends more on its reserves than on enzymes present when stress first hits the body.

The latest study completes the picture of Lon’s sluggish response as senescent cells — a technical term for cells that mimic several key features of the aging process — try to cope with stress.

“In the senescent cells, the Lon levels are drastically low to begin with, and they don’t increase” in response to stress, Davies said.

Scientists have known for decades that mitochondria become less efficient with age, contributing to the body’s loss of energy.

“It may well be that our ability to induce Lon synthesis and our loss of adaptability to stress may be an even more significant factor in the aging process,” Davies said.

Davies and others are investigating potential treatments to boost the function of Lon. Costly enzyme supplements are useless, Davies noted, since the digestive system breaks down the enzyme to amino acids before it can reach its target.

“It’s a lot cheaper to buy a piece of meat and get the same amino acids,” he said.

Davies holds the James E. Birren Chair in Gerontology, with a joint appointment in molecular biology at the USC Dornsife College of Letters, Arts and Sciences.

His co-authors were USC postdoctoral fellow Jenny Ngo, undergraduate students Laura Pomatto and Alison Koop, and former graduate student Daniela Bota, now an assistant professor at the University of California, Irvine Medical Center.

Funding for the research came from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Southern California. The original article was written by Carl Marziali.

Journal Reference:

1. J. K. Ngo, L. C. D. Pomatto, D. A. Bota, A. L. Koop, K. J. A. Davies. Impairment of Lon-Induced Protection Against the Accumulation of Oxidized Proteins in Senescent Wi-38 Fibroblasts. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2011; DOI: 10.1093/gerona/glr145

Researchers at the Johns Hopkins University School of Medicine have found a protein normally involved in blood pressure regulation in a surprising place: tucked within the little “power plants” of cells, the mitochondria. The quantity of this protein appears to decrease with age, but treating older mice with the blood pressure medication losartan can increase protein numbers to youthful levels, decreasing both blood pressure and cellular energy usage.

The researchers say these findings, published online during the week of August 15, 2011, in the Proceedings of the National Academy of Sciences, may lead to new treatments for mitochondrial-specific, age-related diseases, such as diabetes, hearing loss, frailty and Parkinson’s disease.

“We’ve identified a functional and independently operated system that appears to influence energy regulation within the mitochondria,” explains Jeremy Walston, M.D., professor of geriatric medicine at Hopkins. “This mitochondrial angiotensin system is activated by commonly utilized blood pressure medications, and influences both nitric oxide and energy production when signaled.”

Previous research showed that manipulating angiotensin in the body’s cells had unexpectedly affected mitochondrial energy production, so Walston and Peter Abadir , M.D., an assistant professor of geriatric medicine, decided to examine the role of angiotensin within the mitochondria. Using high-powered microscopy, they and their collaborators found evidence within the mitochondria of angiotensin as well as one of the protein receptors that bind to and detect it. They also pinpointed the angiotensin receptor’s exact locations within the mitochondria of mouse kidney, liver, neuron and heart cells as well as in human white blood cells.

The team then treated mitochondria with a chemical known to activate the angiotensin receptors and measured the cell’s response. This resulted in a decrease in oxygen consumption by half and a small increase in nitric oxide production — indicating less energy made by the mitochondria and lowered blood pressure, respectively. Explains Walston, “Activating angiotensin receptors within the mitochondria with these agents led to lowered blood pressure and decreased cellular energy use.”

But they found even more than just an energy-regulating mechanism; after testing the angiotensin system in mitochondria of both young and old mice, they noticed a decrease by almost a third of the amount of the angiotensin receptor type 2 in the mitochondria in older mice, meaning that cells in older mice were unable to control energy use as well. The researchers then tried treating these older mice with the blood pressure lowering drug losartan daily for 20 weeks and found that the number of these receptors increased. “Treatment of the old mice with losartan resulted in a marked increase in the number of receptors that are known to positively influence blood pressure and decrease inflammation,” says Walston.

Declining mitochondria are known to influence chronic diseases in older adults, explains Walston, whose next step is to translate studies from cell culture and animal based studies to human studies in hopes of developing new therapies. “Our findings will help us determine if the drugs that interact with this receptor will also lead to improvement of mitochondrial function and energy production. This, in turn, could facilitate the treatment of a number of chronic diseases of older adults.”

Source: Peter M. Abadir, D. Brian Foster, Michael Crow, Carol A. Cooke, Jasma J. Rucker, Alka Jain, Barbara J. Smith, Tyesha N. Burks, Ronald D. Cohn, Neal S. Fedarko, Robert M. Carey, Brian O’Rourke, Jeremy D. Walston. Identification and characterization of a functional mitochondrial angiotensin system. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1101507108

Researchers have discovered a new mechanism controlling aging in white blood cells. The research, published in the September issue of the Journal of Immunology, opens up the possibility of temporarily reversing the effects of aging on immunity and could, in the future, allow for the short-term boosting of the immune systems of older people.

Weakened immunity is a serious issue for older people. Because our immune systems become less effective as we age we suffer from more infections and these are often more severe. This takes a serious toll on health and quality of life.

Professor Arne Akbar of UCL (University College London), who led this research, explains “Our immune systems get progressively weaker as we age because each time we recover from an infection a proportion of our white blood cells become deactivated. This is an important process that has probably evolved to prevent certain cancers, but as the proportion of inactive cells builds up over time our defenses become weakened.

“What this research shows is that some of these cells are being actively switched off in our bodies by a mechanism which hadn’t been identified before as important in aging in the immune system. Whilst we wouldn’t want to reactivate these cells permanently, we have an idea now of how to wake them from their slumber temporarily, just to give the immune system a little boost.”

Until now, aging in immune cells was thought to be largely determined by the length of special caps on the ends of our DNA. These caps, called telomeres, get shorter each time a white blood cell multiplies until, when they get too short, the cell gets permanently deactivated. This means that our immune cells have a built-in lifespan of effectiveness and, as we live longer, this no longer long enough to provide us protection into old age.

However when Professor Akbar’s team took some blood samples and looked closely at the white blood cells they saw that some were inactive and yet had long telomeres. This told the researchers that there must be another mechanism in the immune system causing cells to become deactivated that was independent of telomere length.

Professor Akbar continues “Finding that these inactive cells had long telomeres was really exciting as it meant that they might not be permanently deactivated. It was like a football manager finding out that some star players who everyone thought had retired for good could be coaxed back to play in one last important game.”

When the researchers blocked this newly identified pathway in the lab they found that the white blood cells appeared to be reactivated. Medicines which block this pathway are already being developed and tested for use in other treatments so the next step in this research is to explore further whether white blood cells could be reactivated in older people, and what benefits this could bring.

Professor Akbar continues “This research opens up the exciting possibility of giving older people’s immune systems a temporary boost to help them fight off infections, but this is not a fountain of eternal youth. It is perfectly normal for our immune systems to become less effective and there are good evolutionary reasons for this. We’re a long way from having enough understanding of aging to consider permanently rejuvenating white blood cells, if it is even possible.”

Professor Douglas Kell, Chief Executive of the Biotechnology and Biological Sciences Research Council, said: “This is a fantastic example of the value of deepening our understanding of fundamental cell biology. This work has discovered a new and unforeseen process controlling how our immune systems change as we get older. Also, by exploring in detail how our cells work, it has opened up the prospect of helping older people’s immune systems using medicines that are already being tested and developed. By increasing the incidence and severity of infection, weakened immunity seriously damages the health and quality of life of older people so this research is very valuable.”

Source: D. Di Mitri, R. I. Azevedo, S. M. Henson, V. Libri, N. E. Riddell, R. Macaulay, D. Kipling, M. V. D. Soares, L. Battistini, A. N. Akbar. Reversible Senescence in Human CD4 CD45RA CD27- Memory T Cells. The Journal of Immunology, 2011; DOI: 10.4049/jimmunol.1100978

The neurotransmitter dopamine is best known for its roles in the brain — in signaling pathways that control movement, motivation, reward, learning and memory. Now, Vanderbilt University Medical Center investigators have demonstrated that dopamine produced outside the brain — in the kidneys — is important for renal function, blood pressure regulation and life span. Their studies, published in the July Journal of Clinical Investigation, suggest that the kidney-specific dopamine system may be a therapeutic target for treating hypertension and kidney diseases such as diabetic nephropathy.

Previous studies had suggested a role for dopamine in regulating kidney function and total body fluid volume, “but how that mechanism works was not clear,” said Raymond Harris, M.D., chief of the Division of Nephrology and Hypertension at Vanderbilt.

To explore dopamine’s role in the kidney, Harris and Ming-Zhi Zhang, M.D., assistant professor of Medicine at Vanderbilt, eliminated kidney-specific dopamine production in mice (by knocking out a dopamine-generating enzyme only in the kidney) and studied the outcome.

They found that mice lacking kidney dopamine had high blood pressure at baseline and became more hypertensive when they consumed a high-salt diet, suggesting they may be a good model of salt-sensitive (essential) hypertension, Harris said. Alterations in the kidney dopamine system may predispose individuals to hypertension, he noted.

The investigators also showed that elimination of kidney dopamine increased renin production, which activates the angiotensin II system to increase salt and water reabsorption — and produce hypertension.

“These animals retain salt and water when they don’t have sufficient dopamine production in the kidney,” Harris said. “Our studies highlight this whole other hormonal system that appears to balance or put the brakes on the renin-angiotensin system.”

Currently, the renin-angiotensin system is the major target for treating chronic kidney diseases. Discovering another target — the kidney dopamine system — is exciting, the researchers said. They are exploring whether specific drugs that enhance the kidney dopamine system are effective in blocking hypertension and treating progressive kidney diseases.

The investigators predicted changes in kidney function in the mouse model, but they were “very surprised” to discover that the modified mice only lived about half as long as normal mice (15 months versus 30 months). They found increases in stress-related proteins in the kidney, heart and vasculature, suggesting that elimination of kidney dopamine causes systemic effects, Harris said.

“This kidney-specific dopamine system is not only important for kidney function and blood pressure regulation, but also for the overall health of the animal,” Harris said. “If the dopamine system in the kidney is altered, the animals have a markedly shortened life span.”

The research was supported by the National Institutes of Health, the Vanderbilt O’Brien Center and by the Veterans Administration. Harris is the Ann and Roscoe R. Robinson Professor of Nephrology.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Vanderbilt University Medical Center, via EurekAlert!, a service of AAAS.

1. Ming-Zhi Zhang, Bing Yao, Suwan Wang, Xiaofeng Fan, Guanqing Wu, Haichun Yang, Huiyong Yin, Shilin Yang, Raymond C. Harris. Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice. Journal of Clinical Investigation, 2011; 121 (7): 2845 DOI: 10.1172/JCI57324

Lack of physical exercise is often implicated in many disease processes. However, sedentary behavior, or too much sitting, as distinct from too little exercise, potentially could be a new risk factor for disease. The August issue of the American Journal of Preventive Medicine features a collection of articles that addresses many aspects of the problem of sedentary behavior, including the relevant behavioral science that will be needed to evaluate whether initiatives to reduce sitting time can be effective and beneficial.

“Epidemiologic and physiologic research on sedentary behavior suggests that there are novel health consequences of prolonged sitting time, which appear to be independent of those attributable to lack of leisure-time physical activity,” commented Neville Owen, PhD, Head of Behavioural Epidemiology at the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. “However, behavioral research that could lead to effective interventions for influencing sedentary behaviors is less developed, especially so for adults. The purpose of this theme issue of the American Journal of Preventive Medicine is to propose a set of perspectives on ‘too much sitting’ that can guide future research. As the theme papers demonstrate, recent epidemiologic evidence (supported by physiologic studies) is consistent in identifying sedentary behavior as a distinct health risk. However, to build evidence-based approaches for addressing sedentary behavior and health, there is the need for research to develop new measurement methods, to understand the personal, social, and environmental factors that influence sedentary behaviors, and to develop and test the relevant interventions.”

Contributed by an international, multidisciplinary group of experts, papers include a compelling cross-national comparison of sedentary behavior, several reports on trends in sedentary behavior among children and a discussion of the multiple determinants of sedentary behavior and potential interventions. The collection is particularly noteworthy because it:

· Represents a major advance in collecting and analyzing current research on sedentary behavior, especially the relevant behavioral science that must be better understood if such behaviors are to change over time to improve health outcomes.

· Adds “momentum” to the discussion about sedentary behavior potentially being an independent risk factor for disease, ie, when examined specifically and distinctly from the effects of physical activity or exercise in large prospective studies, those who sit more often are found to have a greater risk of premature death, particularly from heart disease.

· Indicates that, despite the need for additional research on potential cause-and-effect relationships, and particularly the underlying physiological mechanisms that might be at play, there is now a growing momentum to address the issue of sedentary behavior more proactively in health promotion and disease prevention.

· Shows that children’s current and future health is particularly at risk given that they spend substantial amounts of their day sitting at school, at home and through transport, and that new technologies and entertainment formats may exacerbate this problem. Thus, it is critical to understand what influences children to sit so much, so we can develop effective interventions.

· Has particularly important implications for workplace environments and the potential health benefits of re-engineering workplace design and processes, especially in developed countries where most adults spend most of their workday sitting. These concerns have an important economic, population health and social equity context, even though the studies did not include economic or sociocultural research on this topic specifically.

The authors highlight the fact that broad-reach approaches and environmental and policy initiatives are becoming part of the sedentary behavior and health research agenda. In this context, mass media health promotion campaigns are already beginning to incorporate messages about reducing sitting time in the home environment, together with now-familiar messages about increasing physical activity. In the workplace, there is already active marketing of innovative technologies that will act to reduce sitting time (such as height-adjustable desks). Community entertainment venues or events may also consider providing non-sitting alternatives. Community infrastructure to increase active transport (through walking or biking) is also likely to reduce time spent sitting in cars. If such innovations are more broadly implemented, systematic evaluations of these “natural experiments” could be highly informative, especially through assessing whether changes in sedentary time actually do result.

The articles appear in the American Journal of Preventive Medicine, Volume 41, Issue 2 (August 2011) published by Elsevier.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Elsevier, via AlphaGalileo.

Excess nutrients, such as fat and sugar, don’t just pack on the pounds but can push some cells in the body over the brink. Unable to tolerate this “toxic” environment, these cells commit suicide.

Now, scientists at Washington University School of Medicine in St. Louis have discovered three unexpected players that help a cell overloaded with fat initiate its own demise. They have shown that these molecules leading a cell to self-destruct are not proteins as might be expected, but small strands of RNA, a close chemical cousin to DNA. Since these small nucleolar RNAs play well-known roles in building proteins, the researchers were surprised to implicate them in killing cells.

Under normal conditions (left), the small nucleolar RNAs involved with cell death are not activated and are not visible around the nuclei of these mouse muscle cells (shown in green). In the presence of fats, however (right), the RNA molecules (shown in red) are activated and move out of the cell nuclei and into the cytoplasm, the liquid in the main body of the cell, where they help initiate cell death. This is the first time these small RNAs have been shown to function in the cytoplasm. (Credit: Jean E. Schaffer, M.D.)

The research, published July 6 in Cell Metabolism, is the first to link these small RNA molecules to the cellular damage characteristic of common metabolic diseases like diabetes.

“When these three RNAs are present, the cells die in response to metabolic stress, such as exposure to large amounts of fats,” says cardiologist Jean E. Schaffer, MD, the Virginia Minnich Distinguished Professor of Medicine at Washington University. “But if these three RNAs are missing, the cells don’t die.”

Though cell suicide is a natural process that protects healthy tissues from damaged cells, it can sometimes fall out of balance. If the cell death pathway gets shut down, damaged cells may divide and lead to cancer. On the other hand, too much cell death due to abnormal metabolites, such as high levels of fats and sugar, can impair the function of tissues in the body. Such excess cell death is involved with diabetes complications such as heart failure. Understanding how abnormal metabolites cause cells to die will be helpful in the search for new therapies.

And the fact that small RNA molecules are involved in this cell death pathway is totally unexpected, according to Schaffer, also director of the Diabetic Cardiovascular Disease Center and Diabetes Research Training Center at the School of Medicine.

“When we set out to find genes causing cellular damage due to excess fat, we were expecting to find genes that code for proteins,” she says. “Instead, we identified an entirely new function for three small nucleolar RNAs. Unrelated to their well-defined role in the cell’s protein-making machinery, we discovered they participate in how cells go on to die from overload of nutrients.”

In a classic genetics experiment, Schaffer and her colleagues initially identified a genetic region that, when disabled, allows cells to continue living in high fat and high sugar conditions. While the region codes for a protein, they showed that the protein itself is not involved in initiating cell death.

“At first this result really puzzled us,” Schaffer says. “The mutation occurs in a region that encodes a protein, as we might expect. But returning the protein to the mutated cells did not return the cell death response.”

When reintroducing the protein did not restore the cell’s ability to commit suicide, Schaffer’s team turned its attention to the non-protein-coding areas of the same region. Selectively deleting the small RNAs embedded in the region’s non-coding portion shut down the cell death pathway and solved the puzzle: a mutation in this region protects the cells because it eliminates the small RNAs, not because it eliminates the protein. The three small nucleolar RNAs function together not only to promote cell death from nutrient excess, but also to promote more general mechanisms of cell death in diseased tissues.

“It has taken us a long time to understand this surprising finding,” Schaffer says. “But it has been a fun story to pursue. Often it’s the results you don’t expect that are the most exciting.”

As a cardiologist who treats patients at Barnes-Jewish Hospital, Schaffer says a multifaceted approach is necessary to manage the complexities of metabolic diseases like diabetes and obesity. Encouraging patients to reduce the amount of fat and sugar in the diet might be a primary strategy for treatment, but when that becomes ineffective, it would be helpful to have other ways to reduce cellular damage from excess fats in the muscles, heart, pancreas, liver and other organs. In that instance, manipulating amounts of these small RNA molecules presents one avenue to pursue in the search for possible treatments.

“We have a genetically modified mouse that does not make these three RNAs,” Schaffer says. “So will that mouse somehow be protected against cellular damage from diabetes complications? That’s a very interesting question, and it’s where our future work is headed.”

This work was supported by grants from the National Institutes of Health (NIH), the Burroughs Wellcome Foundation, the Washington University Diabetes Research Training Center and the Washington University Metabolomics facility.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Washington University School of Medicine.

1. Michel CI, Holley CL, Scruggs BS, Sidhu R, Brookheart RT, Listenberger LL, Behlke MA, Ory DS, Schaffer JE. Small nucleolar RNAs U32a, U33 and U35a are critical mediators of metabolic stress. Cell Metabolism, July 2011 DOI: 10.1016/j.cmet.2011.04.009

Self-conscious about your age? Careful where you spit. UCLA geneticists now can use saliva to reveal how old you are. The June 22 advance online edition of the Public Library of Science (PLoS) ONE publishes the findings, which offer a myriad of potential applications. A newly patented test based on the research, for example, could offer crime-scene investigators a new forensic tool for pinpointing a suspect’s age.

“Our approach supplies one answer to the enduring quest for reliable markers of aging,” said principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics and urology at the David Geffen School of Medicine at UCLA. “With just a saliva sample, we can accurately predict a person’s age without knowing anything else about them.”

Vilain and his colleagues looked at a process called methylation — a chemical modification of one of the four building blocks that make up our DNA.

“While genes partly shape how our body ages, environmental influences also can change our DNA as we age,” explained Vilain. “Methylation patterns shift as we grow older and contribute to aging-related disease.”

Using saliva samples contributed by 34 pairs of identical male twins ages 21 to 55, UCLA researchers scoured the men’s genomes and identified 88 sites on the DNA that strongly correlated methylation to age. They replicated their findings in a general population of 31 men and 29 women aged 18 to 70.

Next, the scientists built a predictive model using two of the three genes with the strongest age-related linkage to methylation. When they plugged in the data from the twins’ and the other group’s saliva samples, they were able to correctly predict a person’s age within five years — an unprecedented level of accuracy.

“Methylation’s relationship with age is so strong that we can identify how old someone is by examining just two of the 3 billion building blocks that make up our genome,” said first author Sven Bocklandt, a former UCLA geneticist now at Bioline.

Vilain and his team envision the test becoming a forensic tool in crime-scene investigations. By analyzing the traces of saliva left in a tooth bite or on a coffee cup, lab experts could narrow the age of a criminal suspect to a five-year range.

In a minority of the population, methylation does not correlate with chronological age. Using this data, scientists may one day be able to calculate a person’s “bio-age” — the measurement of a person’s biological age versus their chronological age.

Physicians could evaluate the risk of age-related diseases in routine medical screenings and tailor interventions based on the patient’s bio-age rather than their chronological age. Instead of requiring everyone to undergo a colonoscopy at age 50, for example, physicians would recommend preventive tests according to a person’s bio-age.

“Doctors could predict your medical risk for a particular disease and customize treatment based on your DNA’s true biological age, as opposed to how old you are,” noted Vilain. “By eliminating costly and unnecessary tests, we could target those patients who really need them.”

The UCLA team is currently exploring whether people with lower bio-age live longer and suffer less disease. They also are examining if the reverse is true — whether higher bio-age is linked to a greater rate of disease and early death.

The study was internally funded by UCLA. Vilain’s coauthors included Bocklandt, Wen Lin, Mary Sehl, Francisco Sáncheza, Janet Sinsheimer and Steve Horvath, all of UCLA.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California – Los Angeles Health Sciences.

1. Sven Bocklandt, Wen Lin, Mary E. Sehl, Francisco J. Sánchez, Janet S. Sinsheimer, Steve Horvath, Eric Vilain. Epigenetic Predictor of Age. PLoS ONE, 2011; 6 (6): e14821 DOI: 10.1371/journal.pone.0014821

A group of volunteers ate half a kilo of strawberries every day for two weeks to demonstrate that eating this fruit improves the antioxidant capacity of blood. The study, carried out by Italian and Spanish researchers, showed that strawberries boost red blood cells’ response to oxidative stress, an imbalance that is associated with various diseases.

Scientists have previously tried to confirm the antioxidant capacity of strawberries using in vitro laboratory experiments. Now, a team of researchers from the Marche Polytechnic University (UNIVPM, in Italy) and the University of Granada (UGR, in Spain) have demonstrated this effect in vivo, in a study on human volunteers published in the journal Food Chemistry.

Each day, the scientists fed 12 healthy volunteers 500 grams of strawberries (of the ‘Sveva’ variety) over the course of the day. They took blood samples from them after four, eight, 12 and 16 days, and also a month later. The results show that regular consumption of this fruit can improve the antioxidant capacity of blood plasma and also the resistance of red blood cells to oxidative haemolysis (fragmentation).

“We have shown that some varieties of strawberries make erythrocytes more resistant to oxidative stress. This could be of great significance if you take into account that this phenomenon can lead to serious diseases,” Maurizio Battino, lead author of the study and a researcher at the UNIVPM, said.

The team is now analysing the variations caused by eating smaller quantities of strawberries (average consumption tends to be a 150g or 200g bowl per day). “The important thing is that strawberries should form a part of people’s healthy and balanced diet, as one of their five daily portions of fruit and vegetables,” Battino points out.

“Various strawberry varieties are also being analysed in the laboratory, since they each contain antioxidants in differing amounts and proportions,” explains José Luis Quiles, the Spanish participant in the study and a researcher at the UGR.

The body has an extensive arsenal of very diverse antioxidant mechanisms, which act at different levels. These can be cellular tools that repair oxidised genetic material, or molecules that are either manufactured by the body itself or consumed through the diet, which neutralise free radicals. Strawberries contain a large amount of phenolic compounds, such as flavonoids, which have antioxidant properties.

These substances reduce oxidative stress, an imbalance that occurs in certain pathologies, (such as cardiovascular disease, cancer and diabetes) and physiological situations (birth, aging, physical exercise), as well as in the battles between “reactive kinds of oxygen” — in particular free radicals — and the body’s antioxidant defences.

When the level of oxidation exceeds these antioxidant defences, oxidative stress occurs. Aside from causing certain illnesses, this is also implicated in phenomena such as the speed at which we may age, for example.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Plataforma SINC, via AlphaGalileo.

1. Sara Tulipani, Josè M. Alvarez-Suarez, Franco Busco, Stefano Bompadre, Josè L. Quiles, Bruno Mezzetti, Maurizio Battino. Strawberry consumption improves plasma antioxidant status and erythrocyte resistance to oxidative haemolysis in humans. Food Chemistry, 2011; 128 (1): 180 DOI: 10.1016/j.foodchem.2011.03.025