Scientists at the University of Bonn have discovered a new rare type of haemoglobin. Haemoglobin transports oxygen in the red blood corpuscles. When bound to oxygen it changes colour. The new haemoglobin type appears optically to be transporting little oxygen. Measurements of the blood oxygen level therefore present a similar picture to patients suffering from an inherited cardiac defect. After examining two patients, the scientists now understand that the new type of haemoglobin distorts the level of oxygen measured. The scientists have named the type 'Haemoglobin Bonn'. They have published their discovery in the current issue of the scientific journal Clinical Chemistry. The article can be downloaded from clinchem/cgi/content/full/54/3/594.
Haemoglobin transports oxygen to the body's cells and in return picks up carbon dioxide there. In doing so it changes colour. With an optical measuring instrument, known as a pulse oximeter, you can therefore measure whether there is enough oxygen present in the blood. The cause of anoxia can be an inherited cardiac defect, for example.
This was also the tentative diagnosis in the case of a four-year-old boy who was admitted to the Paediatric Clinic of the Bonn University Clinic. However, after a thorough examin-ation, the paediatricians Dr. Andreas Hornung and his colleagues did not find any cardiac defect. A low saturation of oxygen had also been previously found in the blood of the boy's 41-year-old father, again without apparent signs of a cardiac defect.
Dr. Berndt Zur from Professor Birgit Stoffel-Wagner's team at the Institute of Clinical Chemistry and Pharmacology examined the boy's and the father's haemoglobin. He eventually realised that they were dealing with a new type of the blood pigment. 'The pulse oximeter is put on a finger as a clip and X-rays it with infrared radiation,' he explains. 'Haemoglobin absorbs infrared light in the absence of oxygen. The lower the content of oxygen in the blood, the less light penetrates the finger and reaches the sensor of the oximeter.' But Haemoglobin Bonn absorbs a bit more infrared light than normal oxygen saturated haemoglobin, even when combined with oxygen. 'That's why, at first, we did not understand why the patients did not have any particular health problems,' Dr. Zur says.
Every human has two main heart ventricles. One pumps the blood through the arteries to the lungs, where the haemoglobin releases the carbon dioxide and takes on oxygen. The other one pumps the blood which is saturated with oxygen from the lungs to every cell in the body. Both ventricles must be separated by a wall in the heart, so that the oxygen-rich blood does not mix with the anoxaemic blood. But some people have a hole in this septum. In such cases, the pulse oximeter shows anoxia. Doctors therefore see this as a sign of a cardiac defect. Another cause is what is known as the Apnoea Syndrome. In the patients affected, breathing can cease for more than a minute. That is why the father of the 4-year-old received oxygen treatment at nights for some time. 'If we had known about Haemoglobin Bonn before, father and son could have been spared the fear of a cardiac defect or the Sleep Apnoea Syndrome,' Dr. Zur explains.
This release is available in German.
Source: Dr. Berndt Zur
University of Bonn
понедельник, 30 мая 2011 г.
Males And Females Protected From Hearing Loss By 'Female Sex Hormone'
The "female sex hormone" estradiol is present in both men and women, and is generated from testosterone in men by the protein aromatase. Estradiol plays various roles in addition to its gender-specific ones, including having effects on the hearing (auditory) system. In a new study, Barbara Canlon and colleagues at the Karolinska Institute in Stockholm, Sweden, investigated the role of estradiol-binding proteins, known as estrogen receptors, in response to auditory damage by examining hearing loss recovery in mice with deficiencies in various estrogen receptors. They found that mice deficient in only the estrogen receptor ER-beta had reduced recovery from auditory trauma, and that treatment with ER-beta-binding drugs protected mice from auditory damage. Furthermore, not only was ER-beta found in the ears of both male and female mice, but levels of the nerve-protecting protein BDNF were reduced in mice that lacked either ER-beta or aromatase. The authors therefore concluded that this identification of an auditory-protective role for the estrogen receptor ER-beta may enable the development of new treatments for hearing loss.
TITLE: Estrogen receptor-beta protects against acoustic trauma in mice
AUTHOR CONTACT:
Barbara Canlon
Karolinska Institute, Stockholm, Sweden
Source: Karen Honey
Journal of Clinical Investigation
View drug information on Estradiol.
TITLE: Estrogen receptor-beta protects against acoustic trauma in mice
AUTHOR CONTACT:
Barbara Canlon
Karolinska Institute, Stockholm, Sweden
Source: Karen Honey
Journal of Clinical Investigation
View drug information on Estradiol.
The Secret To Longevity May Be Hidden In Hydrogen Sulfide
Hydrogen sulfide, or H2S, the chemical that gives rotten eggs their sulfurous stench -- and the same compound that researchers at Fred Hutchinson Cancer Research Center successfully have used to put mice into a state of reversible metabolic hibernation -- has now been shown to significantly increase life span and heat tolerance in the nematode worm, or C. elegans.
These findings by Mark Roth, Ph.D., a member of the Center's Basic Sciences Division, and Dana Miller, Ph.D., a postdoctoral research fellow in Roth's lab, appear in the PNAS Online Early Edition, a publication of the Proceedings of the National Academy of Sciences of the United States of America.
In an effort to understand the mechanisms by which hydrogen sulfide induces hibernation in mice, the researchers turned to the tiny nematode, a workhorse of laboratory science because its biology is similar in many respects that of humans. For example, like humans, nematodes have a central nervous system and the ability to reproduce. The worms also are ideally suited for studying life span, because they normally live for only two to three weeks.
The researchers found, to their surprise, that nematodes that were raised in a carefully controlled atmosphere with low concentrations of H2S (50 parts per million in room air) did not hibernate. Instead, their metabolism and reproductive activity remained normal, their life span increased and they became more tolerant to heat than untreated worms.
The H2S-exposed worms lived eight times longer than untreated worms when moved from normal room air (22 C or 70 F) to a high-temperature environment (35 degrees Celsius, or 95 F). Roth and colleagues replicated these results in 15 independent experiments.
"Although the maximum extension of survival time varied between experiments, the effect was quite robust. On average, 77 percent of the worms exposed to H2S outlived the untreated worms," Roth said. The mean life span of worms grown in an atmosphere laced with hydrogen sulfide was 9.6 days greater than that of the untreated population, a longevity increase of 70 percent.
Most genes that influence life span in C. elegans act on one of three genetic pathways: those that control insulin/IGF (insulin growth factor) signaling, those that control mitochondrial function and those that modulate the effects of dietary restriction.
Roth and colleagues ruled out hydrogen sulfide's influence on each of these pathways. Instead, they suspect it acts through a different mechanism. One theory is that exposure to H2S naturally regulates the activity of a gene called SIR-2.1, which has been shown to influence life span in many organisms, including the nematode. Previous studies have found that over-expression of this gene increases the longevity of C. elegans by 18 percent to 20 percent.
"Further research into the genetic mechanisms that influence H2S-induced changes in nematodes may reveal similar mechanisms in higher organisms, including humans, with potentially wide-ranging implications in both basic research and clinical practice," Roth said. For example, understanding how H2S affects physiology in animals may lead to the development of drugs that could delay the onset of age-related diseases in humans such as cancer, Alzheimer's and heart disease.
Roth's hibernation research made headlines worldwide in April 2005 when he was the first to show that exposing mice to minute amounts of hydrogen sulfide could induce a state of reversible "hibernation on demand," dramatically reducing their core body temperature, respiration and need for oxygen. Roth envisions a future in which similar techniques could be used to "buy time" for critically ill patients who otherwise would face injury and death from insufficient blood and oxygen supply to organs and tissues.
Roth hypothesizes that H2S, a chemical normally produced in humans and animals, may help regulate body temperature and metabolic activity. Hydrogen sulfide is similar to oxygen at the molecular level because it binds at many of the same proteins. As a result, H2S competes for and interferes with the body's ability to use oxygen for energy production -- a process within the cell's power-generating machinery called oxidative phosphorylation.
The inhibition of this function, in turn, is what Roth and colleagues believe causes organisms such as mice to shut down metabolically and enter a hibernation-like state pending re-exposure to normal room air, after which they quickly regain normal function and metabolic activity with no long-term negative effects.
The National Institutes of Health, the NIH Center for Research Resources, the Caenorhabditis Genetics Center and a National Research Service Award Fellowship supported this work.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc/.
Source: Kristen Lidke Woodward
Fred Hutchinson Cancer Research Center
These findings by Mark Roth, Ph.D., a member of the Center's Basic Sciences Division, and Dana Miller, Ph.D., a postdoctoral research fellow in Roth's lab, appear in the PNAS Online Early Edition, a publication of the Proceedings of the National Academy of Sciences of the United States of America.
In an effort to understand the mechanisms by which hydrogen sulfide induces hibernation in mice, the researchers turned to the tiny nematode, a workhorse of laboratory science because its biology is similar in many respects that of humans. For example, like humans, nematodes have a central nervous system and the ability to reproduce. The worms also are ideally suited for studying life span, because they normally live for only two to three weeks.
The researchers found, to their surprise, that nematodes that were raised in a carefully controlled atmosphere with low concentrations of H2S (50 parts per million in room air) did not hibernate. Instead, their metabolism and reproductive activity remained normal, their life span increased and they became more tolerant to heat than untreated worms.
The H2S-exposed worms lived eight times longer than untreated worms when moved from normal room air (22 C or 70 F) to a high-temperature environment (35 degrees Celsius, or 95 F). Roth and colleagues replicated these results in 15 independent experiments.
"Although the maximum extension of survival time varied between experiments, the effect was quite robust. On average, 77 percent of the worms exposed to H2S outlived the untreated worms," Roth said. The mean life span of worms grown in an atmosphere laced with hydrogen sulfide was 9.6 days greater than that of the untreated population, a longevity increase of 70 percent.
Most genes that influence life span in C. elegans act on one of three genetic pathways: those that control insulin/IGF (insulin growth factor) signaling, those that control mitochondrial function and those that modulate the effects of dietary restriction.
Roth and colleagues ruled out hydrogen sulfide's influence on each of these pathways. Instead, they suspect it acts through a different mechanism. One theory is that exposure to H2S naturally regulates the activity of a gene called SIR-2.1, which has been shown to influence life span in many organisms, including the nematode. Previous studies have found that over-expression of this gene increases the longevity of C. elegans by 18 percent to 20 percent.
"Further research into the genetic mechanisms that influence H2S-induced changes in nematodes may reveal similar mechanisms in higher organisms, including humans, with potentially wide-ranging implications in both basic research and clinical practice," Roth said. For example, understanding how H2S affects physiology in animals may lead to the development of drugs that could delay the onset of age-related diseases in humans such as cancer, Alzheimer's and heart disease.
Roth's hibernation research made headlines worldwide in April 2005 when he was the first to show that exposing mice to minute amounts of hydrogen sulfide could induce a state of reversible "hibernation on demand," dramatically reducing their core body temperature, respiration and need for oxygen. Roth envisions a future in which similar techniques could be used to "buy time" for critically ill patients who otherwise would face injury and death from insufficient blood and oxygen supply to organs and tissues.
Roth hypothesizes that H2S, a chemical normally produced in humans and animals, may help regulate body temperature and metabolic activity. Hydrogen sulfide is similar to oxygen at the molecular level because it binds at many of the same proteins. As a result, H2S competes for and interferes with the body's ability to use oxygen for energy production -- a process within the cell's power-generating machinery called oxidative phosphorylation.
The inhibition of this function, in turn, is what Roth and colleagues believe causes organisms such as mice to shut down metabolically and enter a hibernation-like state pending re-exposure to normal room air, after which they quickly regain normal function and metabolic activity with no long-term negative effects.
The National Institutes of Health, the NIH Center for Research Resources, the Caenorhabditis Genetics Center and a National Research Service Award Fellowship supported this work.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc/.
Source: Kristen Lidke Woodward
Fred Hutchinson Cancer Research Center
'Green' Alternative For Improving Water Quality
Algae--already being eyed for biofuel production--could be put to use right away to remove nitrogen and phosphorus in livestock manure runoff, according to an Agricultural Research Service (ARS) scientist. That could give resource managers a new eco-friendly option for reducing the level of agricultural pollutants that contaminate water quality in the Chesapeake Bay.
Microbiologist Walter Mulbry works at the ARS Environmental Management and Byproduct Utilization Research Unit in Beltsville, Md., which is located in the Chesapeake Bay watershed. In 2003, Mulbry set up four algal turf scrubber (ATS) raceways outside dairy barns in Beltsville. The shallow 100-foot raceways were covered with nylon netting that created a scaffold where the algae could grow.
For the next three years, from April until December, a submerged water pump at one end of the raceways circulated a mix of fresh water and raw or anaerobically digested dairy manure effluent over the algae. Within two to three weeks after the ATS system was started up every spring, the raceways supported thriving colonies of green filamentous algae.
Algae productivity was highest in the spring and declined during the summer, in part because of higher water temperatures and also because the raceways provided snails and midge larvae ample opportunity to graze on the algae.
Mulbry and his partners harvested wet algae every four to 12 days, dried it, and then analyzed the dried biomass for nitrogen and phosphorus levels. His results indicate that the ATS system recovered 60 to 90 percent of the nitrogen and 70 to 100 percent of the phosphorus from the manure effluents. They also calculated that the cost for this capture was comparable to other manure management practices--around $5 to $6 for each pound of nitrogen that was recovered and around $25 for each pound of phosphorus that was recovered.
Results from this research were published in Bioresource Technology.
Source:
Ann Perry
United States Department of Agriculture-Research, Education, and Economics
Microbiologist Walter Mulbry works at the ARS Environmental Management and Byproduct Utilization Research Unit in Beltsville, Md., which is located in the Chesapeake Bay watershed. In 2003, Mulbry set up four algal turf scrubber (ATS) raceways outside dairy barns in Beltsville. The shallow 100-foot raceways were covered with nylon netting that created a scaffold where the algae could grow.
For the next three years, from April until December, a submerged water pump at one end of the raceways circulated a mix of fresh water and raw or anaerobically digested dairy manure effluent over the algae. Within two to three weeks after the ATS system was started up every spring, the raceways supported thriving colonies of green filamentous algae.
Algae productivity was highest in the spring and declined during the summer, in part because of higher water temperatures and also because the raceways provided snails and midge larvae ample opportunity to graze on the algae.
Mulbry and his partners harvested wet algae every four to 12 days, dried it, and then analyzed the dried biomass for nitrogen and phosphorus levels. His results indicate that the ATS system recovered 60 to 90 percent of the nitrogen and 70 to 100 percent of the phosphorus from the manure effluents. They also calculated that the cost for this capture was comparable to other manure management practices--around $5 to $6 for each pound of nitrogen that was recovered and around $25 for each pound of phosphorus that was recovered.
Results from this research were published in Bioresource Technology.
Source:
Ann Perry
United States Department of Agriculture-Research, Education, and Economics
Not-So-Secret Intentions In The Brain
Every day we plan numerous actions, such as to return a book to a friend or to make an appointment. How and where the brain stores these intentions has been revealed by John-Dylan Haynes from the Max Planck Institute for Human Cognitive and Brain Sciences, in cooperation with researchers from London and Tokyo. For the first time they were able to "read" participants' intentions out of their brain activity. This was made possible by a new combination of functional magnetic resonance imaging and sophisticated computer algorithms (Current Biology).
Our secret intentions remain concealed until we put them into action -so we believe. Now researchers have been able to decode these secret intentions from patterns of their brain activity. They let subjects freely and covertly choose between two possible tasks - to either add or subtract two numbers. They were then asked to hold in mind their intention for a while until the relevant numbers were presented on a screen. The researchers were able to recognize the subjects intentions with 70% accuracy based alone on their brain activity - even before the participants had seen the numbers and had started to perform the calculation.
Participants made their choice covertly and initially did not know the two numbers they were supposed to add or subtract. Only a few seconds later the numbers appeared on a screen and the participants could perform the calculation. This ensured that the intention itself was being read out, rather than brain activity related to performing the calculation or pressing the buttons to indicate the response. "It has been previously assumed that freely selected plans might be stored in the middle regions of the prefrontal cortex, whereas plans following external instructions could be stored on the surface of the brain. We were able to confirm this theory in our experiments", Haynes explained.
The work of Haynes and his colleagues goes far beyond simply confirming previous theories. It has never before been possible to read out of brain activity how a person has decided to act in the future. The trick by which the invisible is made visible lies in a new method called "multivariate pattern recognition". A computer is programmed to recognize characteristic activation patterns in the brain that typically occur in association with specific thoughts. Once this computer has been "trained" it can be used to predict the decisions of subjects from their brain activity alone. An important technical innovation also lies in combining information across extended regions of the brain to strongly increase sensitivity.
The study also reveals fundamental principles about the way the brain stores intentions. "The experiments show that intentions are not encoded in single neurons but in a whole spatial pattern of brain activity", says Haynes. They furthermore reveal that different regions of the prefrontal cortex perform different operations. Regions towards the front of the brain store the intention until it is executed, whereas regions further back take over when subjects become active and start doing the calculation. "Intentions for future actions that are encoded in one part of the brain need to be copied to a different region to be executed", says Haynes.
These findings also raise hope for improvement of clinical and technical applications. Already today the first steps are being made in easing the lives of paralyzed patients with computer-assisted prosthetic devices and so-called brain computer interfaces. These devices focus on reading out the movement the patient intends to - but is unable to - perform. Previous research has shown that patients can move artificial limbs or computer cursors purely by the power of their mind. The current research by Haynes and colleagues now opens up a completely new perspective.
In future it will be possible to read even abstract thoughts and intentions out of patients' brains. One day even the intention to "open the blue folder" or "reply to the email" could be picked up by brain scanners and turned into the appropriate action.
Original work:
John-Dylan Haynes, Katsuyuki Sakai, Geraint Rees, Sam Gilbert, Chris Frith, Dick Passingham
Reading hidden intentions in the human brain
Current Biology, February 20th, 2007.
Contact: Prof. Dr. John-Dylan Haynes
Max-Planck-Gesellschaft
Our secret intentions remain concealed until we put them into action -so we believe. Now researchers have been able to decode these secret intentions from patterns of their brain activity. They let subjects freely and covertly choose between two possible tasks - to either add or subtract two numbers. They were then asked to hold in mind their intention for a while until the relevant numbers were presented on a screen. The researchers were able to recognize the subjects intentions with 70% accuracy based alone on their brain activity - even before the participants had seen the numbers and had started to perform the calculation.
Participants made their choice covertly and initially did not know the two numbers they were supposed to add or subtract. Only a few seconds later the numbers appeared on a screen and the participants could perform the calculation. This ensured that the intention itself was being read out, rather than brain activity related to performing the calculation or pressing the buttons to indicate the response. "It has been previously assumed that freely selected plans might be stored in the middle regions of the prefrontal cortex, whereas plans following external instructions could be stored on the surface of the brain. We were able to confirm this theory in our experiments", Haynes explained.
The work of Haynes and his colleagues goes far beyond simply confirming previous theories. It has never before been possible to read out of brain activity how a person has decided to act in the future. The trick by which the invisible is made visible lies in a new method called "multivariate pattern recognition". A computer is programmed to recognize characteristic activation patterns in the brain that typically occur in association with specific thoughts. Once this computer has been "trained" it can be used to predict the decisions of subjects from their brain activity alone. An important technical innovation also lies in combining information across extended regions of the brain to strongly increase sensitivity.
The study also reveals fundamental principles about the way the brain stores intentions. "The experiments show that intentions are not encoded in single neurons but in a whole spatial pattern of brain activity", says Haynes. They furthermore reveal that different regions of the prefrontal cortex perform different operations. Regions towards the front of the brain store the intention until it is executed, whereas regions further back take over when subjects become active and start doing the calculation. "Intentions for future actions that are encoded in one part of the brain need to be copied to a different region to be executed", says Haynes.
These findings also raise hope for improvement of clinical and technical applications. Already today the first steps are being made in easing the lives of paralyzed patients with computer-assisted prosthetic devices and so-called brain computer interfaces. These devices focus on reading out the movement the patient intends to - but is unable to - perform. Previous research has shown that patients can move artificial limbs or computer cursors purely by the power of their mind. The current research by Haynes and colleagues now opens up a completely new perspective.
In future it will be possible to read even abstract thoughts and intentions out of patients' brains. One day even the intention to "open the blue folder" or "reply to the email" could be picked up by brain scanners and turned into the appropriate action.
Original work:
John-Dylan Haynes, Katsuyuki Sakai, Geraint Rees, Sam Gilbert, Chris Frith, Dick Passingham
Reading hidden intentions in the human brain
Current Biology, February 20th, 2007.
Contact: Prof. Dr. John-Dylan Haynes
Max-Planck-Gesellschaft
Self-Healing Autonomous Material Comes To Life
You've seen it in movies: the human-like, robot assassin quickly regenerates its structure after being damaged beyond recognition. This "Terminator" scenario is becoming less far-fetched as recent advances in structural health monitoring systems have led to a variety of ways to identify damage to a structural system.
Now, in the Journal of Applied Physics, researchers at Arizona State University have created a material that may be able to not only sense damage in structural materials, such as cracking in a fiber-reinforced composite, but to even heal it. The aim of developing "autonomous adaptive structures" is to mimic the ability of biological systems such as bone to sense the presence of damage, halt its progression, and regenerate itself.
The novel autonomous material developed by Henry Sodano and colleagues uses "shape-memory" polymers with an embedded fiber-optic network that functions as both the damage detection sensor and thermal stimulus delivery system to produce a response that mimics the advanced sensory and healing traits shown in biological systems. An infrared laser transmits light through the fiber-optic system to locally heat the material, stimulating the toughening and healing mechanisms.
The material system is capable of increasing the toughness of a specimen by 11 times. After toughening the specimen, the crack can be closed using the shape-memory effect to recover an unprecedented 96 percent of the object's original strength. In fact, after the crack is closed, the new material is nearly five times as tough as the original specimen, even though it has been strained past its original failure strain point by a factor of four. The material and healing process can be applied while the structure is in operation, which has not been possible with existing healing techniques.
Source: American Institute of Physics (AIP)
Now, in the Journal of Applied Physics, researchers at Arizona State University have created a material that may be able to not only sense damage in structural materials, such as cracking in a fiber-reinforced composite, but to even heal it. The aim of developing "autonomous adaptive structures" is to mimic the ability of biological systems such as bone to sense the presence of damage, halt its progression, and regenerate itself.
The novel autonomous material developed by Henry Sodano and colleagues uses "shape-memory" polymers with an embedded fiber-optic network that functions as both the damage detection sensor and thermal stimulus delivery system to produce a response that mimics the advanced sensory and healing traits shown in biological systems. An infrared laser transmits light through the fiber-optic system to locally heat the material, stimulating the toughening and healing mechanisms.
The material system is capable of increasing the toughness of a specimen by 11 times. After toughening the specimen, the crack can be closed using the shape-memory effect to recover an unprecedented 96 percent of the object's original strength. In fact, after the crack is closed, the new material is nearly five times as tough as the original specimen, even though it has been strained past its original failure strain point by a factor of four. The material and healing process can be applied while the structure is in operation, which has not been possible with existing healing techniques.
Source: American Institute of Physics (AIP)
A Potentially Universal Mechanism Of Aging Identified By Researchers
Like our current financial crisis, the aging process might also be a product of excessive deregulation.
Researchers have discovered that DNA damage decreases a cell's ability to regulate which genes are turned on and off in particular settings. This mechanism, which applies both to fungus and to us, might represent a universal culprit for aging.
"This is the first potentially fundamental, root cause of aging that we've found," says Harvard Medical School professor of pathology David Sinclair. "There may very well be others, but our finding that aging in a simple yeast cell is directly relevant to aging in mammals comes as a surprise."
These findings appear in the November 28 issue of the journal Cell.
For some time, scientists have know that a group of genes called sirtuins are involved in the aging process. These genes, when stimulated by either the red-wine chemical resveratrol (web.med.harvard/sites/RELEASES/html/11_1Sinclair.html) or caloric restriction (web.med.harvard/sites/RELEASES/html/sinclair.html), appear to have a positive effect on both aging and health.
Nearly a decade ago, Sinclair and colleagues in the Massachusetts Institute of Technology lab of Leonard Guarente found that a particular sirtuin in yeast affected the aging process in two specific ways - it helped regulate gene activity in cells and repair breaks in DNA. As DNA damage accumulated over time, however, the sirtuin became too distracted to properly regulate gene activity, and as a result, characteristics of aging set in.
"For ten years, this entire phenomenon in yeast was considered to be relevant only to yeast," says Sinclair. "But we decided to test of this same process occurs in mammals."
Philipp Oberdoerffer, a postdoctoral scientist in Sinclair's Harvard Medical School lab, used a sophisticated microarray platform to probe the mammalian version of the yeast sirtuin gene in mouse cells. The results in mice corroborated what Sinclair, Guarente, and colleagues had found in yeast ten years earlier.
Oberdoerffer found that a primary function of sirtuin in the mammalian system was to oversee patterns of gene expression (which genes are switch on and which are switch off). While all genes are present in all cells, only a select few need to be active at any given time. If the wrong genes are switched on, this can harm the cell. (In a kidney cell, for example, all liver genes are present, but switched off. If these genes were to become active, that could damage the kidney.) As a protective measure, sirtuins guard genes that should be off and ensure that they remain silent. To do this, they help preserve the molecular packaging - called chromatin - that shrink-wraps these genes tight and keeps them idle.
The problem for the cell, however, is that the sirtuin has another important job. When DNA is damaged by UV light or free radicals, sirtuins act as volunteer emergency responders. They leave their genomic guardian posts and aid the DNA repair mechanism at the site of damage.
During this unguarded interval, the chromatin wrapping may start to unravel, and the genes that are meant to stay silent may in fact come to life.
For the most part, sirtuins are able to return to their post and wrap the genes back in their packaging, before they cause permanent damage. As mice age, however, rates of DNA damage (typically caused by degrading mitochondria) increase. The authors found that this damage pulls sirtuins away from their posts more frequently. As a result, deregulation of gene expression becomes chronic. Chromatin unwraps in places where it shouldn't, as sirtuin guardians work overtime putting out fires around the genome, and the unwrapped genes never return to their silent state.
In fact, many of these haplessly activated genes are directly linked with aging phenotypes. The researchers found that a number of such unregulated mouse genes were persistently active in older mice.
"We then began wondering what would happen if we put more of the sirtuin back into the mice," says Oberdoerffer. "Our hypothesis was that with more sirtuins, DNA repair would be more efficient, and the mouse would maintain a youthful pattern gene expression into old age."
That's precisely what happened. Using a mouse genetically altered to model lymphoma, Oberdoerffer administered extra copies of the sirtuin gene, or fed them the sirtuin activator resveratrol, which in turn extended their mean lifespan by 24 to 46 percent.
"It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins redistribute with damage or aging, is also applicable to mammals," says Leonard Guarente, Novartis Professor of Biology at MIT, who is not an author on the paper. "This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilize this redistribution of sirtuins over time."
Both Sinclair and Oberdoerffer agree with Guarente's sentiment that these findings may have therapeutic relevance.
"According to this specific mechanism, while DNA damage exacerbates aging, the actual cause is not the DNA damage itself but the lack of gene regulation that results," says Oberdoerffer. "Lots of research has shown that this particular process of regulating gene activity, otherwise known as epigenetics, can be reversed - unlike actual mutations in DNA. We see here, through a proof-of-principal demonstration, that elements of aging can be reversed."
Recent findings by Chu-Xia Deng of the National Institute of Diabetes, Digestive and Kidney Diseases, also discovered that mice that lack sirtuin are susceptible to DNA damage and cancer, reinforcing Sinclair's and Oberdoerffer's data.
This research was funded by the National Institutes of Health, and the Glenn Foundation for Medical Research. David Sinclair is a consultant to Genocea, Shaklee and Sirtris, a GSK company developing sirtuin based drugs.
Written by David Cameron
Full citation:
Cell, November 28, 2008 Volume 135, Issue 6
"SIRT1 Redistribution on Chromatin Promotes Genome Stability but Alters Gene Expression during Aging"
Philipp Oberdoerffer(1), Shaday Michan(1), Michael McVay(1), Raul Mostoslavsky(2), James Vann(3), Sang-Kyu Park(3), Andrea Hartlerode(4), Judith Stegmuller(1,7), Angela Hafner(1), Patrick Loerch(1), Sarah M. Wright(5), Kevin D. Mills(5), Azad Bonni(1), Bruce A. Yankner(1), Ralph Scully(4), Tomas A. Prolla(3), Frederick W. Alt(6), and David A. Sinclair(1)
Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA
Massachusetts General Hospital Cancer Center, Boston, MA
University of Wisconsin, Department of Genetics and Medical Genetics, Madison, WI
Beth Israel Deaconess Medical Center, Boston, MA
The Jackson Laboratory, Bar Harbor, ME
Howard Hughes Medical Institute, Children's Hospital Boston, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, MA
Present address: Max Planck Institute for Experimental Medicine, 37075 Gottingen, Germany
Harvard Medical School hms.harvard has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
Source: David Cameron
Harvard Medical School
Researchers have discovered that DNA damage decreases a cell's ability to regulate which genes are turned on and off in particular settings. This mechanism, which applies both to fungus and to us, might represent a universal culprit for aging.
"This is the first potentially fundamental, root cause of aging that we've found," says Harvard Medical School professor of pathology David Sinclair. "There may very well be others, but our finding that aging in a simple yeast cell is directly relevant to aging in mammals comes as a surprise."
These findings appear in the November 28 issue of the journal Cell.
For some time, scientists have know that a group of genes called sirtuins are involved in the aging process. These genes, when stimulated by either the red-wine chemical resveratrol (web.med.harvard/sites/RELEASES/html/11_1Sinclair.html) or caloric restriction (web.med.harvard/sites/RELEASES/html/sinclair.html), appear to have a positive effect on both aging and health.
Nearly a decade ago, Sinclair and colleagues in the Massachusetts Institute of Technology lab of Leonard Guarente found that a particular sirtuin in yeast affected the aging process in two specific ways - it helped regulate gene activity in cells and repair breaks in DNA. As DNA damage accumulated over time, however, the sirtuin became too distracted to properly regulate gene activity, and as a result, characteristics of aging set in.
"For ten years, this entire phenomenon in yeast was considered to be relevant only to yeast," says Sinclair. "But we decided to test of this same process occurs in mammals."
Philipp Oberdoerffer, a postdoctoral scientist in Sinclair's Harvard Medical School lab, used a sophisticated microarray platform to probe the mammalian version of the yeast sirtuin gene in mouse cells. The results in mice corroborated what Sinclair, Guarente, and colleagues had found in yeast ten years earlier.
Oberdoerffer found that a primary function of sirtuin in the mammalian system was to oversee patterns of gene expression (which genes are switch on and which are switch off). While all genes are present in all cells, only a select few need to be active at any given time. If the wrong genes are switched on, this can harm the cell. (In a kidney cell, for example, all liver genes are present, but switched off. If these genes were to become active, that could damage the kidney.) As a protective measure, sirtuins guard genes that should be off and ensure that they remain silent. To do this, they help preserve the molecular packaging - called chromatin - that shrink-wraps these genes tight and keeps them idle.
The problem for the cell, however, is that the sirtuin has another important job. When DNA is damaged by UV light or free radicals, sirtuins act as volunteer emergency responders. They leave their genomic guardian posts and aid the DNA repair mechanism at the site of damage.
During this unguarded interval, the chromatin wrapping may start to unravel, and the genes that are meant to stay silent may in fact come to life.
For the most part, sirtuins are able to return to their post and wrap the genes back in their packaging, before they cause permanent damage. As mice age, however, rates of DNA damage (typically caused by degrading mitochondria) increase. The authors found that this damage pulls sirtuins away from their posts more frequently. As a result, deregulation of gene expression becomes chronic. Chromatin unwraps in places where it shouldn't, as sirtuin guardians work overtime putting out fires around the genome, and the unwrapped genes never return to their silent state.
In fact, many of these haplessly activated genes are directly linked with aging phenotypes. The researchers found that a number of such unregulated mouse genes were persistently active in older mice.
"We then began wondering what would happen if we put more of the sirtuin back into the mice," says Oberdoerffer. "Our hypothesis was that with more sirtuins, DNA repair would be more efficient, and the mouse would maintain a youthful pattern gene expression into old age."
That's precisely what happened. Using a mouse genetically altered to model lymphoma, Oberdoerffer administered extra copies of the sirtuin gene, or fed them the sirtuin activator resveratrol, which in turn extended their mean lifespan by 24 to 46 percent.
"It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins redistribute with damage or aging, is also applicable to mammals," says Leonard Guarente, Novartis Professor of Biology at MIT, who is not an author on the paper. "This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilize this redistribution of sirtuins over time."
Both Sinclair and Oberdoerffer agree with Guarente's sentiment that these findings may have therapeutic relevance.
"According to this specific mechanism, while DNA damage exacerbates aging, the actual cause is not the DNA damage itself but the lack of gene regulation that results," says Oberdoerffer. "Lots of research has shown that this particular process of regulating gene activity, otherwise known as epigenetics, can be reversed - unlike actual mutations in DNA. We see here, through a proof-of-principal demonstration, that elements of aging can be reversed."
Recent findings by Chu-Xia Deng of the National Institute of Diabetes, Digestive and Kidney Diseases, also discovered that mice that lack sirtuin are susceptible to DNA damage and cancer, reinforcing Sinclair's and Oberdoerffer's data.
This research was funded by the National Institutes of Health, and the Glenn Foundation for Medical Research. David Sinclair is a consultant to Genocea, Shaklee and Sirtris, a GSK company developing sirtuin based drugs.
Written by David Cameron
Full citation:
Cell, November 28, 2008 Volume 135, Issue 6
"SIRT1 Redistribution on Chromatin Promotes Genome Stability but Alters Gene Expression during Aging"
Philipp Oberdoerffer(1), Shaday Michan(1), Michael McVay(1), Raul Mostoslavsky(2), James Vann(3), Sang-Kyu Park(3), Andrea Hartlerode(4), Judith Stegmuller(1,7), Angela Hafner(1), Patrick Loerch(1), Sarah M. Wright(5), Kevin D. Mills(5), Azad Bonni(1), Bruce A. Yankner(1), Ralph Scully(4), Tomas A. Prolla(3), Frederick W. Alt(6), and David A. Sinclair(1)
Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA
Massachusetts General Hospital Cancer Center, Boston, MA
University of Wisconsin, Department of Genetics and Medical Genetics, Madison, WI
Beth Israel Deaconess Medical Center, Boston, MA
The Jackson Laboratory, Bar Harbor, ME
Howard Hughes Medical Institute, Children's Hospital Boston, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, MA
Present address: Max Planck Institute for Experimental Medicine, 37075 Gottingen, Germany
Harvard Medical School hms.harvard has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
Source: David Cameron
Harvard Medical School
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