Wrinkled cell nuclei may make us age

Blocking a aberrant protein could keep cells pert and young.
Helen Pearson

In the continued quest to pinpoint the molecules that turn us wrinkly and grey, some scientists are beginning to think that the walls of the cell nucleus might play an important role.

A new study shows that cells from people over the age of 80 tend to have specific problems with the nucleus that young children's cells do not. The elderly nucleus loses its pert, rounded shape and becomes warped and wrinkled.

The discovery supports the up and coming idea that at least part of the normal ageing process may be driven by the nucleus' decay, and that blocking this might curb some of time's toll upon the body. "If this really has a physiological role in normal elderly people then it's a huge deal," says David Sinclair who studies the molecular mechanisms of ageing at Harvard Medical School, Cambridge, Massachusetts.

Old before our time

Researchers have found many different genes that can alter the lifespan of animals. In addition, some environmental factors, from the amount of food we eat to the number of cigarettes we smoke, are thought to contribute to the speed at which we age. But there is no consensus yet on how, exactly, these things combine to make our cells and bodies start to fail.

One widely held idea is that cells accumulate wear and tear over a lifetime from damaging molecules known as reactive oxygen species. Some researchers have focused on problems with the power-generating components of cells, called mitochondria. And others have looked at how the ends of chromosomes, called telomeres, fray as we get older.

To gain insight into human ageing, in recent years some biologists have focused their attention on a group of diseases known as progerias, in which children can suffer baldness, heart disease and other symptoms of premature ageing.

In 2003, scientists showed that one such rare disorder, called Hutchinson-Gilford progeria syndrome (HGPS), is caused by a mutation that affects the lamin A protein, a building block of the nucleus and its wall. Now Tom Misteli and Paola Scaffidi at the National Cancer Institute in Bethesda, Maryland, have shown that elderly people tend to have the same problem with their cell nuclei, suggesting that this protein is important in the normal ageing process.

Turning back the clock

In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew, the team reports in Science¹. This mirrors the same changes that they previously observed in cells from HGPS children.

The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot.

Critically, blocking production of this deviant protein corrected all the problems with the nucleus. "You can take these old cells and make them young again," Misteli says.

This suggests that drugs that do the same thing might slow or stay some symptoms of ageing. This is the next key experiment that needs to be tried in animals, researchers say.

Cancer cells suppress large regions of DNA by a reversible process that can be tackled

Cancer researchers at Sydney's Garvan Institute, in collaboration with Spanish scientists, have formulated a new concept for how cancer cells can escape normal growth controls, which may have far-reaching implications for the new generation of cancer therapies.
They have found large regions of DNA are 'switched off' in colon cancer. Lead researcher Associate Professor Sue Clark, of the Garvan Institute, says: "These large regions – referred to as suburbs – contain genes that normally function to prevent the development of tumours".
Our cells become cancerous when the normal controls over cell growth and death go awry. This deregulation has traditionally been linked to DNA mutations of single genes or deletion of large sections of the chromosome. However more recently it has become clear that gene silencing in cancer can also occur, in the absence of changes to the DNA sequence: a phenomenon known as 'epigenetics'. DNA methylation is one of the main epigenetic processes.
In cancer, the DNA methylation pattern of many genes changes. However, until now, it was believed that only individual single genes were silenced by methylation. But this is not necessarily the case. "What we've found is that non-methylated genes that reside in a particular suburb near methylated genes are also silenced. Their physical proximity to the methylated genes affects their ability to function. It's a case of being in the wrong neighbourhood at the wrong time", says Assoc. Professor Clark.
The Garvan team developed a new method to scan the entire complement of the 30 000 plus genes – the entire genome – in the cancer tissue samples, which allowed widespread changes to be identified in specific parts of the genome.
They were amazed to find the extent of gene silencing. Assoc. Professor Clark adds: "What we want to do now is determine if these same regions are switched off in other types of cancers".
The team also hope that new cancer therapies, which can reverse DNA methylation, will restore the cell's normal regulation and treat and prevent cancer.

Drumming up better hearing

Scientists at the Lions Ear and Hearing Institute in Nedlands are closer to growing artificial eardrums to replace those damaged by explosions, trauma and infection.
Already they have been the first in the world to successfully harvest and grow eardrum cells - called keratinocytes - in a test tube.
Now a team led by institute molecular geneticist Reza Ghassemifar will take the next step towards completing the tissue engineering process.
Over the next three years they hope to recreate the best biological chemical conditions so the cells grow into a sheet of eardrum that can be transplanted.
"In the next five years we hope to be able to replace a hole in an eardrum with a functional, artificial eardrum," Dr Ghassemifar said.
This would be done by taking a small piece of a patient's own damaged eardrum tissue - to reduce chances of later rejection - and from it growing new cells on a mesh in the laboratory, he said.
Within a few weeks, the new tissue could be given to a surgeon who could use it to patch the hole.
But first, the challenge was to stimulate the harvested cells to grow into the appropriate structure, outside the body.
"Every eardrum is a very thin, translucent, three-layered membrane around 10 microns thick," Dr Ghassemifar said.
"Using a particular chemical mix - which remains closely guarded - we are trying to stimulate the cells to grow and differentiate into the three layers similar to normal eardrums."
Gene therapy will be used to keep the harvested cells alive and improve their ability to "sit tightly" and adhere to their supporting mesh, he said.
Before being trialled in humans, the engineered eardrums will be tested in animals.
The work will be funded by a $240,000 grant from the Garnett Passe and Rodney William Memorial Foundation, which is dedicated to funding leading-edge research in the areas of ear, nose and throat surgery.
-Alison Batcheler

Solar-powered retinal implant

AN IMPLANT that squirts chemicals into the back of your eye may not sound like much fun. But a solar-powered chip that stimulates retinal cells by spraying them with neurotransmitters could restore sight to blind people.
Unlike other implants under development that apply an electric charge directly to retinal cells, the device does not cause the cells to heat up. It also uses very little power, so it does not need external batteries.
The retina, which lines the back and sides of the eyeball, contains photoreceptor cells that release signalling chemicals called neurotransmitters in response to light. The neurotransmitters pass into nerve cells on top of the photoreceptors, from where the signals are relayed to the brain via a series of electrical and chemical reactions. In people with retinal diseases such as age-related macular degeneration and retinitis pigmentosa, the photoreceptors become damaged, ultimately causing blindness.
Last year engineer Laxman Saggere of the University of Illinois at Chicago unveiled plans for an implant that would replace these damaged photoreceptors with a set of neurotransmitter pumps that respond to light. Now he has built a crucial component: a solar-powered actuator that flexes in response to the very low intensity light that strikes the retina. Multiple actuators on a single chip pick up the details of the image focused on the retina, allowing some "pixels" to be passed on to the brain.
The prototype actuator consists of a flexible silicon disc just 1.5 millimetres in diameter and 15 micrometres thick. When light hits a silicon solar cell next to the disc it produces a voltage. The solar cell is connected to a layer of piezoelectric material called lead zirconate titanate (PZT), which changes shape in response to the voltage, pushing down on the silicon disc. In future, a reservoir will sit underneath the disc, and this action will squeeze the neurotransmitters out onto retinal cells.

From here we just need to be able to generate the neurotransmitter in the device.

Nanospheres: complete prostrate tumor elimination

An MIT/Harvard collaboration on treating prostate cancer in mice just published in PNAS:
“A single treatment of drug-bearing nanoparticles effectively destroys prostate cancer tumors in mice, according to experiments by researchers at MIT and Harvard Medical School. This approach could lead to powerful treatments without the side effects associated with cancer therapy, say the scientists.
” ‘We did a single injection of the particles, and then followed the tumor for the next 109 days, and showed that we basically had complete tumor elimination,’ says Omid Farokhzad, assistant professor of anesthesia at Harvard Medical School, who, along with Robert Langer, chemical engineering professor at MIT, led the research. Because the ingredients used to make the nanoparticle drug system have already been okayed by the FDA for other purposes, the researchers hope to win quick approval for testing the new technology in humans…
“The MIT-Harvard researchers are also working on targeting pancreatic cancer and eventually breast cancer and cardiovascular disease…
“Eventually, the MIT-Harvard researchers hope to design nanoparticles that can be injected into the bloodstream, from which they could seek out cancer cells anywhere in the body, making it possible to treat late-stage metastasized cancer.”
“Early toxicity trials of the nanoparticles could begin in two years, if further animal studies go well…”

Regrow Your Own

April 11, 2006
By NICHOLAS WADE
Stem cell therapy has long captured the limelight as a way to the goal of regenerative medicine, that of repairing the body with its own natural systems. But a few scientists, working in a relatively obscure field, believe another path to regenerative medicine may be as likely to succeed. The less illustrious approach is promising, in their view, because it is the solution that nature itself has developed for repairing damaged limbs or organs in a wide variety of animals.
Many species, notably amphibians and certain fish, can regenerate a wide variety of their body parts. The salamander can regenerate its limbs, its tail, its upper and lower jaws, the lens and the retina of its eye, and its intestine. The zebra fish will regrow fins, scales, spinal cord and part of its heart.
Mammals, too, can renew damaged parts of their body. All can regenerate the liver. Deer regrow their antlers, some at the rate of 2 centimeters a day, said to be the fastest rate of organ growth in animals. In many of these cases, regeneration begins when the mature cells at the site of a wound start to revert to an immature state. The clump of immature cells, known as a blastema, then regrows the missing part, perhaps by tapping into the embryogenesis program that first formed the animal.
Initiation of a blastema and the formation of the embryo are obviously separate biological programs, but "the processes must converge at some point," says Jeremy Brockes, a leading regeneration researcher at University College London.
The blastema seems to derive its instructions from the wound-site cells from which it was formed, and is quite impervious to cues from new surrounding tissue if it is transplanted. If a blastema made by sectioning a salamander's limb at the wrist is transplanted elsewhere in the body it will still grow just a wrist and paw, while a shoulder blastema will regrow the whole limb. People, of course, cannot regrow their limbs like newts, and do not form blastemas, so the relevance of regeneration to medicine has long seemed remote. But the capacity for regeneration exists in such a wide variety of species that it is unlikely to have evolved independently in each, regeneration researchers believe.
Rather, they say, the machinery for regeneration must be a basic part of animal genetic equipment, but the genes have for some reason fallen into disuse in many species.
In support of this notion, people are not wholly lacking in regenerative powers.
There are reports that the tip of the finger can occasionally be regenerated, if the cut is above the last joint. And people can vigorously repair damage to the liver. Even after 75 percent has been removed in surgery, the liver regains its original mass in two to three weeks. It is not certain why other organs and limbs have lost this useful capacity, but perhaps only the liver was damaged often enough during its owner's lifetime to make a repair system worth the cost. "I believe that the reason is the extensive and recurring injury that the liver was exposed to in evolution: rotten food, plant toxins, viruses," says Markus Grompe, a liver expert at the Oregon Health and Science University.
The liver can regenerate itself, when all else fails, from stem cells, the versatile cells that produce the mature cells of many organs and tissues. But usually it relies on its own mature cells, which, like those of a blastema, possess a remarkable power to divide and multiply, even though they can only restore the organ's mass, not its original structure.
A more specific reason for thinking regeneration is not a wholly lost ability comes from genes. Last December, Mark Keating, who studies regeneration in zebra fish, identified a gene that is essential for initiating blastema formation when the fish's fin is cut. Both this gene, called fgf20, and another he has found, hsp60, also exist in people, suggesting the genetic basis for regeneration may still be in place even though the body can no longer evoke it.
Dr. Keating, a vice president at the Novartis Institutes for Biomedical Research in Cambridge, Mass., believes stem cells can ordinarily undertake only very limited repairs of organs like the liver and heart, and that the scarring often seen in these tissues is a fallback mechanism put in place when the stem cells' capacities are exceeded.
If the genes that boot up the zebra fish blastema also exist in people but are not switched on, perhaps some drug might be developed that goads them into action. Once a blastema had been induced at some wound site in the body, regeneration researchers suggest, it might regrow the missing limb or organ with no further intervention required. "Maybe there are residual abilities that could be enhanced" in mammals, says Shannon Odelberg, a researcher at the University of Utah. He studies regeneration in the newt, with the eventual goal of inducing blastemas to form in mammals.
Regeneration is studied in only a few laboratories. It was not even on the agenda of the research planning meeting held last October by the California Institute of Regenerative Medicine, which was dominated by stem cell biologists.
One reason for this orphan status is that the model animals used by most biologists, like the roundworm, the fruitfly and the mouse, happen to be ones that do not regenerate.
The genetics of regenerating animals, like the salamander, are largely unknown. Hence the process of regeneration has received little attention from research biologists. But there is a group of vertebrates that can regenerate very successfully, said Dr. Brockes. "It would be rather surprising if there weren't some interesting and important lessons one could learn from them."
"Regeneration is the result of an evolutionary experiment that nature has already done for us," said Alejandro Sánchez Alvarado, a Hughes Institute researcher who studies flatworm regeneration at the University of Utah The blastema, he notes, performs the difficult task — one not faced by the embryo — of integrating new and existing tissues.
Many proponents of regeneration, while conceding they have a great deal more to learn, believe stem cell therapy too may not be as close to clinical use as its advocates sometimes suggest. Dr. Brockes noted that the blastema's reliance on internal information contrasts with a principal assumption of stem cell therapy, that stem cells inserted into a damaged tissue will use local cues to behave appropriately and integrate into the surrounding tissue.
Stem cell therapists assume that injected cells can replace missing tissue with guidance from the invisible template supplied by chemical signals from nearby cells. That is the solution a human engineer might logically think of, Dr. Brockes said, but evolution has chosen a different one.
The basic biology of regeneration is not yet fully understood, but nor is that of stem cells. Indeed, it may be premature to start thinking about how to use stem cells therapeutically, said Dr. Sánchez Alvarado.
"Translating a biological process you don't understand into technology is like trying to translate hieroglyphs without a Rosetta Stone," he said.
Dr. Grompe, the expert on liver regeneration, said that getting stem cells to behave properly in a patient's body "is a very, very difficult problem." With transplanted stem cells, the usual outcome is "nonfunctional at best and cancerous at the worst because the local environment is not able to modulate the behavior," he said. "I think that cell therapy of the nervous system will be extremely difficult because of that. So much for stem cells curing Alzheimer's."
Dr. Keating believes that the expense of stem cell therapy, should it work, is a major consideration. "I would never begin to guess that the whole stem cell approach has no chance of working," he said. But even if it does, developing cells for every patient who needs them would be very expensive. Switching on the regenerative process with drugs, should that prove possible, would be cheap by comparison, he said.
Scientists who work on stem cells reject the idea that the blastema mechanism is the only way to repair the body's tissues. "I agree that blastema regeneration models might have something to tell us, but I wouldn't give up on normal stem cell regeneration," said Irving Weissman, a leading expert on blood stem cells at Stanford University. The stem cells involved in bone marrow transplants "can regenerate drastic loss of tissue," he said.
Bone marrow transplantation is the big success story on which much of the hope for stem cell therapy is based. But regeneration researchers believe the bone-marrow example may be misleading because blood is not an organized tissue, and the marrow's blood-making stem cells are not required to do anything much beyond their usual function.
In disagreement with this view, Dr. Weissman said that blood-making stem cells are highly versatile and have the ability to home in on the marrow and set up shop in their proper niche there, and that neural stem cells appear to have a similar degree of versatility. Human neural stem cells, when put into embryonic mice, will migrate through the mouse's brain and add insulation to mouse neurons that lack it.
Robert Weinberg, a biologist at the Whitehead Institute in Cambridge, said therapeutic regeneration was "decades away" because the cells of animals that regenerate are so different from those of people.
But there is great hope of taking embryonic stem cells, he said, and making them yield primitive adult stem cells that still possess regenerative capability. He placed less confidence in using fully mature adult stem cells, which may have lost the ability to build new tissue. "I think the notion of trying to extract adult stem cells from adult tissues is possibly a fool's errand," he said.
In the light of new knowledge, some stem cell biologists are making more guarded predictions about the imminence of stem cell therapy. Ron McKay, an expert on neural stem cells at the National Institutes of Health, noted that stem cells inserted into the developing brain of a fetal animal "become incorporated in an extraordinary way, as if local cues were controlling their behavior."
But in the adult brain, he said, nothing happens, suggesting that the concept of using stem cells to treat Alzheimer's disease is illusory.
Stem cells head the hierarchy of cells with which nature organizes animal tissues, but so much remains to be understood that it is hard to tell which aspect of their biology may hold therapeutic promise. "I think the idea of cell therapy per se will not be that powerful a tool for most diseases," Dr. McKay said. "But stem cell biology will be a hugely important tool."
Regeneration and stem cell therapy are promising aspects of regenerative medicine but both are still at the research stage. "I'm very bullish on regenerative medicine," said Dr. Keating, alluding to both types. "I think it's going to happen and it will be a revolution, but it will take time. It would be a mistake to oversell it and promise too much too early."

Mayo Clinic Researchers Challenge Sepsis Theory

Propose new approach for better treatment of deadly condition
A Mayo Clinic research team has challenged the accepted theory on the cause of sepsis -- a condition in which the body's cells generate fever, shock and often death. Sepsis is thought to occur when poisons from bacterial infection interfere with the cells. The Mayo researchers challenge that long-held concept with a new theory in an opinion piece in the current issue of Trends in Molecular Medicine http://www.sciencedirect.com/science/journal/14714914. Their findings suggest that sepsis begins with a change in certain cellular receptors that then provoke widespread inflammation, even in the absence of bacteria or their poisons.
"We think people have been focusing too exclusively on a single causal factor of sepsis for the last 150 years and, as a result, therapeutically aiming at the wrong target -- the bacteria and the poisons they produce," says senior author Jeffrey Platt, M.D. "That's why the death rate remains so high despite efforts to block the poisons."
The researchers define a new "first step" that initiates the sepsis syndrome cycle. In this step, a critical receptor for bacterial poisons and for some of the body's own substances is liberated from "natural suppression." Once free to function, the receptor can trigger the catastrophic cascade of events that is sepsis. The sepsis syndrome can occur during a bacterial infection, as the accepted medical principle holds, or -- as the Mayo Clinic team theory suggests -- it also can occur when substances the body makes act like the bacterial poisons. The Mayo investigators suggest that some or even many cases of sepsis may actually be caused by these normal body substances. The Mayo team argues that this new understanding of how sepsis arises could lead to new treatments for this major medical problem.
Significance of the Mayo Clinic Research
Approximately 700,000 cases of sepsis occur annually in the United States, half of which are fatal. Sepsis is the second most common cause for admissions to critical care units and can be a significant complication of some heart surgeries. The Mayo Clinic researchers believe current sepsis treatment isn't more effective because the theory of sepsis is too narrow. Current treatments don't target all causes of sepsis syndrome -- only the bacterial poison cause -- which was described by a 19th century researcher as "the putrid gift."
"Our work is the first to show that this change in receptors in the body is the first true step in the sepsis syndrome, rather than the introduction of a poison," explains Dr. Platt. "The importance then becomes clear. If we really do now have the first cause of sepsis -- not the bacteria, but the unconstrained receptors -- then we can therapeutically interfere with that receptor release mechanism by designing new treatments and possibly, and at long last, develop drugs that treat all cases of sepsis."
Challenging Existing Theories
Dr. Platt and his colleague, Gregory Brunn, Ph.D., say the evidence they've published compels this conceptual shift about sepsis. "The problem with the concept of sepsis, and what provoked some of our interest, is that it has been known for 10 years that when you treat with anything that interrupts bacterial poisons, it has no impact on the septic disease. That suggests that perhaps the poisons don't cause sepsis after all," Dr. Platt says. "Problems such as this caused us to ask, 'Could there be something else driving sepsis, other than the classic poisoning explanation?'"
Mayo Discovers Key Piece of the Puzzle
Dr. Platt and colleagues discovered several years ago that certain naturally-occurring molecules can stimulate receptors once thought to be exclusive for the bacterial poisons (endotoxins). Once stimulated, the receptors (toll-like receptors) set the sepsis cycle into motion. "This finding was very exciting," notes Dr. Platt. "It explained how the sepsis syndrome can occur when there isn't an infection -- which it does in some cases."
However, Drs. Brunn and Platt saw an obvious problem with this explanation. If normal substances from the body can stimulate toll-like receptors and cause the sepsis syndrome, why aren't we all desperately ill with sepsis? Dr. Brunn explains, "Our bodies are not poised to respond to sepsis. Our bodies are held in check by the fact that this molecule-receptor system is constrained in its activity. What causes sepsis -- and the syndrome like sepsis that can happen in cancer or trauma or in response to drugs -- is that this receptor gets released from its constraint. That's the first step that actually initiates sepsis." Research is underway to discover new therapies that could prevent, blunt or reverse the release of the constrained receptor.

For the first time: Longevity modulated without disrupting life-sustaining function

"The central question [is] whether we would be able to genetically manipulate one element of the pathway without disrupting its additional functions," said Dillin. "In this regard, we thought that the life extending function of this pathway would be elusive, whereas the developmental and reproductive functions would be more amenable. We were delighted to find that Smk-1 proved to be specific for the one function we thought the most elusive," he added.
Some of Dillin's earlier research had hinted at the possibility that "specificity" factors may control how and whether insulin and IGF-1 impact a target gene. Identifying those factors one by one would allow scientists to separate the different functions of insulin/IGF-1 signaling and to manipulate them individually without wreaking havoc on the organism's normal functioning.
Together with the lab of another Salk scientist, Tony Hunter, Ph.D., Dillin's team identified a protein in the worm Caenorhabditis elegans that allowed them to do just that. The protein is encoded by the Smk-1 gene. "Smk-1 is the first known gene that regulates longevity without affecting other vital functions of the insulin signaling pathway," said Wolff.
Under favorable conditions, a still unidentified molecule binds to DAF-2, the worms' equivalent of the insulin/IGF-1 receptor, which is located at the cell's surface. A cascade of signaling molecules relays the information deep into the cell till it reaches a protein called DAF-16. Known as a transcription factor, DAF-16 encodes a DNA-binding protein that turns on other genes but when DAF-2 is active, it is unable to enter the cell's nucleus to activate its target genes.
When environmental conditions turn harsh as a result of overcrowding and scarce nutrients, for example, DAF-2 signaling shuts down. No longer marooned outside the nucleus, DAF-16 crosses into the nucleus, and triggers all the necessary genes to help the body take care of the stressful situation. But food shortages aren't the only triggers for the stress program. Others are the heat that scrambles proteins into toxic clumps and marauding parasites. Highly reactive molecules known as free radicals also unleash DAF-16.
If the worms are having a good day in a favorable environment, but for some reason DAF-2 signaling gets turned off precociously, the worms reap the benefit of increased stress resistance and double their lifespan from an average of 20 to 40 days. Except the worms trade a trim life focused on reproduction for a long life with fewer progeny and a tendency to halt larval development and enter a dormant, hibernation-like stage in which they can hang on for months but don't reproduce.

Original article here.

Altering genetic blueprint of receptors in brain could help stroke victims avoid brain damage

A University of Central Florida researcher has demonstrated that altering AMPA receptors in animals improved their chances of surviving strokes and remaining healthier afterwards.
A University of Central Florida researcher has discovered that altering a receptor that mediates communication between nerve cells in the brain significantly improves animals' chances of surviving strokes and allows them to remain healthier afterwards.
YouMing Lu, a professor at the UCF Burnett College of Biomedical Sciences, is hopeful that changing the genetic blueprint of AMPA receptors can help to block lethal flows of calcium into neurons of human stroke victims.
If administered within a few hours of cardiac arrest, such therapies could prevent brain damage. Given later, the therapies could speed up the regeneration of neurons to replace ones killed by the stroke. In both cases, the primary goal is to help patients avoid brain injuries after strokes.
AMPA receptors that are located at the surface of nerve cells are normally responsible for learning and memory formation. During strokes, however, the receptors become toxic to nerve cells.
"We're trying to find out what the major toxic aspects of these receptors are so we can rescue neurons without damaging learning and memory formation," Lu said.
Lu's research was published in the March 2 issue of Neuron, a prestigious biomedical research journal. Lu and his research team at UCF and the University of Calgary are trying to determine the molecular functions that lead to receptors opening up and enabling large, lethal flows of calcium to reach neurons after strokes.
The calcium flows occur in the hippocampus of the brain, an area that is critical for learning and memory processes. The dilemma for researchers is to figure out how to protect neurons from the lethal doses of calcium without causing more damage to learning and memory.
Lu's approach of modifying one part of the genetic blueprint of the AMPA receptor protected the brain in tests with mice and rats, which experience the same pattern of brain damage after cardiac arrest as humans do, Lu said. More tests in animals would be done before clinical trials are conducted.

Originial article here.

AGE Crosslink breaker

I don't know how many people know about this product, but it is currently only under trials for heart conditions and erectile disfunction.  Seems to me it has a good fit in Aubrey's SENS plan.  I'd like to see someone do testing with it to see if it helps longevity in mice.

Alagebrium is the only A.G.E. Crosslink Breaker in advanced human testing. The compound has demonstrated promising results in several Phase 2 human clinical trials and is being developed initially for cardiovascular and vascular diseases. Results to date suggest that alagebrium may be a novel therapy for a number of conditions that occur as a result of myocardial or vascular alterations associated with aging or diabetes. Preliminary evidence suggests that the compound is able to modify both the structure and function of the left ventricle (main pumping chamber of the heart) consistent with a partial reversal of pathology. Similarly, alagebrium has been shown to improve the reactivity and function of the arterial system. In addition, in all clinical testing to date, the compound has demonstrated a clean safety profile.

Some validation for CR in humans

Cutting calories may boost your lifespan
NewScientist.com news service
Roxanne Khamsi
People who substantially cut their calorie intake develop some of the traits associated with longevity discovered in animal tests, a new study reveals.
Cutting calories reduced body temperature and levels of the metabolism hormone insulin, as well as decreasing DNA damage, showed the study. But follow-up tests are necessary to find out if these biological effects, which occurred relatively quickly, last for more than a few months.
Scientists hoping to understand the biological mechanisms that control ageing have increasingly given attention to the idea that reducing food intake can extend life.
Studies in rodents and other lower species have shown that long-term calorie restriction can boost longevity – increasing the maximum lifespan of mice and rats by about 30% and protecting them against blood vessel plaques and cancer. But with less experimental data from humans, researchers remain undecided about what to recommend to people.
Eric Ravussin of Louisiana State University in Baton Rouge, US, and colleagues conducted a trial with 48 volunteers randomly assigned to maintain their weight or reduce their calorie intake.
Calorie burning
Twelve of the people recruited for the trial ate enough food to maintain their weight. Of the remaining 36 people, an equal number were assigned to either cut their calorie intake by 25%, cut their calorie intake by 12.5% and burn 12.5% more calories with exercise, or to follow a stringent diet of just 890 Calories a day (until they lost 15% of their start weight, followed by a weight maintenance diet).
Participants received their prescribed meals at the research centre for the first three months of the experiment. The volunteers also attended weekly group meetings and had mid-week telephone calls to help them stick to their diets.
People on the caloric restriction diets lost an average of 10% or more of their weight. The researchers also found that these subjects had reduced fasting levels of the hormone insulin, a trait associated with longevity in animal research.
They also found that volunteers who restricted their caloric intake by 25% or achieved similar results by cutting calories and upping exercise had a reduced average core body temperature at the conclusion of the six month trial. Lower body temperatures are also associated with longevity.
Each of the low calorie groups also showed a small but statistically significant reduction in DNA damage in their blood cells, when compared with the control individuals. This is noteworthy, the researchers say, because some of the chemical by-products of food metabolism attack DNA, which might contribute to cancer and accelerate the effects of ageing.
Journal reference: Journal of the American Medical Association (vol 295, p1539)

Bio-engineered bladders successful in patients

NewScientist.com news service
Roxanne Khamsi
Bladders engineered in the laboratory from patients' own cells and then implanted into the body have succeeded in their first clinical trial.
The feat was accomplished by Anthony Atala, at Wake Forest University Medical School in Winston-Salem, North Carolina, and his colleagues. He says that while scientists have had success with skin transplants grown on scaffolds in the past, this is the first time they have grown and transplanted a discrete, complex organ.
The success is the culmination of an idea that the team began exploring 16 years ago. Atala adds that they are also working on growing bio-engineered hearts and pancreases in the lab. Growing organs from a patient's own cells means the organs are not rejected after transplantation.
To create the new bladders, the researchers took a biopsy from patients whose bladders functioned poorly due to an inherited nervous system disorder. The team then placed muscle cells and cells from the bladder lining on a biodegradable bladder-shaped scaffold and allowed them to grow for about two months.
The scaffolds were made of the structural protein collagen, in some cases adding polyglycolic acid, a polymer used in surgical sutures.
Major milestone
The team then transplanted these new bladders into their patients in a delicate operation and monitored their recovery. Two of the patients did not provide follow-up information. But Atala’s group did track the progress of seven patients, aged between 4 and 19 years, for an average of nearly four years.
The patients with the bio-engineered bladders gained better urinary control. The improvements were similar to those resulting from standard surgery that relies on intestinal grafts to fix the bladder. But the new technique does not require any damage to the intestine, the researchers note.
“Atala and his colleagues should be praised for the milestone they have reached, but further multi-institutional studies are needed with longer follow-up,” writes Steve Chung, of the Advanced Urology Institute of Illinois in Spring Valley, Illinois, in a commentary on the study appearing in the Lancet. Until then, he adds, surgery using intestinal tissue to repair the bladder “remains the gold standard”.
Bladder disease does not only cause urinary control problems but can lead to kidney damage. At present, reconstructive surgery is often performed to treat severe bladder problems.
This procedure involves grafting tissue from a section of the small intestine or stomach. But medical experts say that many complications can arise from this type of procedure.
Journal reference: Lancet (DOI: 10.1016/S0140-673(06)68438-9)