Live Healthy till you Die?

[muse]

Hoping two drugs carry a side effect: Longer life
By Nicholas Wade

Tuesday, July 22, 2008
CAMBRIDGE, Massachusetts: One day last month, clad in white plastic garments from head to toe, David Sinclair showed a visitor around his germ-free mouse room here at Harvard Medical School.

The mice, subjects in studies of health and longevity, are kept in wire baskets under intensive nursing care. A mouse gym holds a miniature exercise machine that tests the rodents' ability to balance on a rotating bar. In a nearby water maze, mice must recall visual cues to swim to safety on a hidden platform, a test of their powers of memory. Those that forget their lessons are rescued as they start to submerge and humanely dried out under a heat lamp, Sinclair assured his visitor.

Sinclair is a co-founder of Sirtris, a company that itself has been swimming in uncharted waters as it works to develop drugs that may extend the human life span. But it seemed to have found a safe platform last month when it was bought last month by the pharmaceutical giant GlaxoSmithKline for $720 million.

Sirtris has two drugs in clinical trials. One is being tested against Type 2 diabetes, one of the many diseases of aging that the company's scientists hope the drugs will avert. With success against just one such disease, the impact on health "could be possibly transformational," said Patrick Vallance, head of drug discovery at GlaxoSmithKline.

The new drugs are called sirtuin activators, meaning that they activate an enzyme called sirtuin. The basic theory is that all or most species have an ancient strategy for riding out famines: switch resources from reproduction to tissue maintenance. A healthy diet but with 30 percent fewer calories than usual triggers this reaction in mice and is the one intervention that reliably increases their life span. The mice seem to live longer because they are somehow protected from the usual diseases that kill them.

But most people cannot keep to a diet with a 30 percent cut in calories, so a drug that could activate the famine reflex might be highly desirable. Leonard Guarente, an M.I.T. biologist who founded the field of sirtuin biology, thinks the famine reflex is mediated through the sirtuin enzymes. Sinclair, his former student, discovered that sirtuins could be activated by drugs. The most potent activator that emerged from his screens was resveratrol, a natural substance found in red wine, though in amounts probably too low to be significant for health.

The Sirtris drug being tested in diabetic patients is a special formulation of resveratrol that delivers a bloodstream dose five times as high as the chemical alone. This drug, called SRT501, has passed safety tests and, at least in small-scale trials, has reduced the patients' glucose levels.

The other drug is a small synthetic chemical that is a thousand times as potent as resveratrol in activating sirtuin and can be given at a much smaller dose. Safety tests in people have just started, with no adverse effects so far.

The hope is that activating sirtuins in people would, like a calorically restricted diet in mice, avert degenerative diseases of aging like diabetes, heart disease, cancer and Alzheimer's. There is no Food and Drug Administration category for longevity drugs, so if the company is to submit a drug for approval, it needs to be for a specific disease.

Nonetheless, longevity is what has motivated the researchers and what makes the drugs potentially so appealing.

Christoph Westphal, the chief executive of Sirtris, said of the potential of the drugs, "I think that if we are right, this could extend life span by 5 or 10 percent." He added that his goal was to develop drugs against specific diseases, with the extension of life being "almost a side effect of our medicine."

Sirtris was founded in 2004 after Westphal, then working at a Boston venture capital firm, approached Sinclair. Because of widespread interest in the sirtuin activation idea, Westphal had little difficulty raising money and recruiting distinguished scientists to Sirtris's advisory board.

He later decided to sell the company to GlaxoSmithKline, he said, because it was getting harder to raise money and clinical trials could proceed faster with the larger company's resources. Sirtris was acquired at an 84 percent premium, better than the 50 percent at which most companies are bought, Westphal said.

The impact of Sirtris's drugs, if successful, could extend beyond the drug industry. Guarente believes that many people might start taking them in middle age, though after having started a family because they may suppress fertility.

Mice on the drugs generally remain healthy right until the end of their lives and then just drop dead."If they work in people that way, one would look to an extension of health span, with an extension of life as a possible side effect," Guarente said. "It would necessitate changing ideas about when people retire and when they stop paying into the system."

GlaxoSmithKline could put SRT501, its resveratrol formulation, on the market right away, selling it as a natural compound and nutritional pharmaceutical that does not require approval by the FDA "We haven't made any decisions, but that clearly is an option," Vallance said.

If GlaxoSmithKline decides instead to seek FDA approval, it will need to prove that resveratrol is safe in the large doses required for efficacy. Resveratrol seems to exert many influences on the body, some of which are not exerted through sirtuin. "None of us should be naïve enough to think resveratrol won't have multiple effects, including some you don't want," Vallance said.

GlaxoSmithKline's purchase of Sirtris has pushed the optimism of sirtuin researchers and others to new heights. "We are all holding our breath," said Huber Warner, editor of the Journals of Gerontology. But the success of the drugs is far from assured.

Most potential drugs fail to make it past clinical trials, and the same may prove true for Sirtris's candidates. The sirtuin-activating chemicals the company has designed could turn out to be toxic. Another uncertainty is that the underlying science is still in flux and debate rages among academic researchers over many details of how caloric restriction works.

Some biologists think that sirtuin is not the only mediator of the famine reflex, and that resveratrol may not work through sirtuin at all in exerting its beneficial effects on mice. "There are data both for and against that hypothesis, though that doesn't dissuade one from pursuing it as a potential benefit," said Thomas Rando, who studies aging in stem cells at Stanford University.

In initial tests in mice, resveratrol has doubled muscular endurance, lowered the bad form of cholesterol, protected against various bad effects of a high-fat diet and suppressed colon cancer. New reports are confirming some of these benefits, but others are ambiguous or puzzling.

According to a study published on July 3 in the journal Cell Metabolism by Sinclair and Rafael de Cabo of the National Institute on Aging, resveratrol given to aging mice reduced their cataracts, strengthened their bones, improved coordination and enhanced their health in several other ways. Yet despite their better health, the mice lived no longer than usual.

"Minimally this calls into question one pillar of the GSK investment," said Ronald Evans, a leading expert on hormonal responses at the Salk Institute. Evans said that sirtuin research was promising but unproved, and that he did not agree that sirtuin was the probable mediator of the famine reflex, a concern that "calls into question the second pillar of the GSK investment."

The frontiers of science are often turbulent, and it can take years for clarity to emerge from confusion. Westphal said the decision to ignore the academic debate about exactly how resveratrol may work was one of two principal reasons for Sirtris's quick success. The other was to focus the company's limited resources on developing just two drugs.

The researchers at Sirtris are no strangers to skepticism. Guarente and Sinclair were ridiculed when they first started looking for longevity genes more than 15 years ago, because aging was then considered to be an intractable problem. His colleagues, Guarente said, "thought I was nuts."

Sinclair, when he first arrived as a young postdoctoral student in Guarente's lab to work on longevity, was downcast to learn of the other students' severe doubts. "The view even in Lenny's lab was that this problem was going nowhere, it was a house of cards that would fall down any month now." He called his parents in Australia to tell them he may have made a big mistake. But the research led eventually to the discovery of the sirtuinlike proteins and their role in extending the life span of yeast, worms and flies.

He and Guarente developed the sirtuin field with the hope of increasing longevity. But because of Sirtris's focus on developing drugs that have the FDA's approval for specific diseases, both are being less explicit about their hopes of reversing aging. "There's a much greater chance of a drug that can treat disease than of extending life span," Sinclair said.

"I'm becoming more boring in my old age," he added apologetically.

GlaxoSmithKline's press releases refer to the sirtuins as "enzymes that the company believes control the aging process." But Vallance is more guarded, saying aging is too hard to measure. The goal is not the extension of human life span; rather, "The prolongation of health is the aim," Vallance said.

 

[su-47]

there is a difference between health and living. a long life need not be a healthy one. My great grandmother died aged 94. her life had been long, but was always plagued by ill health. her life was extended by medicines and surgeries more than anything else. she had lost her memory, and had been in bedrest with round the clock care for over 6 months before she died. it was really horrible.

on the other hand, her husband, my great grandpa, died aged 86, but was very healthy throughout his life. he never had health problems (except minor diabetes) and died peacefully in his sleep.

i think this research is moving in the right direction. for years we have had medicines and even equipments like synthetic hearts to prolong life, but not much has been done to prolong health. This will be a landmark in medical history if it succeeds

 

[araz]

I think a lot of people pay too much emphasis on living. I think one lives to fulfill certain aims and once those are achieved, the concept of death does not sound too drastic. But I entirely agree with oyur point that the only life worth living is life with good health.Without good health you become a nuisense both for yourself and for others. I often remember my grand ma and mother praying to God to lift them up when they are still healthy and walking and dependant on no one. My Mum is now 86(Ma Sha Allah) and although weak she still does her own chores and looks after herself. Seems like the prayer has paid off. I would wish the same goes for me(Amen)
Araz

 

[muse]

Couch Potatos of the world, Unite! and Rejoice!



Drugs offer promise of fitness without effort
By Nicholas Wade

Friday, August 1, 2008
Can you enjoy the benefits of exercise without the pain of exertion? The answer may one day be yes — just take a pill that tricks the muscles into thinking they have been working out furiously.

Researchers at the Salk Institute report they have found two drugs that do wonders for the athletic endurance of couch potato mice. One drug, known as Aicar, increased the mice's endurance on a treadmill by 44 percent after just four weeks of treatment.

A second drug, GW1516, supercharged the mice to a 75 percent increase in endurance, but had to be combined with exercise to have any effect.

"It's a little bit like a free lunch without the calories," said Dr. Ronald Evans, leader of the Salk group.

The results, Evans said, seem reasonably likely to apply to people, who control muscle tone with the same underlying genes as do mice. And if the drugs work and prove to be safe, they could be useful in a wide range of settings.

They should help people who are too frail to exercise and those with health problems such as diabetes that are improved with exercise, he said.

But such muscle-enhancing drugs would also have obvious appeal to athletes seeking to gain an edge in performance. With funds from the Howard Hughes Medical Institute, Evans has devised test to detect whether an athlete has taken the drugs, and has made it available to the World Anti-Doping Agency, which prepares a list of forbidden substances for the International Olympic Committee.

Officials at the anti-doping agency confirmed that they were collaborating with Evans on testing procedures but could not say when they would start using them.

Experts not involved in the study agreed that the drugs held promise for treating disease. Dr. Johan Auwerx, a specialist in metabolic diseases at the University Louis Pasteur in Strasbourg, France, said the result with the Aicar drug "looks pretty good' and could be very helpful in the treatment of diabetes and obesity. "The fact you can mimic exercise is a big advantage because diet and exercise are the pillars of diabetes treatment," he said.

Dr. Richard Bergman, an expert on obesity and diabetes at the University of Southern California, said the drugs could become widely used if they prove safe. "It is possible that the couch potato segment of the population might find this to be a good regimen, and of course that is a large number of people," he said.

The idea of a workout in a pill seems almost too good to be true, but Evans has impressive research credentials, including winning the Lasker award, which often presages a Nobel prize. He is an expert on how hormones work in cells, and on a powerful gene-controlling protein called PPAR-delta which instructs fat cells to burn off fat.

Four years ago he found that PPAR-delta played a different role in muscle. Muscle fibers exist in two main forms. Type 1 fibers have copious numbers of mitochondria, the organelles that generate the cell's energy, and are therefore resistant to fatigue. Type 2 fibers have fewer mitochondria and tire easily. Athletes have lots of Type 1 fibers, and people with obesity and diabetes have far fewer Type 1 and more Type 2 fibers.

Evans and his team found that PPAR-delta remodels the muscle, producing more of the high endurance type of fiber. They genetically engineered a strain of mice whose muscles produced extra amounts of PPAR-delta. These mice grew more Type 1 fibers and could run twice as far as on a treadmill as ordinary mice before collapsing.

Given that people cannot be improved in this way, Evans wondered if levels of the gene-controlling protein could be raised by drugs. Pharmaceutical companies have long tried to manipulate the protein because of its role in fat metabolism, and Evans found several drugs were already available, although they had been tested for different purposes.

In a report published in the Friday issue of Cell, he describes the two drugs that successfully activate the muscle-remodeling system in mice. One, GW1516, activates PPAR-delta but the mice must also have exercise training to show increased endurance. It seems that PPAR-delta switches on one set of genes, and exercise another, and both sets are needed for great endurance.

The second drug, called Aicar, improves endurance without any training. Evans believes it both mimics the effects of exercise and activates PPAR-delta, thus being able to switch on both sets of genes needed for the endurance signal.

Aicar works by mimicking a by-product of energy metabolism, signalling the cell that it has burned off energy and needs to generate more. The drug is "pretty much pharmacological exercise," Evans said.

He said the drugs work off a person's own genetics, pushing the body to an improved set-point that is otherwise gained only by strenuous training. "This is not just a free lunch, it's pushing your genome toward a more enhanced genetic tone that impacts metabolism and muscle function. So instead of inheriting a great set-point you are using a drug to move your own genetics to a more activated metabolic state."

Aicar is a well known chemical that has been tested for various diseases since 1994. But neither Aicar nor GW1516 has been tested in people for muscle endurance so the health effects of the drugs, particularly over the long term, are not precisely known.

This may change if pharmaceutical companies pursue Evans's findings. "The drugs' effect on muscle opens a window to a world of medical problems," Evans said. "This paper will alert the medical community that muscle can be a therapeutic target."

The new drugs activate at least one of the pathways triggered by resveratrol, a substance found in red wine though in amounts probably too low to significantly affect muscle.

In 2006 Auwerx and colleagues showed that large doses of resveratrol would make mice run twice as far as usual on a treadmill before collapsing. It is unclear just how resveratrol works, but one of its effects may be to bind with a protein that helps activate PPAR-delta. Auwerx's resveratrol-treated mice remodeled their muscle fibers into a type that contains larger numbers of the energy-producing mitochondria.

This is the same result that Evans has found can be obtained with Aicar.

 

[su-47]

these drugs always have side effects. medical expereince has taught us that any artificial tampering on our body creates some side effect or the other, sometimes immediately, sometimes later in life.

personnaly i wouldnt use these. i exercise almost everyday and i enjoy working for my fitness, rather than swallowing pills.

 

[muse]

Scientists decode set of cancer genes
By Denise Grady

Thursday, November 6, 2008

For the first time, researchers have decoded all the genes of a person with cancer and found a set of mutations that may have caused the disease or aided its progression.

Using cells donated by a woman in her 50s who died of leukemia, the scientists sequenced all the DNA from her cancer cells and compared it to the DNA from her own normal, healthy skin cells. Then, they zeroed in on 10 mutations that occurred only in the cancer cells, apparently spurring abnormal growth, preventing the cells from suppressing that growth and enabling them to fight off chemotherapy.

Mutations are genetic mistakes, and the ones found in this research were not inborn, but developed later in life, like most mutations that cause cancer. (Only 5 to 10 percent of all cancers are thought to be hereditary.)

The new research, by looking at the entire genome — all the DNA — and aiming to find all the mutations involved in a particular cancer, differs markedly from earlier studies, which have searched fewer genes for individual mutations. The project, which took months and cost $1 million, was made possible by recent advances in technology that have made it easier and cheaper to analyze 100 million DNA snippets than it used to be to analyze 100.

The study was done at Washington University in St. Louis and is being published Thursday in the journal Nature. It is the first report of a "cancer genome," and researchers say many more are to come.

The findings will not help patients immediately, but researchers say they could lead to new therapies and will almost certainly help doctors make better choices among existing treatments, based on a more detailed genetic picture of each patient's cancer. Though the research involved leukemia, the same techniques can also be used to study the genomes of other cancers, and the researchers expect to apply them to breast, brain and lung cancers.

"This is the first of many of these whole cancer genomes to be sequenced," said Richard Wilson, director of Washington University's Genome Sequencing Center and the senior author of the study. "They'll give us a whole bunch of clues about what's going on in the DNA when cancer starts to bloom."

Wilson said he hoped that in 5 to 20 years, DNA sequencing for cancer patients would consist of dropping a spot of blood onto a chip that slides into a desktop computer and getting back a report that suggests which drugs will work best for each person.

"That's personalized genomics, personalized medicine in a box," he said. "It's holy grail sort of stuff, but I think it's not out of the realm of possibility."

Until now, Wilson said, most work on cancer mutations has focused on just a few hundred genes already suspected of being involved in the disease, not the 20,000 or so genes that make up the full human genome.

The earlier research has uncovered many mutations and led to the development of a few so-called targeted drugs, which treat some cancers by homing in on specific defects in the cells. Examples include the drug Herceptin, for women with a certain type of breast cancer, and Gleevec, for a type of leukemia and a rare gastrointestinal cancer.

So the older approach is useful, Wilson said. But he added, "if there are genes mutated that you don't know about or don't expect, you'll miss them."

Indeed, 8 of the 10 mutations his group found in the leukemia patient had never been linked to the disease before and would not have been found with the more traditional, "usual suspects" approach.

But researchers have debated which method is best.

"We had a lot of people who said it was a stupid idea to sequence the whole cancer genome," Wilson said, noting that a private donor had paid for most of the study and that the National Cancer Institute had chipped in relatively little, and only after the work was well under way. However, the cancer institute did pay for preliminary work and is now supporting research to decode more cancer genomes.

A cancer expert not involved with the study, Dr. Steven Nimer, chief of the hematology service at Memorial Sloan-Kettering Cancer Center, called the research a "tour de force" and the report "a wonderful paper." He said the whole-genome approach seemed likely to yield important information about other types of cancer as well as leukemia.

"It is supporting evidence for the idea that you can't just go after the things you know about," Nimer said.

He added: "It would be nice to have this kind information on every patient we treat."

Nimer also predicted that oncologists would quickly want to start looking for these mutations in their patients or in stored samples from former patients, to see if they could help in predicting the course of the disease or selecting treatments.

Studying cancer genomes has become a major thrust of research. In the past few years the government has spent $100 million dollars for genome studies in lung and ovarian cancers and glioblastoma multiforme, a type of brain tumor. But that project, The Cancer Genome Atlas, has not decoded an entire genome. So far, it has identified mutations in brain and lung cancers, also reported in Nature in September and October. One discovery is expected to affect medical practice — a mutation that can cause some patients with the brain cancer to get worse instead of better if they are given a common chemotherapy.

The person who gave her cells for the study at Washington University became not only the first cancer patient, but also the first woman to have her entire genome decoded. Her information will be available only to scientists and not posted publicly, to protect her privacy and that of her family. The only other complete human genomes open to researchers so far have come from men, two scientists known for ego as well as intellect, who ran decoding projects and chose to bare their own DNA to the world: James Watson and J. Craig Venter. Their genomes are available for all to inspect.

The woman at Washington University had acute myelogenous leukemia, a fast-growing cancer that affects about 13,000 people a year in the United States and kills 8,800. Its cause is not well understood. Like most cancers, it is thought to begin in a single cell, with a mutation that is not present at birth but that occurs later for some unknown reason. Generally, one mutation is not enough to cause cancer; the disease does not develop until other mutations occur.

"Most of them are just these random events in the universe that add up to something horrible," said Dr. Timothy Ley, a hematologist at Washington University and the director of the study.

The researchers chose to study this disease because it is severe and the treatment has not improved in decades.

"It's one of the nastiest forms of leukemia," Wilson said. "It's very aggressive. It affects mostly adults, and there's really no good treatment for it. A very large fraction of the patients eventually will die from their disease."

Ley said, "We wanted to start studying a cancer where it would make a difference to people and their families if we could begin to unravel its genetic roots."

They chose this particular patient because she was a perfect example of one of the toughest challenges in treating the disease: figuring out early on which patients have a bad prognosis and immediately need the most aggressive therapy, like a bone-marrow transplant.

Doctors routinely try to gauge the severity of this leukemia by examining patients' chromosomes, the structures that carry genes. The testing does not examine the DNA itself, but just checks to see if the chromosomes look normal. Certain abnormalities warn of a bad outlook. But some patients whose chromosomes look perfectly fine turn out to have a vicious form of the disease anyway. And that was true of the woman in the study.

Her chromosome test was normal, but she still died just two years after the disease was diagnosed, despite a barrage of chemotherapy and two bone-marrow transplants. Had the doctors known her prognosis early in her illness, they would have treated her even more aggressively from the start, Ley said.

Before starting treatment, she had donated samples of bone marrow and skin, so the researchers could compare her normal skin cells to cancer cells from her bone marrow. After she died, her family gave the scientists permission to sequence her entire genome. Wilson said the family knew that her DNA — - and therefore some of their own as well — had now become part of history. The family wishes to remain anonymous, Wilson said. They did not respond to a request for an interview with The New York Times that was passed on to them by the researchers.

Some of the patient's mutated genes appeared to promote cancer growth. One probably made the cancer drug-resistant by enabling the tumor cells to pump chemotherapy drugs right out of the cell before they could do their work. The other mutated genes seemed to be tumor suppressors, the body's natural defense against dangerous genetic mistakes.

"Their job is surveillance," Wilson said. "If cells start to do something out of control, these genes are there to shut it down. When we find three or four suppressors inactivated, it's almost like tumor has systematically started to knock out that surveillance mechanism. That makes it tougher to kill. It gets a little freaky. This is unscientific, but we say, gee, it looks like the tumor has a mind of its own, it knows what genes it has to take out to be successful. It's amazing."

It will take more research to determine exactly what the mutations do. Researchers would also like to know the order in which they occurred, and whether there was one that finally tipped the balance towards cancer.

"When this patient came to the cancer center and had a bone marrow biopsy, she already had 10 mutations," Wilson said. "You'd love to know, if you had taken a bone marrow sample a year before, what would you have seen?"

Tests of 187 other patients with acute myelogenous leukemia found that none had the eight new mutations found in the first patient.

That finding suggests that many genetic detours can lead to the same awful destination, and that many more genomes must be studied, but it does not mean that every patient will need his or her own individual drug, Wilson said.

"Ultimately, one signal tells the cell to grow, grow, grow," he said. "There has to be something in common. It's that commonality we'll find that will tell us what treatment will be the most powerful."

 

[pakistanMYheart]

I am also concerned about the yet unknown dangers, that may come as we try to manipulate genetic structures.