November 7, 2006
Aging Drugs: Hardest Test Is Still Ahead

By NICHOLAS WADE
A new class of drugs is looming on the horizon that could, if they live up to their promise, avert heart disease, diabetes, cancer and neurodegenerative disorders. By suppressing the common killers of age, the drugs, sirtuin activators, could significantly prolong both health and lifespan.

But is the promise a mirage or a serious possibility?

The drugs are designed to mimic the effects of caloric restriction, a low calorie but healthful diet known to make laboratory mice live longer and more healthily but is too hard for all but the most ascetic of humans to keep to. One such drug, resveratrol, also a very minor ingredient of red wine, hit the headlines last week with a report by David Sinclair of Harvard Medical School and colleagues that it negates the bad effects of a high-fat diet in mice.

Behind the proposed new drugs lies some 15 years of research, much of it by Leonard Guarente of M.I.T. and a talented but fractious group of former students, several of whom have presumed to challenge aspects of his ideas. The research has now reached a point at which at least two companies, Elixir Pharmaceuticals and Sirtris, are trying to develop drugs based in whole or in part on its implications.

But success is by no means guaranteed, for several reasons. Caloric restriction has not been proved to improve health or prolong life in people; even if it does, the effect could be much smaller than the 30 percent of extra life and health enjoyed by laboratory mice.

Nor is it clear that the genetic mechanism that Dr. Guarente believes is responsible for the effects of caloric restriction, a group of genes known as the SIRT family, is the only one involved. Some biologists suspect that drugs like resveratrol may act not through the SIRT genes but in some other way, which would mean the results reported last week give no support to the idea that the SIRT genes mediate the response to caloric restriction.

Finally, the benefits of caloric restriction are assumed to have evolved as a strategy for switching resources between reproduction and tissue maintenance. Such a mechanism would greatly help an organism ride out successive waves of feast and famine. That would explain why mice on caloric restriction generally become infertile.

So it is somewhat puzzling that the fat mice fed resveratrol by Dr. Sinclair showed no decline in fertility. Nor have a group of female rhesus monkeys who have been eating a reduced-calorie diet since 1987, scientists at the National Institute on Aging reported recently. If there’s no trade-off between longevity and fertility, the theory of the evolution of caloric restriction could be wrong or incomplete.

The road to the discovery of the first SIRT-type gene began in 1991 when two graduate students at M.I.T. asked Dr. Guarente if they could join his laboratory to study the process of aging. They were Brian Kennedy, now at the University of Washington, and Nicanor Austriaco, now a Dominican priest who teaches biology and theology at Providence College in Rhode Island.

Aging had long been a difficult and unpromising field for biologists, but Dr. Guarente said his students could have a year to search for genes that might affect aging in yeast. In the event, they took four years just to find a strain of yeast that lived longer than others. A gene called sir-2, for silent information regulator-2, turned out to be responsible for this longevity effect.

The lab was then joined by David Sinclair, a young postdoctoral student from the University of New South Wales in Australia, who figured out the unusual mechanism by which sir-2 repressed aging in yeast. Dr. Guarente then found that the gene is activated by a common chemical that reflects the level of metabolism in a cell. He proposed that sir-2 and its counterpart genes in animals were the mediators of caloric restriction: the genes sense when the body is running low on nutrients and direct a wide range of metabolic adjustments, from preserving tissues to burning off fat reserves.

Meanwhile a certain amount of tension was developing between Dr. Guarente and Dr. Sinclair, who in 1999 started his own laboratory at Harvard Medical School. Dr. Sinclair published a report that caloric restriction worked through a quite different mechanism in yeast than the one Dr. Guarente had identified. The rivalry was not just scientific. Dr. Guarente, with Dr. Cynthia Kenyon of the University of California, San Francisco, had founded Elixir Pharmaceuticals to develop drugs for greater health and lifespan. Dr. Sinclair started a rival company, Sirtris, to pursue similar goals.

“This has run me through so many emotions, some of which I didn’t know I had,” Dr. Guarente told Science magazine in 2004 in an article about the falling out between him and his former student.

But continuing research has brought about a realignment of forces. Dr. Guarente and Dr. Sinclair have reconciled, saying their disagreements were technical and never personal. Each of their proposed mechanisms is correct, they say, and yeast uses both to respond to caloric restriction.

They have found a common cause in disputing a challenge raised by two other former students of Dr. Guarente, Brian Kennedy and Matt Kaeberlein, who argue that yeast longevity via caloric restriction does not operate through sir-2 at all.

These disagreements about the mechanism of caloric restriction are confined to yeast, but may portend future disputes in the far more complex systems of mice and men. Both species possess a gene called SIRT1, which is the counterpart to the sir-2 gene. But they have also evolved six extra SIRT genes, known as SIRTs 2 to 7, which seem to perform related tasks. The protein enzymes made by the genes are known as sirtuins, a word biologists have derived, with a simplicity likely to make etymologists wince, from sir-2.

To figure out the role of the seven SIRT genes, both Dr. Guarente and Dr. Sinclair have engineered two sets of genetically altered mice. For each SIRT gene, one strain lacks the gene entirely and another makes extra amounts of the gene’s product. The knockout mice, by their deficiencies, should show what the lost gene does. And its effects will be larger in the overexpressor mice.

Dr. Guarente believes that the full suite of seven genes is deployed in response to the stress of caloric restriction. Researchers used to think that the response to caloric restriction was a passive affair, with the organism living longer because it created fewer damaging byproducts of metabolism. This is incorrect in Dr. Guarente’s view.

Rather, the seven SIRTs take specific actions to protect the body against insult, including against common diseases of aging. This prompts the hope that approvable drugs could be developed to trigger one or more SIRTs into the actions that ward off specific diseases. The SIRTs intervene in the body’s metabolism in intricate ways that are only beginning to be understood. Mice that overexpress SIRT1 show eight properties of caloric restriction, including low cholesterol and low glucose and insulin blood levels, Dr. Guarente said in a recent talk at the Mount Sinai School of Medicine.

As for the other SIRT genes, SIRT2 is mostly expressed in the brain, Dr. Guarente said in an interview last month. Its role there is unknown because the SIRT2 knockout mouse appears normal. SIRT genes 3, 4 and 5 are active in the mitochondria, the energy-producing organelles that are part of every cell. They may “vindicate the school of thought that mitochondria are important in aging,” Dr. Guarente said. SIRT6 is active in the nucleus of the cell and SIRT7 in the nucleolus, a compartment of the nucleus reserved for the assembly of ribosomes, the cell’s protein-making machines.

A special property of the SIRT1 gene is to increase the number of mitochondria produced by neurons, Jill Milne of Sirtris reported at a recent meeting on the molecular genetics of aging. With extra energy, brain cells may be better able to ward off neurodegenerative diseases like Alzheimer’s. The sirtuins could also improve memory, a fact often on the mind of Dr. Sinclair, who has been taking resveratrol for three years.

One day last month, he and a reporter spent five minutes searching a Harvard Medical School parking lot for a grimy green Honda Accord. Dr. Sinclair had forgotten where he had parked his car. “So much for resveratrol improving memory,” he grumbled.

The car retrieved, he drove to Sirtris’s headquarters in Cambridge, where he shares an office with Christoph Westphal, the company’s chief executive. Dr. Westphal disagrees with his colleague that taking resveratrol is a good idea, saying a therapeutic dose cannot be maintained in the bloodstream. He politely conceded Dr. Sinclair’s position that a lower dose might be effective over the long term.

Sirtris has developed a modified form of resveratrol, called SRT501, that reaches high levels in the bloodstream. It is now being tested in people for safety and its ability to control glucose levels. Dr. Westphal plans to gauge the drug’s use in treating diabetes and a rare form of dementia caused by defective mitochondria. Sirtris has also developed several other chemicals that activate sirtuins at doses one-thousandth that of resveratrol. The F.D.A. will approve them, if safe and effective, only to treat specific diseases, but it could be inferred that the drugs might thereby extend lifespan. “We believe this is a new therapeutic modality,” Dr. Westphal said. “We think it can change medical care.”

Sirtris has raised $82 million so far. It has a heavyweight group of biotech entrepreneurs on its board and well-known M.I.T. researchers, like Philip Sharp and Robert Langer, on its scientific advisory board. Still, these luminaries could be backing the wrong horse. Across town, that is the view at Sirtris’s rival, Elixir Pharmaceuticals.

Elixir has chosen to emphasize leads developed from Dr. Kenyon’s work on a different set of genes that affect aging, rather than on the sirtuin work of Dr. Guarente. “We think the sirtuins are extraordinarily interesting but just don’t yet have the proof that these enzymes will be useful in metabolic disease,” said William Heiden, Elixir’s chief executive.

“It’s a proven artifact that resveratrol activates sirtuins,” said Peter DiStefano, Elixir’s chief scientific officer, referring to Dr. Sinclair’s 2003 search for such chemicals.

Both Elixir executives argue that the biology of the seven SIRT genes needs to be better worked out before it is worth trying to develop drugs based on them. In their view, it is not even clear if the sirtuins should be activated or inhibited for best effect. Indeed, Elixir has developed several chemicals that inhibit SIRT1’s sirtuin.

This has brought about the odd circumstance that Sirtris is trying to activate SIRT1 and Elixir to inhibit it. Can both companies possibly be right? Dr. Guarente’s consulting agreement with Elixir has expired, and he welcomes the interest that Sirtris is now taking in his work. Both activation and inhibition of SIRT1 could be useful, he says judiciously, if during caloric restriction the gene’s activity goes up in some tissues and down in others.

The body’s metabolism is governed by such a complex array of genetic circuits that it will be years before the role of the seven SIRTs is fully understood. But if they really embody an ancient mechanism for fortifying the body against disease, then all that is needed is a safe drug that tricks the SIRT genes into thinking feast is famine. The theory is enticing, even if sirtuins and certainty still lie far apart.

Unrelated, but interesting:




November 7, 2006
It May Come as a Shock

By AMANDA SCHAFFER
In ancient Rome, patients with unbearable head pain were sometimes treated with jolts from the electricity-producing black torpedo fish, or electric ray.

Scribonius Largus, physician to Emperor Claudius, was a staunch advocate of the remedy. “To immediately remove and permanently cure a headache, however long-lasting and intolerable, a live black torpedo is put on the place which is in pain, until the pain ceases and the part grows numb,” he wrote in the first century.

Electric fish have long disappeared from the medical armamentarium. And patients with headaches are most frequently treated with pharmaceuticals.

But recently, electrical or electromagnetic devices that hark back to the head-zapping torpedo fish have come into vogue among the country’s most prominent migraine researchers. Two different kinds of stimulatory devices are now in large-scale clinical trials for possible use in patients with the most severe migraine cases. Many researchers believe that such devices are likely to play a greater role in migraine treatment in the future.

Roughly 30 million Americans suffer from migraines, an inherited neurological disorder characterized in part by painful, throbbing headaches.

Dr. Richard B. Lipton, a professor of neurology at the Albert Einstein College of Medicine and director of the Montefiore Headache Center, says that while there are many drugs to treat the disorder or ward off the pain of an attack, some people do not respond or cannot tolerate the side effects.

“There is still a lot of unmet need,” Dr. Lipton said. “So the idea of having stimulatory devices that can be used to prevent headaches or to treat them acutely is very attractive to me, and I think very attractive to patients as well.”

The two kinds of stimulatory approaches now in large-scale clinical trials are occipital nerve stimulation, or O.N.S., and transcranial magnetic stimulation, or T.M.S.

In occipital nerve stimulation, a pacemakerlike device is connected to electrodes placed at the back of the head just under the skin. Electrical current is delivered through these electrodes, with the goal of inhibiting or preventing migraine pain.

In transcranial magnetic stimulation, a magnetic device is pressed to the back of the head, and brief pulses are delivered, altering electrical activity inside the brain in hopes of halting the migraine before it progresses. This approach is being studied only for patients whose migraines begin with an aura, or premonitory phase, that is typically characterized by flashing lights or other visual disturbances.

Experts say approaches like these represent a powerful new trend in migraine research.

“Since 1990, there have been well over 100 clinical trials for migraine drugs,” said Dr. Lipton, who added that by comparison virtually every stimulatory-device study that has been started is still going.

Some patients who have undergone the treatments say that they have helped.

Cheryl Myers, a mother of two who lives near Columbus, Ohio, said that for 9 or 10 years she suffered from chronic and disabling migraines that forced her to stop working and often confined her to bed.

“The only thing that helped was narcotics,” said Ms. Myers, 49. “But I couldn’t be taking them three or four times a week.”

In 2004, Ms. Myers enrolled in a clinical trial at the Michigan Head-Pain and Neurological Institute, where she had an occipital nerve stimulator surgically implanted.

The pacemakerlike device was placed in her upper buttocks and connected, by way of wires tunneled under the skin, to electrodes at the base of her neck, on either side.

Soon after the device was turned on, Ms. Myers said, she began having fewer migraines, and those she did have were less severe. Within a few months, she was also able to return to work several days a week. “I am not headache-free,” she said, adding that she still has “one or two headaches a week” and takes Percocet, a pain-relieving narcotic.

“However, I am enjoying a much more normal life,” she said.

Dr. Joel R. Saper, director of the neurological institute, said that in the treatment, electrodes are positioned to stimulate the greater occipital nerve, which runs along the back of the head on either side. The occipital nerve converges in the upper or cervical spinal cord with the trigeminal system, which includes neurons and neural pathways responsible for conveying much of the throbbing pain associated with migraine, he said.

Dr. Saper says it is not clear precisely how occipital nerve stimulation works. But one possibility is that it effectively inhibits activity in the trigeminal system, dampening the patient’s pain.

Three companies are conducting large-scale clinical trials of three different occipital nerve stimulators for use in migraine patients. The companies are Advanced Neuromodulation Systems, a division of St. Jude Medical; Advanced Bionics, a Boston Scientific company; and Medtronic.

Though the studies are not done, Dr. Saper, who has served as an advisory board member for all three companies, said that outside of the trials, “it is clear that some people get better but some people don’t.”

Dr. Saper said the treatment was appropriate only for patients who did not respond to less invasive approaches.

In 2003, Kerrie Smyres of Seattle was implanted with an occipital nerve stimulator that was not part of a clinical trial. In 2005 the leads from the electrodes began slipping out of position. When the leads moved, they caused a sharp pinching pain and sometimes set off another migraine.

The device meant that some kinds of activity that had helped her maintain a positive state of mind were off limits, including yoga and kayaking.

“Over time, I realized that it caused more pain and was more limiting than it was helping,” she said of the device.

So in September, Ms. Smyres had her stimulator removed.

“More than anything, I worry about patients who act on desperation like I did and then have their hearts broken, like I did,” said Ms. Smyres, who in 2005 began a blog about migraines called The Daily Headache.

Transcranial magnetic stimulation, the other type of stimulation being tested for migraines in large trials, does not require a surgical procedure. Rather, it uses magnetic pulses, delivered through the skin, to induce electrical changes in a particular brain area.

Dr. Yousef M. Mohammad, a neurologist at Ohio State University Medical Center, said preliminary research, conducted by his group and others, indicated that this approach might prove helpful to migraine patients who experience an aura before developing a pounding headache.

In a study of 43 patients conducted by Dr. Mohammad and his colleagues in 2004 and 2005, participants came to the medical center’s emergency room when they began to experience an aura, and were then given either transcranial magnetic stimulation or a sham treatment.

Two hours after being treated, 74 percent of the patients who received magnetic stimulation said they had no headache or a mild headache, compared with 45 percent of the patients in the control group.

Dr. Mohammad presented the results at the annual conference of the American Headache Society in June.

Christina Sidebottom, a retired technical writer who participated in the study, said that after stimulation, she would still get a mild headache, but never the intense throbbing pain she had before. “It was like having discovered Aladdin’s cave,” she said.

Initially, the study participants were required to come to the emergency room for treatment because the magnetic stimulation devices were cumbersome (weighing roughly 80 pounds, they are modified versions of machines used for brain mapping).

The California-based company Neuralieve has since developed smaller, portable devices that resemble ray guns and weigh just under three pounds. It is these devices that are being tested in the current trial, which involves several medical centers (Dr. Lipton heads the Neuralieve medical advisory board).

Gary H. Stroy, president and chief executive of Neuralieve, said that depending on the result of the trials and whether the Food and Drug Administration approves the device, a portable stimulator could be on the market in about 18 months. The stimulator is available now only to migraine patients participating in the research study.

Dr. Mohammad, who is on Neuralieve’s medical advisory board, said the idea of using electrical or electromagnetic stimulation to treat migraines resulted partly from a shift in how neurologists understood the disorder. Modern medicine has viewed migraines primarily as a vascular problem. Blood vessels in the brain constricted, then subsequently dilated, irritating the nerve endings around them and causing pulsating pain.

More recently, however, scientists have come to view these vascular changes as secondary to underlying neural events. For some patients who experience an aura, a wave of electrical excitation appears to spread through an area of the brain called the occipital cortex. Because this area governs vision, patients may see flashing lights, dancing bright spots or wavy lines, or they may experience a blind spot in their vision. If the excitation spreads to other areas, other neurological symptoms — like numbness, tingling or difficulty speaking — may occur.

Intense excitation is soon followed by exhaustion or depression of the affected brain cells, Dr. Mohammad said. The end result of this process, known technically as “cortical-spreading depression,” is irritation of trigeminal nerve fibers — and a throbbing, pounding headache.

The goal of transcranial magnetic stimulation is to interfere with the initial wave of excitation, thereby preventing the migraine from proceeding to the headache phase.

Dr. Mohammad offered an analogy of a forest fire. “If you cut some trees in the middle then the fire will not spread,” he said. “That is what we’re doing with T.M.S.”

The treatment is noninvasive and does not appear to have side effects, he added. So for some patients, it might be a first or second approach, rather than a treatment of last resort. “We are treating electricity with electricity rather than treating electricity with chemicals,” Dr. Mohammad said.

Roughly 20 percent of migraine patients experience an aura, according to the National Headache Foundation. But for those who do not, it is not clear whether cortical-spreading depression occurs in some other area of the brain or whether an entirely different mechanism is at play. It is also unclear whether transcranial magnetic stimulation would be useful in these cases.

Dr. David W. Dodick, a professor of neurology at the Mayo Clinic Arizona, said that while the biology and treatment of migraine have come a long way in the last 20 years, scientists needed to develop a better understanding of the mechanisms that initiate an attack, as well as the mechanisms by which some patients develop frequent and sometimes daily headaches.

Genetics are thought to play a major role in predisposing people to migraines. And in those who are predisposed, migraine attacks can occur spontaneously or be set off by a host of environmental factors, including stress, noise, bright lights, changes in sleep patterns and certain foods, as well as fluctuating estrogen levels, which may be why the disorder is about three times more common in women than in men.

But how these factors interact and the specific ways in which they exert an influence on neural processes are not well understood, said Dr. Dodick, who is involved in experimental work on occipital nerve stimulation and has served as a science adviser to Neuralieve.

Neurologists also do not know where in the brain a migraine begins and how additional areas are involved as the attack progresses, the details of which may be different for different patients.

Cortical-spreading depression may occur in some people, Dr. Dodick said. But other neural mechanisms are almost certainly at play, as well, and may turn out to be even more fundamental. Dysfunctional pain control centers in the brain stem may prove to be a root cause of the disorder, at least for some.

Nonetheless, he said, once the basic science of migraine is better understood, it will be possible to develop pharmaceuticals that aim to prevent attacks without untoward side effects. “That’s where I believe the future is.”

J. Steven Poceta, a neurologist at the Scripps Clinic in La Jolla, Calif., who is not involved in the current trials, also focused on the importance of new drug discoveries. Dr. Poceta emphasized that migraines are a progressive disorder, with headaches often becoming more frequent and less amenable to treatment. The goal, he said, is to develop drugs that can stop the progression before it gets to the point where nothing works.

“The brain is an organ that learns,” he said. “That’s its basic job. So the more it does something, the more it tends to do that same thing.”