Study results aren't definitive, but emotional issues require attention

Study results aren't definitive, but emotional issues require attention
by Theresa Tamkins


If you're a fan of Desperate Housewives or Sex and the City, this may come as a bit of a shock: A large chunk of women in their 30s and 40s aren't obsessed with finding a hot new lover; they're worried about a lack of interest in sex with their current partner—or anyone else, for that matter.

As many as one in four women of any age report sexual dissatisfaction, and when it comes to middle-aged women, one survey found that 42% to 68% said they never or rarely experience sexual desire. Yikes!

So on behalf of women everywhere, let's say thank you to the researchers and their guinea pigs who recently tested a testosterone spray as a possible remedy for women ages 35 to 45.

Although testosterone is thought of as a "male hormone," women do produce the hormone in their ovaries and adrenal glands. While estrogen production starts to plummet around the time of menopause, testosterone declines much more slowly. Can testosterone help you get your mojo back?

To find out, a team led by Susan Davis, MD, PhD, of Monash University in Australia, tested three doses of an experimental testosterone spray (not yet FDA approved, so you can't buy it) against a placebo spray in 260 women.

None of the women had undergone menopause, and all had at least one sexual "event" per month, either alone or with a partner. However, they had all experienced a decline in sexual satisfaction in recent years that concerned them (and had relatively low testosterone levels).

The good news is that all the women had more satisfying sex during the 16-week study. But studies like this often yield murky results, and that's the case here. It's not clear if the spray had anything to do with it. Only women taking the medium dose of testosterone had more events per month (0.8 events to be exact) than placebo users, while those taking the high and low doses had the same amount of satisfying sex as the placebo users. In other words, just being in the experiment may have cause the "more satisfying" result.

"My take-home message from that study was that there’s no evidence now of useful benefit from testosterone in premenopausal women. That was the situation before the study, and that’s still the situation," said Rosemary Basson, MD, director of sexual medicine at the University of British Columbia, who also wrote an editorial published with the study in the Annals of Internal Medicine.

Dr. Basson is concerned about the lack of safety data on testosterone; it's unclear if—like estrogen—it will increase the risk of certain cancers. And an accidental pregnancy while taking testosterone is a very bad idea. It can cause the fetus to develop ambiguous genitalia, or genitals that are somewhere between male and female. One woman in the study had an unplanned pregnancy, but luckily she was in the placebo group and had a healthy baby.

Another potential drawback? Unwanted body hair (hypertrichosis). At the highest dose, 28% of women had hair growth—often at the spot on their belly where the spray was administered.

Experts recommend that women who are worried about their sex life take stock of their mental health (depression is a classic mood-killer) and their relationship with their partner.

"Desire or lack thereof is the canary in the coal mine and tells you something is wrong but doesn’t tell you what is wrong," says Andrew Goldstein, MD, author of the book Reclaiming Desire. "Women can have decreased desire for many reasons. They can have decreased desire because their partner is a jerk. Testosterone isn’t going to make their husband vacuum, take out the garbage, or pick the kids up from school."

However, he thinks testosterone could have potential for some women, and the drug deserves more study.

"Whereas it may be natural to have a decreasing sex drive, that doesn't mean it's necessarily desirable," he says.

'Testosterone link' to depression

Older men with lower levels of the male sex hormone testosterone in their blood may be more prone to depression, a study suggests.
A study of about 4,000 men aged over 70 found those with lowest testosterone were three times more likely to be depressed than those with the most.

Researchers suspect the hormone may affect levels of key brain chemicals.

The study, by the University of Western Australia, features in Archives of General Psychiatry.

Research has found that women are more likely to be depressed than men until the age of 65, when the difference between the genders almost disappears.

Testosterone levels decline with age - but there is wide variation.

The Australian team studied 3,987 men over the age of 70. Each gave blood samples and took part in tests to determine whether they were depressed.

In total 203 of the participants were assessed as being depressed.

They had significantly lower levels of both total testosterone, and free testosterone, which is not bound to proteins.

The researchers then adjusted the data to take account of factors such as educational attainment and body fat levels.

They found those men whose level of free testosterone was in the bottom 20% were three times more likely to be depressed than those in the top 20%.

The researchers said further work was required to confirm their findings.

But their work raised the possibility that treatment to boost testosterone levels in older men may be an effective way to treat depression.

Raised death risk

A previous study of 800 men over the age of 50 found that those with low levels of testosterone had a 33% increased risk of death over an 18-year period than those with higher levels.

They appeared significantly more likely to have a cluster of risk factors associated with cardiovascular disease and diabetes.

This raises the possibility that men with low testosterone levels may be prone to depression because they are also more likely to be in poor physical health.

However, the Australian researchers concluded that this could not fully explain the link, and that some other factor must also be in play.

Testosterone replacement therapy has also been shown to help elderly men with mild Alzheimer's disease.

Research has suggested that levels of testosterone in men of all ages are falling.

Professor David Kendall, an expert in pharmacology at the University of Nottingham, said there was a wealth of evidence to show that testosterone levels were linked to mood.

For instance, farmers had long castrated their stock to pacify them.

Research on animals had also shown that removal of their gonads blocked the action of anti-depressants on key mood-controlling chemicals in the brain.

"It would be no surprise that low testosterone reduces mood," he said.

"Testosterone therapy offers a relatively simple intervention, potentially, for some groups of older depressives with hypogonadism (low production of sex hormones)."

Professor Stafford Lightman, a hormone expert at the University of Bristol, said testosterone potentially had many small effects which could raise the risk of depression. For instance, low levels had been linked to poor cognitive performance.

However, he warned that depression, particularly in elderly people, was often the result of many different, inter-relating factors, and warned against placing too much emphasis on one in isolation.

"My view is that low testosterone could be a contributory factor to depression, but probably not a very powerful one," he said.

http://news.bbc.co.uk/1/hi/health/7274481.stm

Older Women Have Harder Time Preserving Muscle Than Men

(HealthDay News) -- Keeping in good shape is more difficult for older women than men because it's harder for women to replace muscle that's lost naturally as they age, say U.S. and British researchers.

The study of 29 healthy women and men, aged 65 to 80, found that women were less able to use protein to build muscle mass -- a key difference in the way women's and men's bodies react to food. This may be due to menopause-related hormone changes in women, said the researchers from the Washington University School of Medicine in St. Louis and The University of Nottingham. One possible culprit is estrogen, which is known to be needed to maintain bone mass.

The findings, published in the current issue of the Public Library of Science One, seem to fit with preliminary results showing that older women have less muscle-building response to weight training than older men. This difference is not apparent in younger women and men.

"Nobody has ever discovered any mechanistic differences between men and women in muscle loss before. This is a significant finding for the maintenance of better health in old age," and reducing demand on health-care systems, Michael Rennie, a professor of clinical physiology at the University of Nottingham, said in a prepared statement.

The findings of this new study show that it's important for older women to consume plenty of protein-rich foods such as eggs, fish, chicken and lean red meat and to do resistance training (lifting weights in a gym), the researchers said.

"Rather than eating more, older people should focus on eating a higher proportion of protein in their everyday diet. In conjunction with resistance exercise, this should help to reduce the loss of muscle mass over time. There is also a case for the beneficial hormonal effect of limited HRT (hormone replacement therapy), although this has to be balanced against the other risks associated with such treatment," Rennie said.

The researchers noted that maintaining muscle is essential in reducing the risk of falls, one of the major causes of premature death in older adults. After age 50, people lose up to 0.4 percent of muscle mass per year.

Women are at particular risk for muscle mass decline, because they tend to have less muscle and more fat than men in early and middle age, which means they're already closer to the "danger" threshold of becoming frail when they're in their 50s and 60s, the researchers said.

More information
The U.S. Centers for Disease Control and Prevention has more about healthy aging for older adults.

Gene Linked to Form of Parkinson's Disease

(HealthDay News) -- Mutations in a gene called GIGYF2 may be directly linked to the development of Parkinson's disease in families with a history of the neurodegenerative condition, U.S. researchers report.

"These findings may ultimately help open the door to the development of new therapeutic -- and possibly even preventive -- strategies that target the underlying cause of Parkinson's disease, improving quality of life of the many people worldwide who are affected by this devastating disorder," senior author Dr. Robert J. Smith, professor of medicine at the Warren Alpert Medical School of Brown University, said in a prepared statement.

His team analyzed DNA samples from 249 Parkinson's patients with at least one first-degree relative (parent, child, sibling) with the disease, and compared them to DNA samples from 200 healthy people.

The researchers found that GIGYF2 resides on a chromosomal region called PARK11, which is linked to Parkinson's.

"Our data provides strong support for GIGYF2 as a PARK11 gene with a causal role in familial Parkinson's disease," said Smith, who is also director of the division of endocrinology and the Hallett Center for Diabetes and Endocrinology at Rhode Island Hospital.

"The next step is to zero in on this gene to learn more about its involvement in triggering Parkinson's. It will also be important to evaluate additional and larger families with Parkinson's and these genetic mutations, as well as the frequency of GIGYF2 mutations in patients with the more common, idiopathic form of the disease," he said.

The study appears online in the American Journal of Human Genetics and will be published in the April 11 print issue of the journal.

Smith and his colleagues said GIGYF2 is one of only a few genes so far linked to Parkinson's and one of just two genes known to be a common contributor to the disease, which has no known cause or cure and affects as many as one million Americans.

They noted that less than one-quarter of all Parkinson's cases are familial. But findings about genes like GIGYF2 could improve understanding of the mechanisms behind Parkinson's and may help lead to new treatments for all forms of the disease, the researchers said.

They also identified a possible association between Parkinson's and insulin and the related growth hormone called insulin-like growth factor (IGF). This adds to a growing body of research linking insulin and IGF to Parkinson's, Alzheimer's and other neurodegenerative diseases.

"A better understanding of the link between insulin or IGF and Parkinson's may lead us to new treatment strategies for Parkinson's and also new insights into the connection between diabetes and nervous system disorders," Smith said.

More information
We Move has more about Parkinson's disease.

Diabetic mice cured with drugs

US scientists have managed to rid diabetic mice of the effects of the disease using a cocktail of drugs.
The mice, who had type 1 diabetes, started producing their own insulin after taking a mixture of four drugs.

Previously the same team at Harvard University had only been able to stop the destruction of the cells which make insulin, not regenerate them.

But in a study reported in the New Scientist, they say adding another drug to the original cocktail did just that.

They now hope to start trials in humans.

Type 1 diabetes is usually managed through regular injections of insulin and until now, research into a cure has focused on transplanting the pancreatic beta cells which produce the hormone from donors.

However this is complicated - both because of the difficulty in finding a donor and the problems of rejection - so regenerating a person's own cells is seen as far better option.

Extra enzyme

Last year, Dr Terry Strom and his team demonstrated that they could stop the on-going destruction of insulin-producing beta cells in mice using a combination of three drugs, although they were unable to regenerate the cells.

However, when they added an extra ingredient - an enzyme called alpha 1 anti-trypsin - a significant rise in the number of beta cells was seen.

It is thought this extra drug may ease the inflammation of pancreas, a key feature of the disease.

"It would appear that by altering the inflammatory state that surrounds this autoimmune disease, you can create an environment that enables expansion of the beta cell mass," said Dr Strom.

He added that it was too early to say whether the beta cells which had stopped making insulin had recovered, or whether new ones were being produced.

http://news.bbc.co.uk/2/hi/health/7267586.stm

Dr Iain Frame, director of research at Diabetes UK said: "This could potentially be very important research in finding a better treatment for diabetes.

"More research is needed as initial studies have only been conducted in mice, but Diabetes UK is pleased that clinical trials are planned and look forward to hearing the results."

Starved for Sleep? Watch Your Waistline

(HealthDay News) -- Could the key to weight loss for some people be as simple as getting some extra shuteye?

Possibly. New research suggests that people who don't get enough sleep tend to weigh more -- and that sleep can affect levels of the appetite-regulating hormones leptin and ghrelin.

"There is a dynamic balance between proper sleep and proper health. Sleep deprivation affects weight and a lot of other things. If you cheat sleep, there are a number of consequences, including affecting your hormones, appetite and mood," said Dr. Patrick Strollo, medical director of the University of Pittsburgh Medical Center's Sleep Medicine Center.

Two out of three Americans are overweight, and almost one in five are obese, according to the U.S. Centers for Disease Control and Prevention. And, while most people are aware of the relationship of diet and exercise to excess weight, few realize that the amount of sleep they get each night can also affect their weight.

Researchers at the Sleep Disorders Center at Sentara Norfolk General Hospital in Virginia conducted two studies, each included 1,000 men and women, and they found that those who reported sleeping less tended to weigh more.

Of course, it could be that being overweight might make it harder to get a restful night sleep.

"People who are overweight may have less restful sleep due to heartburn, snoring or more serious sleep disorders like sleep apnea or night eating syndrome," said Dr. Michelle May, author of "Am I Hungry? What To Do When Diets Don't Work."

But, she said, "It works both ways," and that a lack of sleep can affect your weight. Sleep deprivation affects your body chemistry, appetite and the choices that you make throughout the day, May said.

Another recent study included 12 healthy men in their 20s. Each of the men slept only four hours for two nights. The study found that levels of leptin, a hormone that tells the brain it's time to stop eating because the stomach is full, decreased by 18 percent during the two-day study period. Levels of another hormone, ghrelin, which turns the hunger mechanism on, increased by 28 percent.

On average, the men reported that their hunger pangs increased by 24 percent.

"Hormones change with sleep loss and deprivation," said Strollo. "Sleep deprivation can affect appetite and also the type of food that one desires. When you're sleep-deprived, you generally don't crave carrot sticks."

May agreed, adding, "When you're tired, you're less resilient to stress and other common emotional triggers for eating. When you eat to help you cope with emotions, you're more likely to choose comfort foods like chocolate, ice cream or chips. And, since eating only helps temporarily, you may find yourself reaching for food again and again to try to make yourself feel better.

"Getting enough sleep is the best way to prevent sleep deprivation from contributing to weight gain," May advised. "When you aren't able to get your Zzzs, pay more attention to how much you eat and how you handle fatigue and stress. A short walk will be a better energy boost than a trip to the candy machine."

Strollo said that while most people need between seven and eight hours of sleep a night, there are some people who need as many as 10 and others who may do well on just five hours.

The best way to figure out how much sleep you need, he said, is to take a long vacation and after a couple of days of catching up on your sleep debt, see how many hours of sleep you need to wake without an alarm clock. Since many Americans don't take long vacations, if you feel that you're not fully functional all day, or that you're doing things to stay awake, like a double-espresso shot, you're probably not getting enough sleep, he said.

May added that it's important to remember that "healthy eating, physical activity and sleep are not luxuries, they are necessities."

More information

To learn more about the connection between sleep and your weight, visit the National Sleep Foundation.

Cure hope over diabetes therapy

A pioneering treatment for diabetes is being rolled out across the country with experts believing it could eventually lead to a cure.
Six centres are receiving nearly £10m of government funding to offer transplants of insulin-producing cells.

The technique has been used on a handful of patients already to reduce the risks of coma-inducing blood sugar attacks in people with type 1 diabetes.

Experts hope the therapy can be refined in the future to offer a complete cure.

People with type 1 diabetes do not produce enough insulin, which means they have to rely on injections of the hormone.


There are about 250,000 people with the condition, which usually develops in childhood and is unconnected with lifestyle factors such as obesity unlike the type 2 version of the disease.

The procedure involves obtaining cells - known as islet cells - from the pancreas of a dead donor and injecting them into the patient's liver.

Once there, the cells get to work producing insulin.

The major international breakthrough was announced in 2000 in Canada but the first UK transplant was carried out by London's King's College Hospital in 2002.

Since then 12 patients have undergone the therapy across the country.

It has been used on people at risk of hypoglycaemia - low blood sugar that can lead to coma-inducing attacks.

The treatments give protection against hypoglycaemia and in some of the patients have freed them from needing daily insulin injections for a period.


However, the patients need to take immunosuppressant drugs for the rest of their lives and it is likely re-transplants will be likely in the future as doctors do not expect the hypoglycaemia protection to last for ever.

The government-funding will mean many more patients will be able to benefit from the technique, with up to 20 transplants planned in the first year before the numbers are gradually built up to about 80.

From April, the Department of Health will fund two laboratories - in London and Oxford - to receive donor pancreases and prepare the cells for transplantation.

The labs will be able to provide the cells to six transplant centres based at the Oxford Radcliffe, Newcastle-up-on Tyne, North Bristol, Central Manchester, Kings College and Royal Free NHS trusts.

Extreme cases

It will mean in time the 2,000 patients at risk of hypoglycaemia will be able to get the treatment if needed.

The only alternative at the moment is to have a complete pancreatic transplant, but that is only ever done in the most extreme cases.

Professor Stephanie Amiel, a diabetes expert at King's College Hospital, said "Allowing King's and the other centres to continue to offer this life-changing treatment will have enormous benefit for those patients who are suitable for islet transplantation in its present form.

"It will also allow the UK to develop the technique to be suitable for more people with type 1 diabetes and may, in time, lead to a 'cure'."

Diabetes UK chief executive Douglas Smallwood added: "The decision to fund this programme will be life-changing for some people.

"Resolving the worst cases could save the NHS a significant amount of money, as hypoglycaemic attacks cost £15m a year in hospitalisations and ambulances alone. "
http://news.bbc.co.uk/1/hi/health/7238418.stm

Faulty Fountains of Youth

Skin sags. Hair grays. Organs don't work quite like they used to. A gradual wearing out and running down of the body's tissues seems an inherent part of growing older. Rejuvenation of skin, muscles, and other body parts naturally declines with the passing years.

Scientifically speaking, however, this observation is much less self-evident. Some cells in a person's body can resist the tide of aging. Consider the reproductive cells a person carries that will become the cells of newborn children who have 80-plus years of life to look forward to. Generation after generation, these reproductive cells form an unbroken line stretching for millennia.

The reason that an otherwise healthy person grows old and dies remains a mystery. Scientists have suggested several suspects for why people's bodies wear out with age, including accumulated damage to DNA, free radicals, and the shortening of telomeres—the caps on the ends of chromosomes. While each of these factors may play a part, biologists acknowledge that their understanding of aging is incomplete.

Enter stem cells. Scientists have long known that people have small reservoirs of stem cells in some of their tissues, such as bone marrow. These stem cells are distinct from those found in newly fertilized embryos—the more controversial embryonic stem cells. The embryonic type can become any type of cell in the body.

Adult stem cells, in contrast, can normally generate new cells only for the tissue in which they're found: blood cells for blood, intestinal cells for the intestines. As old cells in these tissues are damaged or wear out, nearby stem cells can manufacture new ones to take their place. At the same time, the stem cells produce more copies of themselves, maintaining a seemingly indefinite pool of cells capable of churning out a stream of replacement cells.

Until recently, most scientists thought that adult stem cells existed only in tissues that need to constantly replace their cells, such as skin, blood, and the lining of the intestine. But over the past few years, researchers have found stem cells in many, perhaps most, of the body's organs and tissues. Even the brain, which scientists once thought never replaced its nerve cells during adulthood, is now known to have stem cells that make new nerve cells throughout life (SN: 6/16/07, p. 376).

With the realization that so much of the body contains self-renewing stem cells, scientists began wondering whether changes in these stem cells over time might contribute to aging.

Imagine that, as a person ages, these fountains of cellular youth might start to run dry. As the supply of fresh cells dwindles, tissues would gradually decline and show signs of age. "That was the initial model" of how stem cells could be involved in aging, says Norman E. Sharpless, a stem cell expert at the University of North Carolina in Chapel Hill. And some data support this idea.

Graying of hair, for example, could be caused by a decline in melanocyte stem cells that accompanies aging, as observed by Emi K. Nishimura and her colleagues at Dana-Farber Cancer Institute in Boston. Melanocytes make the hair pigment melanin, so depleting these stem cells eventually causes loss of hair color, the team reported in Science in 2005.

Elderly people also have diminished resistance to disease because their immune systems make fewer of the disease-fighting white blood cells known as lymphocytes. In mice, bone marrow stem cells produce fewer lymphocytes as the mice get older, Derrick J. Rossi, now at Harvard Stem Cell Institute in Cambridge, reported in 2005 in the Proceedings of the National Academy of Sciences.

Yet evidence is mounting that the connection between adult stem cells and aging is more complex. Some kinds of stem cell actually grow more abundant with age. And just as stem cells affect aging, the aging body affects stem cells.
Tinkering with time

To untangle these effects, scientists led by Thomas A. Rando of Stanford University surgically joined pairs of mice like reconnected Siamese twins. The team linked the animals' circulatory systems so that blood from each member of a pair flowed through both mice. One mouse in each pair was old; the other was young.

Scientists knew that the ability of muscle stem cells (also called satellite cells) to repair damaged muscles declines substantially with age. Rando's team wanted to find out whether such declines should be attributed to changes in the satellite cells themselves or to changes in the cells' environment as the animals aged.

"There clearly is an effect of aging on stem cells," Rando says. "But I think the other question is ... are those changes reversible or irreversible?"

Amazingly, the blood of the young mice completely restored the tissue-healing powers of the satellite cells in the older mice, Rando's team reported in 2005 in Nature. Exposure to the young blood reactivated a system of proteins inside the cells called the Notch signaling pathway, which is crucial for triggering the cells' muscle-repair functions. Notch signaling in satellite cells normally declines in old age, but Rando's experiment showed that this decline is a response to changes in the blood, not the result of an inherent wearing out of the satellite cells themselves.

This influence of the cells' environment is possible because all cells receive signals—including hormones and other messenger proteins—from their surroundings, and these signals allow the cells to behave appropriately for their context. So a change in these external messengers in aging mice could diminish the satellite cells' muscle-repair activity.

Stem cells' surroundings also wield an influence in fruit fly testes. Changes in the stem cell–harboring niche inside the testes contribute to a decline in the number of sperm-making stem cells with age, according to research by D. Leanne Jones of the Salk Institute for Biological Studies in La Jolla, Calif., and her colleagues. As the flies grew old, the niche produced less of a protein that activates a gene in the stem cells called unpaired, which triggers self-renewal of the cells, the team reported in the Oct. 11, 2007 Cell Stem Cell.

"We definitely see changes in the environment long before we start to see" signs of intrinsic aging, Jones says. In mice testes as well, "there seems to be evidence for the environment aging instead of the stem cells themselves."

In other cases, though, stem cell aging seems independent of context. Blood-forming stem cells from bone marrow age in an unusual way. When scientists transplant blood stem cells from an old mouse into a young mouse, allow the young mouse to grow old, and then repeat the process for several generations, the stem cells lose none of their ability to make copies of themselves. In fact, in some mouse strains, blood stem cells become even more numerous with age.

But that's not necessarily a good thing. While old age doesn't appear to affect blood stem cells' power of self-renewal, it does gum up their ability to make specialized offspring cells. Ideally, each time a stem cell divides, one of the daughter cells would remain a stem cell, and the other would continue dividing to produce a fresh crop of specialized cells to replenish the tissue. That way, the stem cell's lineage always contains only one stem cell at a time to replace the original, keeping the total number of stem cells constant.

For that number to increase, daughter cells must sometimes both become stem cells, decreasing production of tissue-replenishing cells.

Even when these elderly stem cells do spawn new lines of specialized cells, the process goes awry. Blood stem cells must give rise to a whole family of specialized cells: red blood cells, lymphocytes, monocytes, macrophages, and others. As the stem cells age, something goes wrong in this specialization process, skewing it away from making lymphocytes. So the old-age slump in germ-fighting lymphocytes happens not because the stem cells peter out but because they charge ahead with their specialization machinery slightly broken. In mice, this misbehaving of blood stem cells occurs even when scientists repeatedly transplant the cells into young animals, leading them to conclude that the stem cells themselves become damaged with time.
Fighting death with aging

In trying to understand how stem cells in various organs deteriorate with age, scientists have run up against the perennial nemesis of cell biology: cancer.

"Having all these cells around that can divide all the time is quite dangerous for an organism," Sharpless says. Cells continually accumulate DNA damage, but copying and segregating the DNA during cell division is particularly hazardous. Every time a cell divides, there's some error of replication.

Most of these mistakes get fixed by repair enzymes, but certain lingering errors in DNA can cause a cell to begin growing and dividing out of control, which is how cancer arises. Cells have elaborate tools for detecting DNA damage early and either fixing it or shutting down the affected cell. Recent data suggest that these mechanisms for thwarting cancer could cause the body to cull some of its own stem cell supplies.

For example, researchers led by Sean J. Morrison of the University of Michigan in Ann Arbor found a link between the decline in nerve stem cells in mouse brains and the potent anticancer gene p16. This gene causes cells to enter a dormant state called senescence. Mice bred without p16 retained significantly more of their nerve stem cells into old age than did mice that had the gene, Morrison's team reported in Nature in 2006.

The famous tumor-fighting gene p53 also reins in damaged stem cells in old age. Blocking the activity of p53 in stem cells restored populations of intestinal stem cells in elderly mice, K. Lenhard Rudolph of Hannover Medical School in Germany and his colleagues reported in the January 2007 Nature Genetics.

Whether the bodily declines that come with aging are due to the depletion of stem cells depends on which organ is in question—and on which scientist you ask. Most scientists agree that adult stem cells play an important role in aging; the other thing that they seem to agree about is that this role is complicated. "There's still a tremendous amount of debate about even the [blood stem cell] system, which is one of the best-studied systems," Jones says.

In blood and other tissues with high cell turnover, decline of stem cells may make a greater contribution to the signs of aging than it does in tissues with slower cell turnover.

In skin, which constantly produces new cells, a decline in stem cell vigor is expected by some scientists to play a big part in the sagging and poor elasticity of skin that comes with old age. For organs such as the brain and heart, which retain most of their cells throughout adulthood, signs of old age more likely come from traditional mechanisms of aging acting on the organs' mature, specialized cells.

But even this guideline may be too simple. Alzheimer's disease, a form of dementia that commonly occurs in the elderly, is characterized by plaques accumulating in the brain. Young people's brains make the plaque proteins as well, but some data suggest that immune cells called macrophages patrol the brain and clear out budding plaques. Macrophages are continuously being made by—you guessed it—blood stem cells. So even for organs in which cell renewal by stem cells proceeds very slowly, the declines of old age might be caused by the decline of adult stem cells elsewhere in the body.

Some aspects of aging will likely prove unrelated to stem cells, Sharpless says, but these cells now appear far more important for aging than scientists once thought. "I've stopped trying to predict which symptoms of aging are related to [stem cell] proliferation and which are not," Sharpless says. Scientists "used to be so confident about this 10 years ago. Now I'm prepared to be wrong."



http://www.sciencenews.org/articles/20080209/bob8.asp

Weighty Evidence

Living large can mean dying large, as familiar reminders about obesity's link to cardiovascular disease and diabetes repeatedly emphasize. But those warnings often overshadow another threat from obesity: cancer. Excess weight accounts for 14 percent of cancer deaths in men, and 20 percent in women, researchers estimate. Among all preventable cancer risk factors, only smoking claims more lives.

Obesity's link to cancer should come as no surprise. Signs of that relationship began to emerge 2 decades ago. In the late 1980s, laboratory researchers found connections between cancer and insulin—one of the major hormones that responds to obesity.

While the findings got little attention then, today at least a half-dozen companies are developing cancer drugs that interfere with the hormone's cousin—insulinlike growth factor 1 (IGF-1).
"We've been working on this for 20 years," says Derek LeRoith of the Mount Sinai School of Medicine in New York City. Yet until recently, "nobody ever bought into it." After all, even if a tumor does need insulin, the rest of the body does too. The early research was seen as hardly relevant for disease treatment.

Not so today. If clinical trials find that dampening IGF-1 shrinks tumors in cancer patients, scientists will have not only a new kind of cancer drug but also a new source of insight into the interplay between body weight, metabolism, and cancer. In 2003, a study in the New England Journal of Medicine estimated that if the U.S. population were of a healthier weight, "90,000 deaths due to cancer could be prevented each year." That number may not fall for generations, as obesity rates among even the youngest Americans continue to soar.

Heavy hormones
Lower weight and more physical activity can affect the production of insulin, the hormone that allows the body to soak up fuel. After a meal, food is broken down into glucose, which is the body's main source of energy. Insulin triggers cells to take up and use glucose. As a person gains excess weight, the cells can become resistant to insulin's actions. To compensate, the pancreas begins to produce more insulin, but it can't stay in overdrive indefinitely. Eventually, insulin production will fall and blood glucose levels rise in some people.

The potent hormone IGF-1 and the related IGF-2 are very similar to insulin, helping support rapidly dividing cells, especially during childhood and adolescence. IGF-1 is a powerful driver of cell growth and body size: A toy poodle is a standard poodle with a faulty IGF-1 system.

The link between these insulinlike hormones and obesity is less clear than the connection between insulin and obesity. Although insulin and IGF-1 have individual parking places, or receptors, on a cell, some experiments suggest that at high enough levels, insulin starts to trespass on the IGF-1 receptor, LeRoith says.

In the late 1980s, laboratory researchers demonstrated that IGF-1 might have a role in cancer. Tumor cells were found to contain the IGF-1 receptor. In 1989, experiments with mice showed that blocking the receptor with an antibody could stop tumor growth. Researchers also found that mice bred to lack IGF-1 receptors in all their tissues were born tiny, thereby establishing the hormone's significance in growth. More important for cancer research, cells taken from the miniature mice lacking IGF-1 receptors could not be transformed into tumor cells.

"A cancer cell has to have the IGF-1 receptor," says Renato Baserga of the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, one of the field's pioneers. "If not, it cannot grow."

At first, results like these were puzzling. Unlike cancer genes that encode other proteins and start down the path to cancer after mutating, the IGF-1 receptor gene wasn't altered in tumors. Also, IGF-1 receptors show up in normal tissues throughout the body. The hormone itself is such a basic substance for animal life that even flies produce it. It was hard to imagine that a normal receptor found in normal cells could have anything to do with cancer.

Then scientists had an idea. Malignant cells may be overly dependent on IGF-1 receptors, on a scale far surpassing the dependence of normal cells. A tumor is like a car—a gas-guzzling Hummer—with a stuck accelerator and no brakes. Even if IGF-1 doesn't spark the ignition, the hormone keeps the gas tank full. Block IGF-1, according to this line of thinking, and the tumor suddenly finds itself running on empty.

Fueling cancer
Still, this notion might have stalled without two other developments. First, epidemiological studies began to find links between cancer and the insulin-IGF axis in people. Then, the entire field of cancer treatment underwent a transformation.

"What got people's attention was the epidemiologic data," says Doug Yee of the University of Minnesota Cancer Center in Minneapolis. In 1998, researchers reported in the journal Science that the risk of prostate cancer among men with the highest circulating levels of IGF-1 was four times as great as the risk among men with the lowest IGF-1 levels. Similar findings quickly followed in breast, colon, and other cancers.

So far, colon cancer has the most consistent association with insulin and IGF-1 levels, says Edward Giovannucci of the Harvard School of Public Health, a coauthor of the 1998 Science study. In 1999, he and his colleagues reported that colon cancer rates were more than twice as high among men who had the highest levels of IGF-1 as they were among men with the lowest IGF-1 levels.

Such findings fit with global patterns of the disease. "If you look at the rates of colon cancer across the world, populations where you expect people to have low insulin invariably have low rates of colon cancer," Giovannucci says. Physical activity and reduced calorie intake can lower insulin levels; populations with more sedentary jobs and calorie-dense diets have higher rates of obesity and higher insulin levels.

"Once you become economically developed, colon cancer rates go up," Giovannucci says. Also, the risks for colon cancer read largely like a list of red flags for type 2 diabetes. Diabetes itself is a risk factor for colon cancer.

Scientists are quick to point out that a higher insulin level isn't the only chemical change that can occur with obesity. Levels of hormones that cause inflammation also rise, as do sex hormones, which can be produced in fat tissue. These and other changes in the body could themselves drive cancer. Or all these fluctuations could work in concert to feed malignancies.

And it might be not only the IGF-1 of middle age that matters, but also the IGF-1 production that orchestrates development early in life. Studies have suggested that babies born at the highest birth weights—and children experiencing early growth spurts—have a greater risk of cancer as adults.

While epidemiologists gathered evidence for a relationship between insulin and cancer, a second, unrelated advance gave the insulin-cancer connection new life: treatment success using antibodies that can attach to precise targets. Antibody-based drugs are large molecules that take the parking space so its rightful owner can't use it. Herceptin, an antibody-based breast cancer treatment, came on the market in 1998, followed by others. Targeted antibodies were suddenly more than theory.

"I think once people got more comfortable making these drugs, the floodgates opened," says Yee. And when pharmaceutical companies started casting for other promising targets for antibody development, the IGF-1 receptor suddenly looked attractive.

"They turned around and said, 'You know, there's this IGF receptor,'" says LeRoith of Mount Sinai. Drug development didn't happen, and perhaps couldn't have, until epidemiology and the technology caught up with the laboratory evidence.

Broad target
Nonetheless, an antibody that interferes with IGF-1 in people raises concerns. Although the full role of IGF-1 in adult tissues is still being worked out, rapidly growing tissues such as those in bone marrow and the intestine might become innocent by-standers of chemotherapy.
"You're going to hit a receptor that's present on every cell in the body, except the liver," LeRoith says.

Also, in a case of molecular friendly fire, the drug might hit unintended targets. Because the insulin receptor and the IGF-1 receptor are cousins—they are actually more than 70 percent alike—some drugmakers worry about the possibility of accidentally interfering with the insulin receptor and making a cancer patient diabetic.

As an endocrinologist, LeRoith isn't as disturbed by these scenarios as some of his colleagues may be. He believes chemotherapy-induced diabetes would be only temporary, and treatable. In the larger picture, it would not be as grave a threat as the cancer itself. Also, he says, chemotherapies already on the market cripple rapidly growing cells in the intestine, bone, and elsewhere. While these drugs do cause notorious side effects, the complications are generally accepted as the price of disease treatment.

So far, though, the experimental drugs haven't caused major problems in early tests. Results of the first human-safety studies are starting to appear, most just in the past few months. The results are encouraging enough that companies are easing into larger studies.

"This was a target that was on everybody's radar screen, but nobody jumped so strongly at it," says Kapil Dhingra of Roche Pharmaceuticals in Nutley, N.J.

They have now. In October, at the International Conference on Molecular Targets and Cancer Therapeutics, researchers from Roche described a study of 34 patients with advanced tumors who received infusions of an experimental drug designed to target the action of IGF-1. Disease in nine patients stabilized. The most common side effects were fatigue, weight loss, and anorexia—complaints that are also often found in patients with advanced cancer. Subjects' blood sugar levels appeared to remain stable.

The trial was designed to test the safety, and not the effectiveness, of the drug. But the researchers noted that it seemed to have a remarkable result in one of the study participants with Ewing's sarcoma, a cancer of children and young adults that Yee in Minnesota had long ago identified as feeding heavily off IGF-1.

"We have a patient, a young woman in her 20s, who really has had honestly one of the best responses I've seen in 20 years," says Razelle Kurzrock of the University of Texas M.D. Anderson Cancer Center in Houston. "When you see something like that in cancer, you've usually hit the molecular target."

Within 6 weeks, the woman's tumor melted away. The results were promising enough that Roche plans to test more patients.

The antibody-based drug that appears to be the farthest along in testing comes from Pfizer Inc., which has moved beyond safety studies into tests that gauge its effectiveness on cancer. Last summer, during a meeting of the American Society of Clinical Oncology, company researchers described results of a trial involving 70 patients with advanced lung cancer. About 46 percent of patients who received the drug in combination with standard chemotherapy improved, compared with 32 percent of those who did not get the anti-IGF-1 drug. Twenty percent of the patients getting the treatment experienced a jump in blood-glucose levels, implying some interaction with insulin. Later this year, the company hopes to report the effects of treatment on patient survival.

Other companies are also working on antitumor antibodies or on smaller molecules that will block the IGF-1 receptor. In the end, researchers say, the drugs may have a role in combination with standard treatments, and trials will probably also find that some tumors are more dependent than others on IGF-1.

"It's not realistic to think that any one target is going to hit all of them," says Kurzrock. Still, she says, "I would say this is going to be a good molecule." If so, a line of research almost lost to the past could one day benefit cancer patients of the future.

http://www.sciencenews.org/articles/20080216/bob9.asp