Link identified between age, cardiovascular disease

CORVALLIS, Ore. -- Researchers in the Linus Pauling Institute at Oregon State University have discovered a fundamental mechanism that causes aging blood vessels to lose their elasticity – a literal "hardening of the arteries" that is often a prelude to high blood pressure and cardiovascular disease.

An understanding of this mechanism, scientists say, provides an important new target for both drugs and dietary changes that might help prevent or treat atherosclerosis and heart disease. This is a leading cause of death around the world that, in some form, affects about 80 percent of older Americans.

The findings were just published in Aging Cell, a professional journal. The study was funded by the National Institute on Aging, National Center for Complementary and Alternative Medicine, and the American Heart Association.

"This could ultimately provide a new, fundamental and possibly inexpensive way to treat or prevent high blood pressure," said Tory Hagen, an OSU associate professor of biochemistry and biophysics, and lead author on the study. "It's also a key to understanding the biological effects of inflammation, which increasingly seems to be implicated not only in heart disease but other chronic and neurologic diseases."

The research, which was done in test tubes and animal models, needs to be confirmed in humans before it could form the basis for new therapies. But the fundamental findings reveal an important insight into how blood vessels change with age and lose much of their ability to relax, contract, and facilitate the circulation of blood in the body.

Blood vessels in humans, like those of other animals, have vascular "smooth muscles" that can alternatively relax and contract to accommodate fluctuations in blood flow and volume. A thin layer of "endothelial cells" in the vessels serves, in part, as a sensor mechanism to help regulate this process. And proper function of the endothelial cells, in turn, is driven by specific enzymes and signaling pathways.

What has been known for some time is that blood vessels, as they age, lose much of their capacity to relax – according to the OSU research, about half of that capacity, even in healthy vessels. If the vessels are narrowed by atherosclerotic lesions the problem is further exacerbated. High blood pressure is often the result, which in turn can lead to heart attacks, strokes, and death.

Some of the most common high blood pressure medications, in fact, function by helping to address this loss of elasticity in blood vessels. The nitroglycerin pills used by many people with unstable angina provide an immediate boost of nitric oxide, which serves to relax blood vessels.

What has not been known is exactly why this "hardening" of the blood vessels occurs with age. The new OSU study answers much of that question. "Basically, we've learned that in older blood vessels, the cellular signaling process is breaking down," said Hagen. "The vessels still have the ability to relax much as they did when they were younger, but they are not getting the message."

A complex enzymatic process outlined in the new study explains how this "failure to communicate" occurs. An enzymatic reaction called "phosphorylation," which is essential to the signaling process, loses about half of its effectiveness in aging blood vessels. This loss of phosphorylation is due to less activity in one enzyme, AKT, that facilitates the process, and excess activity of phosphatases, that reverse it.

The researchers also discovered that ceramides, one type of lipid, or fat, are primarily responsible for the excessive activity of phosphatases. And in laboratory experiments with blood vessels from rats, they were able to inhibit ceramide synthesis.

"The laboratory studies were very compelling," Hagen said. "We were able to make aging blood vessels behave as if they were young again."

According to Balz Frei, professor and director of the Linus Pauling Institute, and co-author on this study, a strength of this approach is that it points the way to use diet to prevent the decline in blood vessel function with age, and to treat it, if necessary, through drugs.

"A compound we're already using showed the ability to lower ceramide levels and improve the cell signaling process, and this compound would be a good starting point for possible drug therapies," Hagen said. "And certain types of diet may help reduce this natural, age-related process."

As is appropriate for many other disease concerns and health conditions, Frei said, a diet that's heavy in fruits and vegetables seems to slow down the loss of blood vessel function. However, the scientists also are doing research with lipoic acid, a powerful antioxidant, that is very promising and may ultimately show it could play a role as a dietary supplement to help address this problem.

This overall process, the researchers said, is linked to a low-grade, chronic inflammation that occurs with aging, in blood vessels and probably many other metabolic functions. Efforts to understand and address these inflammatory processes are some of the most promising areas of chronic disease prevention and treatment, they said.

Original Article

Plaque bomb

Dentists could soon be out of a job - a "smart bomb" antimicrobial drug
that kills the bacteria that live in plaque could stop tooth decay in
its tracks.

Traditional antibiotics are too indiscriminate to be used against
/Streptococcus mutans/ because they also kill commensal or "friendly"
bacteria, paving the way for other mouth infections. Now Wenyuan Shi of
the University of California, Los Angeles, has created an antimicrobial
that spares commensal bugs.

He linked a peptide that specifically targets /S. mutans/ to the active
region of Novispirin G10, a broad-spectrum antibiotic that destroys
bacterial membranes. The compound killed /S. mutans/ grown in liquid or
as biofilms without harming other oral streptococci (/Antimicrobial
Agents and Chemotherapy/, vol 50, p 3651).

Giving the antimicrobial as a one-off treatment, or at regular
intervals, to kill off /S. mutans/ might enable less harmful bacteria to
colonise its niche, says Shi, making it more difficult for the bug to
regain a toehold. It is unlikely that the bug would develop resistance
to the drug because it would have to go through multiple mutations to
thwart membrane destruction, he adds.

Shi believes that such "selectively targeted antimicrobial peptides" or
STAMPS, might also work against other infections in mixed microbial
environments such as the middle ear, vagina and gastrointestinal tract.

From issue 2578 of New Scientist magazine, 22 November 2006, page 21
Original Article

RNA Activation

The latest twist on the Nobel prizewinning method of RNA interference, or RNAi, could prove to be a real turn-on. Whereas standard RNAi silences a target gene, switching protein production off, the new technique boosts gene activity, providing a genetic "on" switch.

RNAi can silence genes in two ways. It can block the messenger RNA that is the intermediate between gene and protein and it can also interfere with "promoter" sequences that boost a gene's activity. It was while investigating this second phenomenon that Long-Cheng Li of the University of California, San Francisco, and his colleagues stumbled on the new method, dubbed RNA activation.

Li tried to silence several genes in human cells using short pieces of double-stranded RNA, 21 bases long. But to his surprise, he found that they had precisely the opposite effect (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0607015103).

Although the exact mechanism remains unclear, Li's team has already found that it requires a protein called Ago2, which is also involved in the standard RNAi process. Li believes RNA activation could find widespread use, for example in treating cancer by boosting the activity of tumour suppressor genes.

Original Article

Dartmouth researchers identify a gene that enhances muscle performance

Dartmouth College Office of Public Affairs • Press Release
Posted 11/14/06 • Susan Knapp • (603) 646-3661

A team of researchers, led by scientists at Dartmouth Medical School and Dartmouth College, have identified and tested a gene that dramatically alters both muscle metabolism and performance. The researchers say that this finding could someday lead to treatment for muscle diseases, including helping the elderly who suffer from muscle deterioration and improving muscle performance in endurance athletes.

The researchers report that the enzyme called AMP-activated protein kinase (or AMPK) is directly involved in optimizing muscle activity. The team bred a mouse that genetically expressed AMPK in an activated state. Like a trained athlete, this mouse enjoyed increased capacity to exercise, manifested by its ability to run three times longer than a normal mouse before exhaustion. One particularly striking feature of the finding was the accumulation of muscle glycogen, the stored form of carbohydrates, a condition that many athletes seek by "carbo-loading" before an event or game. The study appears in the Nov. 14 online issue of the American Journal of Physiology: Endocrinology and Metabolism.

"Our genetically altered mouse appears to have already been an exercise program," says Lee Witters, the Eugene W. Leonard 1921 Professor of Medicine and Biochemistry at Dartmouth Medical School and professor of biological sciences at Dartmouth College. "In other words, without a prior exercise regimen, the mouse developed many of the muscle features that would only be observed after a period of exercise training."

Witters, whose lab led the study, explains that this finding has implication for anyone with a muscle disease and especially for the growing proportion of the population that is aging. Deteriorating muscles often make the elderly much more prone to fall, leading to hip and other fractures. According to Witters, there is tremendous interest in the geriatric field to find ways to improve muscle performance.

"We now wonder if it's possible to achieve elements of muscular fitness without having to exercise, which in turn, raises many questions about possible modes of exercise performance enhancement, including the development of drugs that could do the same thing as we have done genetically," he says. "This also might raise to some the specter of 'gene doping,' something seriously being talked about in the future of high-performance athletes."

Witters says that the carbohydrate, glucose, is a major fuel that powers muscles, and this contributes directly to a muscle's ability to repetitively contract during exercise. The activated AMPK in the Dartmouth mouse appears to have increased glycogen content by actually switching on a gene that normally synthesizes liver glycogen.

"The switching on of this liver gene in muscles," he says, "is a shift in the conception of the biochemistry of muscle metabolism, since many enzyme genes are thought to only be active in just one tissue."

Other authors on the paper include Laura Barré, Christine Richardson, and Steven Fiering, all at Dartmouth; Michael Hirshman and Laurie Goodyear of Joslin Diabetes Center in Boston; Joseph Brozinick with Eli Lilly and Company; and Bruce Kemp of the St. Vincent's Institute in Australia.

Have a longer, healthier life

Avoiding health risk factors in midlife such as smoking, being overweight, excessive drinking and hypertension is associated with a longer and healthier life in men, according to a study in the November 15 issue of JAMA, a theme issue on men's health.

Bradley J. Willcox, M.D., of the Pacific Health Research Institute and Kuakini Medical Center in Honolulu, presented the findings of the study today at a JAMA media briefing on men's health in New York.

Persons alive at age 85 years or older are the fastest-growing age group in most industrialized countries and are among the largest consumers of health care resources. Identifying strategies for remaining healthy, vigorous, and disability-free at older ages has become a major priority, according to background information in the article. Studies with substantial numbers of long-lived participants and characteristics associated with longer survival are rare but essential to identify risk factors for health and survival at older ages.

Dr. Willcox and colleagues examined potential biological, lifestyle, and sociodemographic risk factors present at middle-age to identify risk factors for healthy survival. The study included 5,820 Japanese-American middle-aged men (average age, 54) in the Kuakini Honolulu Heart Program/Honolulu Asia Aging Study. The participants were free of illness and functional impairments and were followed for up to 40 years (1965-2005) to assess overall and exceptional survival. Exceptional survival was defined as survival to a specified age (75, 80, 85, or 90 years) without incidence of 6 major chronic diseases and without physical and cognitive impairment. The diseases were coronary heart disease, stroke, cancer (excluding nonmelanoma skin cancer), chronic obstructive pulmonary disease, Parkinson disease, and treated diabetes. Of the 5,820 original participants, 2,451 participants (42 percent) survived to age 85 years and 655 participants (11 percent) met the criteria for exceptional survival to age 85 years.

The researchers found that high grip strength and avoidance of overweight, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with both overall and exceptional survival. In addition, high education and avoidance of hypertriglyceridemia (elevated triglyceride level) were associated with exceptional survival, and lack of a marital partner was associated with death before age 85 years.

Risk factor models based on cumulative risk factors (survival risk score) suggest that the probability of survival to age 85 years is as high as 69 percent with no risk factors and as low as 22 percent with 6 or more risk factors. The probability of exceptional (healthy) survival to age 85 years was 55 percent with no risk factors but decreased to 9 percent with 6 or more risk factors

"Anthropometric [measurement and study of the human body and its capacities] measures from this study, such as grip strength, suggest that it is important to be physically robust in midlife. This is consistent with theories of aging that suggest that better-built organisms last longer and that physiological reserve is an important determinant of survival," the authors write. This may also be a marker of physical fitness.

"In summary, we have identified several potentially important risk factors for healthy survival in a large group of middle-aged men. These risk factors can be easily measured in clinical settings and are, for the most part, modifiable. This study suggests that common approaches that target multiple risk factors simultaneously, such as avoidance of smoking or hypertension, and approaches that enhance insulin sensitivity, such as maintaining a lean body weight, may improve the probability of better health at older ages. This may be especially important for men, few of whom survive to oldest-old age," the researchers conclude.

Cool down ? you may live longer

11:20 03 November 2006
NewScientist.com news service
Roxanne Khamsi

The refrigerator is used to lengthen the life of your food, and a new study suggests a similar principle could prolong your life, too.

Researchers have found that lowering the body temperature of mice by just 0.5°C extends their lifespan by around 15%. In the future, people might be able to take a drug to achieve a similar effect on body temperature and enjoy a longer life, they say.

The only previously proven method of significantly increasing the lifespan of an animal has been through a restricted calorie diet.

Bruno Conti at Scripps Research Institute in La Jolla, California, US, and colleagues designed genetically engineered mice with a specific brain-cell defect in a region called the lateral hypothalamus. The defect forces brain cells into "overdrive", causing the region to heat up and become warmer than in a normal mouse.
Female benefit

Since, in mice, the lateral hypothalamus sits just 0.8 millimetres away from the brain’s body-temperature-controlling thermostat – called the preoptic area – it was tricked into thinking its body temperature was too high, causing the mouse to cool down.

The average body temperature of the genetically engineered mice was about 0.6°C lower than that of their control counterparts.

Even this small decrease in body temperature appeared to have a noticeable effect on lifespan, extending their lives by 12% to 20%. And the decrease in body temperature extended the lifespan of female mice more than male mice, the team found, although they are unsure why.
Free radicals

Caloric restriction, another method shown to extend animals’ lives, also causes a decrease in body temperature, Conti notes. In his study, both groups of mice ate about the same amount. In fact, the genetically engineered male mice ended up about 10% heavier than the normal male mice.

Conti says the findings show it is the lowering of body temperature – and not necessarily the consumption of fewer calories – that plays the most important role in extending lifespan.

This may be because the body burns less fuel when it is at a lower temperature, which results in the production of fewer free-radical compounds that damage cells and promote the wear and tear of ageing. Previous studies have shown that worms and fish that have decreased body temperatures live longer.

Conti says that in the future people might be able to take a drug that specifically targets the preoptic “thermostat” area in their brains to trick the body into cooling down slightly. Coming up with such a drug “will be very challenging”, but he hopes it would allow people to live longer without cutting back on the calories.

Journal reference: Science (DOI: 10.1126/science.1132191)

Resveratrol

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature05354.html

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.