MIT researcher reports oxygen free radicals don’t cause aging

MIT researchers reported in Nature results that counter the idea that oxygen free radicals cause aging, instead that calorie restriction prolongs life because it increases respiration, not because it decreases oxygen free radicals.

MIT biologist Leonard Guarente believes “the conventional wisdom on oxygen radicals is dead wrong. Our results (in yeast) are contrary to the frequent suggestion that calorie restriction functions by slowing metabolism and thereby slowing the generation of free radicals.”

Guarente, who is working on a book on aging to be published this fall, discovered in 2000 that calorie restriction activates the silenced information regulator (SIR2) gene, which has the apparent ability to slow aging. This gene makes a protein called Sir2, which Guarente has shown is integrally tied to extending life span in yeast and in the roundworm. Humans carry a similar gene.

Rather than a slower metabolism leading to a slower rate of respiration, it turns out that respiration in yeast cells under calorie restriction goes up, not down. “The increase in anti-oxidant enzymes that is reported to occur during calorie restriction in animals may be a result of an increase in respiration rather than a cause of the observed longevity,” Guarente said.

“A high respiration rate is intimately connected with calorie restriction in yeast,” he said. “A high respiration rate activates SIR2. When respiration goes up, NAD (nicotinamide adenine dinucleotide, a co-enzyme that activates SIR2) goes up and SIR2 goes up. When SIR2 goes up, longevity happens.”

A MIRACLE PILL

The prospect of a possible future drug seems too good to be true: Lose weight and live longer. Guarente’s aim is just such a drug.

Calorie restriction extends life span in a wide spectrum of organisms. It is the only regimen known to lengthen the life span of mammals such as mice and rats. One conventional theory for why this works is that to conserve energy and live within the means of limited food intake, the organism’s metabolism slows down.

Because a 30 percent reduction in calories is too difficult for most people to maintain, Guarente hopes to find the knowledge that would allow a pharmacological “trick” to make the organism think that it is calorie-restricted even when it is not. The hoped-for result is that this will trigger longevity.

DIVERTING ENERGY

When a yeast cell metabolizes food, the process can lead to respiration or fermentation, both of which supply the cell with energy.
When there is plenty of food available, yeast cells prefer to use food for fermentation. When food is scarce, the cell opts for respiration. Guarente found that this metabolic shift toward respiration increases SIR2’s activity and thus life span, just as calorie restriction does.

In mammals, excess carbon is used to make fatty acids and store carbohydrates. If there is a way to mimic this metabolic shift in humans, it would mean that more food would be used for respiration and less would be stored as fat. The result? We could live longer and be thinner.

THE CULPRIT BEHIND AGING

Studies have suggested that calorie restriction slows aging primarily because it decreases oxygen free radicals. Oxygen free radicals are byproducts of oxidation, the body’s process of turning oxygen into energy.

Free radicals are thought to be toxic, causing damage to DNA and cells. Although antioxidants “clean up” free radicals, this process becomes more inefficient as we age. Many scientists speculate that free radical damage is the primary culprit behind age-related diseases and the symptoms of aging.

Contrary to these previous findings, Guarente says in the current paper that oxygen free radicals do not limit the reproductive life span of yeast and are not central to the extension of life span by calorie restriction.

Co-authors for the paper are Su-Ju Lin, Matt Kaeberlein, Pierre-Antoine Defossez of the MIT Department of Biology; biology graduate student Alex A. Andalis and MIT Professor of Biology Gerald Fink of the Whitehead Institute for Biomedical Research and Lori A. Sturtz and Valerie C. Culotta of the Johns Hopkins School of Public Health.
This work is supported by the National Institutes of Health, the Ellison Medical Foundation, the Seaver Institute and the Howard and Linda Stern Fund.

——————————————————————–

Article adapted by MD Only from original press release.

——————————————————————–

Contact: Deborah Halber
MIT News.

Acne meds linked to higher cholesterol

By CHRISTINE DELL’AMORE
UPI Consumer Health Correspondent

In an observational study, researchers found people who take a particular acne medication had higher cholesterol levels than previously thought, although doctors point out the side effects are easily reversible.

Teenagers and adults who took the medication isoretinoin, marketed as Acutane, had elevations in total cholesterol; triglycerides, or blood fats, which lead to cardiovascular disease; and increases in liver enzymes, which can create liver problems.

“Isoretinoin is undeniably the most effective medication we have for treating severe acne, and it can truly be a life-changing medication for people whose acne affects them greatly,” said lead author Dr. Lee T. Zane, an assistant professor of clinical dermatology at the University of California, San Francisco.

“It’s not a cause for concern until we work out the clinical outcomes.”
The study, published in the August issue of the Archives of Dermatology, a JAMA/Archives journal, is the largest population-based study to date to look at laboratory abnormalities in patients on isotretinoin therapy.

Past studies have shown patients on isoretinoin have elevated triglycerides and liver enzymes, but at lower incidence rates. Other side effects such as pancreatitis and leukopenia, a decrease in circulating white blood cells in the bloodstream, have been reported.

Because the study was not an experiment, it does not prove whether isoretinoin actually caused these side effects, or if it was something else that accounted for the results.

The team wanted to observe how a large number of isoretinoin patients are managed in a typical way by practitioners on the job. They did not focus on how these results could be translated into actual health problems, such as cardiovascular disease.

Zane and colleagues studied records of 13,772 men and women aged 13 to 50 — average age 19 — who were taking oral isotretinoin between 1995 and 2002. The researchers did not record their ethnicity.

The team analyzed laboratory tests taken from the patients before, during and after their treatment with isoretinoin. They measured the amount of trigyclerides, total cholesterol, liver transaminase levels and other blood indicators.

The amount of abnormalities in hermatoligic parameters, which could be precursors of blood disease, did not change over the course of the study.

Zane found the patients taking the acne treatment had substantial abnormalities over time in their cholesterol and liver readings.

Of the total group, 10,656 had normal triglycerides at the start of the study, versus 6,035 with normal readings while on treatment. Likewise, 9,154 of the participants had normal total cholesterol readings at the study’s start; 5,729 had normal readings during treatment.

Overall, 44 percent of the isoretinoin patients had high trigyclerides, 31 percent had high total cholesterol and 11 percent had elevated liver values.

The package insert for Acutane, manufactured by Roche, indicates that approximately 25 percent of users experience higher triglyceride levels, and 15 percent have higher liver enzymes.

Scientists aren’t exactly sure why isoretinoin is linked to higher cholesterol and liver enzymes, Zane said.

As the gold standard for acne treatment, isoretinoin’s long-term acne remission rates are as high as 89 percent, the authors wrote. That’s why “we have to keep the safety issue in perspective, and balance it against the benefits,” Zane said.

As a precaution, most doctors now recommend their patients to undergo frequent laboratory testing while on isoretinoin treatment.

Dr. Stephen Stone, president of the American Academy of Dermatology, said the “overwhelming majority” of dermatologists follow their patients’ laboratory results closely. Side effects reported by Zane and colleagues have been known about and monitored for years, and “doesn’t really represent a danger to the patient,” Stone said.
“What this study tells us is it might be more common than we thought,” he said.
The cholesterol effects, at least, are quickly reversible, either by lowering the dosage of the medication, modifying diet, or in some cases recommending the patient take a cholesterol-lowering statin.

A past study suggested elevated triglycerides of teens on isoretinoin may uncover a genetic predisposition to high cholesterol in later years. Physicians may want to use such a situation as an opportunity to talk to parents about the child’s possible risk later on, said Dr. Diane Thiboutot, professor of dermatology at Penn State University College of Medicine in Hershey, Penn.

In addition, other factors could explain the results, Zane said.

For one, the diet of the patients could have influenced the laboratory analyses: It’s possible the patients did not always fast before their blood was drawn for triglyceride tests.

The next step will be to examine the clinical relevance of these side effects, and see if they lead to harmful diseases, Zane said.

Reprinted from UPI.com, in the “Consumer Health Daily – Reports” section.

Copyright © 2006 UPI. Displayed by permission. All rights reserved. UPI.com logo is a registered trademark of UPI. The iCopyright logo is a registered trademark of iCopyright, Inc.

Active Ingredient in Chinese Herb Used to Reduce High Blood Pressure

Some 50 million Americans have hypertension, that is, blood pressure measuring above the normal range (less than 120/80 mmHg). If untreated, it can lead to heart attacks, strokes, or kidney disease. Lifestyle changes are the first-stage treatment for the disease, but if they fail, medications are prescribed.

Many patients with high blood pressure have sought relief from complementary and alternative medicine (CAM). In so doing, many have consumed danshen, a Chinese herb used in Oriental medicine that promotes blood flow and treats cardiovascular disease.

Tanshinone IIA is an active ingredient of danshen. Since tanshinone IIA is widely available, a team of researchers has used it to investigate if this active ingredient can reduce blood pressure. In a soon-to-be-released study, using an animal model, the scientists have found that tanshinone IIA does reduce blood pressure.

Summary of Methodology

To assess the effect of tanshinone IIA, the protocol consisted of several parts. The researchers applied the 2-kidney-1-clip protocol to induce renal hypertension in male golden Syrian hamsters. The animals were anesthetized and a retroperitoneal approach was used to place a silver clip to constrict the right renal artery. Sham-operated hamsters and mice underwent the same procedure, except for the placement of a clip.

Both sets of hamsters received 50 ¦Ìg of tanshinone IIA/100g of body weight once a day for two weeks. After the two-week treatment period, mean arterial blood pressure was measured in the right carotid artery. To examine the microvascular actions of tanshinone IIA researchers applied it topically to the hamsters¡¯ cheek pouch or mice cremaster muscles to achieve the final concentration of one ¦Ìg/ml or five ¦Ìg/ml. After the application of tanshinone IIA, the experiment was continued for an additional 60-minute period in order to measure arteriolar diameter and peri-arteriolar nitric oxide concentration.

Results

Tanshinone IIA was found to have significantly reduced blood pressure in the hamsters. The experimental constriction of the renal artery increased mean arterial pressure to 161.2¡À6.9 mmHg relative to 114.3¡À9.2 mmHg in age-matched hamsters. Treatment with 50 ¦Ìg tanshinone IIA/100g body for two weeks reduced the mean arterial pressure from 161.2¡À6.9 to 130.0¡À7.8 mmHg.

The research team also discovered that tanshinone IIA caused widening of the arterioles in the hamster cheek pouch microcirculation via enhanced expression of endothelial nitric oxide synthase. The topical application of tanshinone IIA at one ¦Ìg/ml and five ¦Ìg/ml caused significant dose-related vasodilation, indicated by the increased agent/control ratio of arteriolar diameters from 1.0 to 1.25¡À0.08 and 1.57¡À0.11, respectively, in the hamster cheek pouch. The increase in arteriolar diameter ratio was significant relative to the vehicle for each concentration as well as for comparison between the two concentrations of tanshinone IIA.

Conclusions

As a result of the findings the researchers concluded that tanshinone IIA: (1) significantly reduced blood pressure in hamsters, (2) enhanced the expression of endothelial nitric oxide synthase, (3) increased the production of nitric oxide and (4) induced blood pressure changes through vasodilation in hamster blood microvessels. While the mechanisms of how tanshinone IIA or danshen work in hypertension are not yet fully understood, these results contribute to the effort to bring complementary and alternative medicine and allopathic care closer together in the treatment of hypertensive patients.

—————————-
Article adapted by MD Only from original press release.
—————————-

Contact: Donna Krupa
American Physiological Society

Their study will soon be published in the American Journal of Physiology ¨C Heart and Circulatory Physiology (December 15, 2006), doi:10.1152/ajpheart.01027.2006, and is entitled Endothelial Nitric Oxide Synthase is a Molecular Vascular Target for the Chinese Herb Danshen in Hypertension. It was conducted by the team of David D. Kim, PhD, OMD; Fabiola A. S¨¢nchez, PhD; Ricardo G. Dur¨¢n, BS; Takehito Kanetaka, MD; and Walter N. Dur¨¢n, PhD, all of the Program in Vascular Biology, Department of Pharmacology and Physiology and Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ.

JOURNAL PUBLICATION INFORMATION: American Journal of Physiology ¨C Heart and Circulatory Physiology Articles in Press, doi: 10.1152/ajpheart.01027.2006.

Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS) has been an integral part of this scientific discovery process since it was established in 1887.