|July 2003 |
Zinc deficiency causes DNA damage in lung tissue
A study conducted by University of California Berkeley's Bruce N Ames and his colleagues tested the effects of zinc deficiency in human lung tissue and found increases in oxidative stress, DNA damage and repair, and downregulation of other DNA repair genes. The report was published in the August 2003 issue of the Journal of Nutrition.
The researchers cultured human lung fibroblasts in a zinc deficient medium and exposed a second group of the cells to a zinc chelator in order to render the cells deficient in the mineral. Both methods resulted in a reduction of approximately 50 percent of cellular zinc levels. Gene microarray analysis identified the presence of oxidative stress, upregulation of several genes involved in DNA damage and repair and impairment of other DNA repair genes in both groups of cells. Further investigatory methods showed that deficiency of the mineral caused in increase in oxidant production and a significant amount of single strand breaks in DNA. Expression of the tumor suppressor p53 protein was enhanced. Additionally, zinc deficiency downregulated mitochondrial electron transport chain proteins, which increases oxidant release.
The results of this study show that zinc deficiency causes oxidative stress and DNA damage, while impairing antioxidant defenses as well as DNA repair mechanisms. Dr Ames and his colleagues note the fact that 10 percent of the population in the U.S. consumes less than half of the recommended daily allowance of zinc and suggest that a large portion of the population may be at risk for developing cancer due to DNA damage.
DHEA improves insulin sensitivity and endothelial function
A report published in the July 2003 issue of the Journal of Clinical Endocrinology and Metabolism detailed findings of Japanese researchers that the hormone dehydroepiandrosterone (DHEA), when given to men, improved two physiological functions that decline with age: endothelial function and insulin sensitivity. Dysfunction of the endothelium of the blood vessels is characterized by an impairment of the vessels' ability to dilate, which contributes to cardiovascular disease. Changes in endothelial function may precede the development of insulin resistance. Additionally, studies have demonstrated a relationship between changes in insulin function and cardiovascular disease, and it is well known that decreased insulin sensitivity is associated with aging. Levels of DHEA also decline with age.
The study included twenty-four men with elevated cholesterol levels who were randomized to receive 25 milligrams DHEA or a placebo for twelve weeks. Participants were assessed for endothelial function and had blood samples drawn at the study's onset and at four, eight and twelve weeks. Blood samples were evaluated for plasminogen activator inhibitor type 1 (which increases blood clotting), plasma glucose, insulin and other factors.
Flow-mediated vasodilation of the brachial artery increased significantly over the course of twelve weeks in subjects who received DHEA, while that of the placebo group remained comparable with baseline levels . Plasminogen activator inhibitor type 1 levels were reduced significantly over the course of the study with DHEA supplementation while remaining unchanged in those who did not receive the hormone. While insulin levels did not decline in the DHEA group, fasting plasma glucose levels were lowered, demonstrating increased insulin sensitivity. The combined benefits found to be associated with DHEA in this study could help to minimize the progression of cardiovascular disease or other age-related diseases if the hormone were prescribed to an older population.
Anemia predicts physical decline in older individuals
In the first longitudinal study to reveal the finding, research partly funded by the National Institute on Aging has uncovered a significant association between physical decline in later life and anemia. Anemia, a condition of the blood in which there are too few red blood cells, is diagnosed when blood testing reveals hemoglobin levels lower than 13 grams per deciliter in men and 12 grams per deciliter in women. The condition can result from a deficiency of iron or vitamin B12, or from one of many diseases including cancer and kidney disease. The report was published in the August 1 2003 issue of the American Journal of Medicine.
The Wake Forest University Researchers followed 1,146 men and women aged 71 and older for a four year period, during which three tasks (standing balance, a timed eight-foot walk, and rising from a chair) were assessed. Blood testing provided the subjects' hemoglobin levels which were correlated with the task assessment scores. Participants who were diagnosed with anemia were found to have double the risk of experiencing serious physical decline, and those with borderline anemia experienced 1.5 times the risk of those whose hemoglobin levels were normal.
Research team leader Brenda Penninx, PhD of Wake Forest University School of Medicine in Winston-Salem, North Carolina, commented, "Although no study yet shows that treating anemia in older people reduces the incidence of physical decline, our study certainly suggests that this may be the case. Anemia deserves clinical attention. That's the take home message. Our results suggest that anemia is an independent risk factor for physical decline, which puts older adults at higher risk for nursing home admission, disability and death. Future research should explore whether the treatment of late-life anemia helps preserve physical function."
Omega-3 fatty acids reduce Alzheimer's risk
A prospective study published in the July 2003 issue of Archives of Neurology: a journal of the American Medical Association, found that consuming omega-3 fatty acids and fish was associated with a lower risk of Alzheimer's disease. The study, conducted between 1993 and 2000, included men and women aged 65 to 94 who were participants in the Chicago Health and Aging project. Subjects provided dietary information via food frequency questionnaires 1.9 years following baseline interviews and were contacted at three years for follow-up interviews. At this time, a sampling of 815 subjects was selected for clinical evaluation to determine the incidence of Alzheimer's disease. One hundred thirty-one patients in the sampling were found to have developed the disease.
Of the subjects who reported fish consumption once per week or more frequently there was a 60 percent lower risk of developing Alzheimer's disease compared to those who reported rarely or never eating fish. Individuals whose omega-3 polyunsaturated fatty acid intake was in the top fifth of the participants experienced a 70 percent lower risk of developing Alzheimer's than those whose intake was in the lowest fifth. When the omega-3 fatty acid docosahexaenonic acid (DHA) was examined separately the protective effect against Alzheimer's disease increased with its intake. The same benefit was not observed for the other fish-derived omega-3 fatty acid, EPA, but the authors noted that the range of intake was low and that higher doses obtained from fish oil supplements may have an effect. Since DHA is the most abundant fatty acid in the phospholipids of the cerebrum, and composes 45 to 65 percent of the phosphatidylserine in the mitochondria, which plays a role in neuronal signaling, this may explain some of its protective effects in Alzheimer's disease.
Ibuprofen or aspirin cuts breast cancer risk
The American Association of Cancer Research's annual meeting held in Washington DC was the site of the a presentation on July 13 by Randall Harris, codirector of the Center of Molecular Epidemiology and Environmental Health at Ohio State University, who reconfirmed the protective benefits of the nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and aspirin against breast cancer. A survey of 80,741 postmenopausal participants in the Women's Health Initiative determined whether the women had used NSAIDs and if so, for what length of time, as well as how often they exercised, whether hormone replacement therapy was used, and if there was a family history of cancer.
The researchers found that women who reported using two or more tablets of one the drugs per week for five to nine years experienced a 21 percent lower incidence of breast cancer than women who did not take NSAIDs and that usage for ten or more years conferred a 28 percent reduction. While aspirin use lowered breast cancer risk by 22 percent, ibuprofen cut the risk of the disease by 50 percent.
Dr Harris explained, "We're discovering that these compounds - NSAIDs - aren't just for pain and inflammation relief. This study shows that these drugs also have significant anticancer effects . . . We think that NSAIDs turn off unnecessary inflammation by blocking COX-2. Toning down this kind of dysfunctional, uncontrolled inflammation can block critical steps in tumor development, such as cell division, the growth of new blood vessels and the spread of the tumor to other areas of the body
He added, "There's too much converging and compelling evidence to deny the effects of NSAIDs. Most malignant tumors, including colon, breast, prostate, and lung, appear to be inhibited by NSAID use . . . It's the sustained inhibition of COX-2 that impedes the risk of carcinogenesis."
Meta-analysis shows NSAIDs help prevent Alzheimer's disease
A review of nine studies published in the July 19 2003 issue of the British Medical Journal has found that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) offers some protection against developing Alzheimer's disease. Nonsteroidal anti-inflammatories are a class of drugs used chronically by individuals with arthritis or other painful conditions, and include aspirin and ibuprofen.
The review analyzed studies published between 1966 and October of 2002 that evaluated the NSAIDs' ability to prevent Alzheimer's disease in a total of 14,654 subjects. Studies examining exposure to other pain relievers, or in which vascular dementia was the primary outcome were excluded from the analysis.
The researchers separately analyzed studies that determined Alzheimer's disease risk in users of all NSAIDs, in users of aspirin, and in users of NSAIDs according to duration of use. They found that individuals over the age of 55 who used NSAIDs experienced three-fourths risk of developing the disease than that of subjects not taking the drugs, and that the longer the drugs are used, the greater their benefits appeared to be. When aspirin use alone was evaluated, a small but nonsignificant benefit was found, however, this finding may have been due to the smaller number of studies that specifically evaluated the protective effect of aspirin. The appropriate dose and duration of use of nonsteroidal anti-inflammatories to prevent Alzheimer's disease remains to be determined.
It seems that every few weeks another benefit is revealed for the over-the-counter wonder drug aspirin. This week the July 2003 issue of The Journal of Clinical Investigation has released the findings of researchers at Dartmouth School of Medicine in New Hampshire that the major metabolite of aspirin known as salicylic acid (SAL) helps to combat staphylococcus aureus ("staph") infections by downregulating two of its genes. The compound had previously been shown to reduce the virulence of the bacteria in experimental models of endocarditis (inflammation of the lining of the heart) by an antimicrobial and antiplatelet effect.
Staphylococcus aureus has long been identified as an infectious agent in diseases such as pneumonia, septicemia, endocarditis and abscesses. Due to the emergence of antiobiotic resistant strains of bacteria, intensive antibiotic treatment is often unsuccessful.
Researchers Ambrose Cheung and colleagues discovered that salicylic acid, acting at the level of gene transcription, downregulates the production of fibrinogen, fibronectin, and alpha-hemolysin, which are virulence factors needed for bacteria to adhere to host tissues. This adherence is followed by invasion of the cells and the degradation of the infected tissue. By preventing the ability of staph bacteria to attach to host cells, the infectious process can be prevented.
In an accompanying commentary in the journal, Professor Mathias Herrmann, Director of the Department of Bacteriology and Hygiene at the University of Saarland, Germany stated, "The establishing of a straightforward, unequivocal strategy to downregulate staphylococcal virulence using a cheap, simple, relatively nontoxic, resorbable compound such as SAL may be seen as major progress in the development of intervening strategies in addition to antimicrobial drugs."
Antioxidant amino acid cysteine associated with decreased breast cancer risk
On July 14 2003 at the Annual Meeting of the American Association for Cancer Research, Brigham and Women's Hospital and Harvard Medical School researcher Dr Shumin Zhang reported that plasma levels of the amino acid cysteine are inversely associated with breast cancer risk in women. Cysteine is the precursor of glutathione, which is a part of one of the body's powerful natural antioxidants, glutathione peroxidase. A precursor of cysteine is N-acetyl-cysteine, another strong antioxidant.
The investigation, led by Dr Zhang, involved participants in the Nurses' Health study which enrolled 32,826 women beginning in 1976 at Brigham and Women's Hospital and is the longest running women's health study in history. Seven hundred twelve participants diagnosed with breast cancer were matched to an equal number of participants without the disease according to age, time of day blood was drawn, menopausal status, use of hormone replacement and other factors. Blood testing provided plasma cysteine levels. The investigators found that women whose plasma cysteine was in the highest group had a 56 percent lower risk of breast cancer than those whose cysteine levels fell into the lowest group. This association did not change when other major breast cancer risk factors were analyzed with the exception of a stronger association among lean women. Dr Zhang concluded, "The findings suggest that higher levels of total cysteine may predict a reduced risk for breast cancer. Based on these results, we are hopeful that cysteine or its precursors may have potential chemopreventive benefits against breast cancer."
The American Cancer Society predicts that 40,000 women will die of breast cancer in the U.S. this year.
International Liaison Committee on Resuscitation recommends hypothermia after cardiac arrest
The July 8 2003 issue of the American Heart Association journal Circulation published an advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation, which recommends the following:
"Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32 degress Celsius to 34 degrees Celsius for 12 to 24 hours when the initial rhythm was ventricular fibrillation.
Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest."
The advisory statement was the result of the committee's review of published evidence to date, including randomized trials conducted in Europe and Australia, demonstrating improved neurologic outcome in cardiac arrest due to ventricular fibrillation. Ventricular fibrillation is the rapid fluttering contractions of the heart's lower chambers that can result in a cessation of heart beat. Although studies have shown that these patients may gain the greatest benefit from hypothermia, other evidence has shown that cardiac arrest survivors from other causes may benefit as well.
The authors provide several possible mechanisms of action for hypothermia's protective benefit to cardiac arrest patients, including reduced cerebral metabolic rate for oxygen, and suppression of free radical production, excitatory amino acid release and calcium shifts. They recommend cooling the patient as soon as possible after the return of spontaneous circulation but note that the therapy has shown success even if delayed four to six hours. More research is needed to determine the optimal duration of the procedure as well as the best target temperature. The benefits of hypothermia may become greater as better techniques become available. (Nolan JP et al, "Therapeutic hypothermia after cardiac arrest," Circulation July 8 2003, pp 118-121.)
Polyphenols lower IGF-1 stimulated prostate cancer cell growth
The July 2003 issue of the Journal of Nutrition published the findings of researchers from Ohio State University College of Medicine and Public Health that the polyphenols geinstein, daidzein, and biochanin A from soy, and quercetin, kaempferol and rutin from tomatoes modulated prostate cancer induced by insulin-like growth factor-1 (IGF-1) in a rat cancer cell line. Elevations of IGF-1 have been linked with increased prostate cancer risk in several epidemiologic studies, and may be a key stimulate of prostate carinogensis. Other studies have found consumption of tomatoes and soy to be associated with a lower incidence of prostate cancer, and feeding soy isoflavones to mice has slowed prostate cancer progression.
When administered to the cells in a concentration of 50 micrograms per liter, IGF-1 produced maximum proliferation of the cancer cells and lowered the amount of apoptosis, or programmed cell death. Genistein, quercetin, kaempferol and biochanin A inhibited the IGF-stimulated growth of the cancer cells dose-dependently, as well as counteracting IGF-1's antiapoptotic effects. When tested on a human prostate epithelial cell line, these four polyphenols were also effective at inhibiting growth, while daidzein's and rutin's actions were minimal. Cell cycle progression, which was stimulated by IGF-1, was arrested by geinstein and kaempferol. The researchers found that the polyphenols tested in this investigation targeted components of the IGF-1 signaling cascade involving tyrosine kinase activity, each acting in a slightly different manner. They announce that these studies are the first to their knowledge to show that IGF-1-regulated events in prostate cancer cells are blocked by polyphenols, and write, "tomato and soy products provide a diverse array of compounds that together, over a long period of dietary exposure, may provide an important opportunity to slow prostate carcinogenesis." (Wang S, DeGroff VL, Clinton SK, "Tomato and soy polyphenols reduce insulin-like growth factor-1-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase," J Nutr, Jul 2003, pp 2367-2376)
Depression genes linked with shorter lifespan
Research funded by the National Institute of Mental Health, published in the American Journal of Medical Genetics, has determined the location on human chromosomes of areas that control depression and some addictions. University of Pittsburgh researchers studied the genome of eighty-one families with members diagnosed with recurrent, early-onset major depressive disorder. They found nineteen loci that influenced depressive disorders. They also found that deceased members of the families died eight years earlier than average, with more than forty percent not surviving to age sixty-five. The mortality difference was spread across lifespan and included deaths several times the average from liver disease, suicide and homicide. The number of children who died in their first year was five times that of the general population. However, the majority of early deaths were from such common causes as heart disease, stroke and cancer.
Team leader and University of Pittsburgh School of Medicine professor of psychiatry George S. Zubenko, MD, PhD, commented, "Tracking down the risk genes in these regions is an obvious priority, and we expect that the research will connect clinical depression and other medical disorders at their most fundamental levels. The identification and characterization of susceptibility genes and their products will provide new opportunities for drug development and disease prevention, new information about the biology of mood and its regulation, and new insights into the interactions of mental illness and the human life span. Genotyping markers in chromosomal regions that harbor susceptibility genes may provide more immediate advances in the treatment of major depression. For example, individuals with particular genetic markers in these regions may respond better to particular current treatments than others. This strategy may enable clinicians to use genetic markers to better match individual patients to treatments to which they will optimally respond, while minimizing side effects."
Two hundred longevity genes identified
In an advance, online publication, the journal Nature reported the results of research from the lab of University of California San Francisco professor of biochemistry Cynthia Kenyon that uncovered two hundred genes influencing longevity that flow from one mutation: a change in the daf-2 gene. Previous research by Dr Kenyon revealed that a mutation in the daf-2 gene, which encodes a receptor similar to the human receptors for the hormones insulin and IGF-1, caused a doubling of the worm C elegans' lifespan. Daf-2 affects lifespan through another gene, daf-16, which controls a number of other genes. The current research found that this mutation acts by influencing antimicrobial genes, metabolic genes and genes that control the stress response in cells, and by hindering genes that shorten lifespan.
Dr Kenyon and colleagues used a technique called RNA interference to partially disable one gene at a time, leading them to discover that no single gene by itself determined lifespan. Dr Kenyon explained, "This study tells us that there many genes that affect lifespan, each on its own having only a small effect. The beauty of the daf-2 gene is that it can bring all of these genes together into a common regulatory circuit. This allows it to produce these enormous effects on lifespan . . . The diversity of these lifespan gene functions is just remarkable. The marvelous thing about this new study is that it provides an explanation not only for the remarkable longevity of these animals, but also for their ability to stay healthy so long. They just turn up the expression of many, many different genes, each of which helps out in its own way. The consequences are stunning, and if we can figure out a way to copy these effects in humans, we might all be able to live very healthy long lives. "