Gene that causes premature aging identified
The May 1 2004 issue of the journal Genes and Development reported the findings of researchers from Johns Hopkins Kimmel Cancer Center of a gene mutation that causes premature aging.
Johns Hopkins Director of Pediatric Oncology, Robert Areci MD, and colleagues had previously discovered that the Proliferation Associated SNF2-like Gene (PASG) is involved in cell growth, and that mutated forms of the gene are found in acute leukemias. When not mutated, PASG decreases the activity of other genes by aiding methylation or by modifying protein structures known as histones.
In the current study, mice were genetically engineered with a knocked out portion of the PASG gene, which decreased methylation throughout the genome and activated genes associated with premature aging. The mice experienced low birth weight, growth problems, and early aging signs such as gray hair, hair loss, skeletal abnormalities, reduced fat and premature death.
Dr Areci elaborated, "In order to grow and stay alive, cells depend on the PASG gene to reduce the activity of other genes, but it's a very complicated process - much like modifying the engine of an F-15 fighter jet while it's flying. To keep body tissues working correctly, the PASG gene appears to help cells regenerate, mature and prevent early aging. Each cell is programmed with a set number of replications before it dies. With a mutated PASG gene, the cell may replicate only a fraction of the time, and then it dies prematurely. If PASG's methylation activity could be blocked in human cancer cells, we could potentially cause them to age faster and die earlier. “
Curcumin corrects cystic fibrosis defect
In a report published in the April 23 2004 issue of Science, researchers at Yale University and the Hospital for Sick Children in Toronto discovered that curcumin, a compound found in the spice turmeric, corrects the defect in cystic fibrosis the leads to the manifestation of the disease. Cystic fibrosis is an inherited disease that is caused in the majority of cases by a mutation in the Delta-F508 gene that subsequently produces a misfolded Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein. This leads to failure of the CFTR, a chloride channel that transports chloride ions and water in and out of the cell, to reach its place on the cell surface. The result is a disease characterized by an overproduction of thick mucus which clogs the lungs and gastrointestinal tract, which ultimately leads to respiratory failure and premature death.
The research team, led by Yale professors Michael Caplan, MD and Marie Egan, MD, found that the Delta-F508 defect is corrected in tissue culture by administration of curcumin, which releases the CFTR protein from its inappropriate compartment within the cell and allows the CFTR to move to the cell surface. When the compound was tested in mice with the genetic defect, nasal and rectal epithelia regained near normal function and the mice survived nearly as long as normal mice.
Dr Caplan commented, “While these data are very encouraging, it is much too early to say whether curcumin will offer an effective treatment for most people with CF. In the next phase of this research, we will work to determine precisely how curcumin is achieving these effects and to optimize its potential as a possible drug. Plans are underway for a human clinical trial of curcumin, which will be carried out under the auspices of Cystic Fibrosis Foundation Therapeutics, Inc."
Iron supplements improve cognitive function in young women
In yet another presentation of interest at the Experimental Biology 2004 meeting, researchers from Pennsylvania State University revealed that iron supplements improved cognitive function in iron deficient women between the ages of 18 to 35. Iron deficiency and anemia are estimated to effect 9 to 11 percent of women during their reproductive years and in nonindustrialized countries the figure jumps to 40 percent of nonpregnant and 50 percent of pregnant women.
The study, presented by Dr Laura Murray-Kolb, a postdoctoral fellow in the lab of Dr. John Beard, enrolled 149 women who were iron sufficient, iron deficient without anemia, or anemic. At the beginning of the study cognitive function tests were administered, and health history assessed. One hundred thirteen women completed the four month treatment period during which they received 60 milligrams iron or placebo, and were retested upon completion.
The initial testing found that iron deficient women completed the tasks in the same amount of time as those whose iron levels were sufficient, but they performed more poorly on the tests. Anemic women also performed more poorly and took longer to do so. A greater degree of anemia was correlated with longer time for task completion. At the completion of the study it was found that iron supplementation significantly improved scores of memory, attention, learning, and task completion time among iron deficient as well as anemic women.
This study is the first to systematically examine the effect of iron supplements on cognitive functioning in young women. Additionally, the findings are important because they demonstrate the effects on memory, attention and learning of iron deficiency that has not progressed to anemia. It has recently been found that many organs experience an impairment of function when iron becomes deficient, before there is a drop in iron hemoglobin levels that is diagnostic of anemia.
Phenolic compounds slow breast cancer cell growth
In more news from the Experimental Biology 2004 meeting, held April 17 to 21 in Washington, DC, S. Pinheiro-Silva, I. Azevedo, and C. Calhau from the Universidade do Porto, in Portugal have shown that the phenolic phytochemicals epigallocatechin gallate (EGCG), xanthohumol, and resveratrol slow breast cancer growth in human cell cultures. The compounds are found in tea, beer, and wine respectively, a fact that appears to contradict the results of previous research that established an association between alcohol consumption and an increased risk of breast cancer in women. However, the researchers caution that the findings of this study do not suggest that women increase alcohol consumption.
The Portuguese team cultured breast cancer cells in the presence of varying concentrations of EGCG, xanthohumol and resveratrol for various periods of time. At the end of each treatment period the number of cells and the ratio between dead and live cells was calculated. In other experiments, 3H-thymidine incorporation was evaluated, which measured the effect of each treatment on DNA synthesis.
It was discovered that all of the compounds possessed an inhibitory effect on breast cancer cell growth, with xanthohumol eliciting an antiproliferative effect more rapidly and at a lower concentration than the other compounds. Although EGCG demonstrated the lowest potency of the compounds tested, it also showed the least cytotoxicity , meaning that it can be administered in higher doses. A decrease in 3H-thymidine incorporation was also observed in the presence of the phenolic compounds.
The authors conclude that the findings support epidemiological studies that relate consumption of specific beverages with a lesser incidence of cancer and that clinical studies are needed to support recommending the compounds as cancer preventives.
Tea polyphenols slow prostate cancer cell growth
In the first study of its kind to determine the absorption and antitumor effects of tea polyphenols in human tissue, researchers from the University of California, Los Angeles found tea polyphenols in prostate tissue when subjects consumed tea for only a short amount of time. Polyphenols are the compounds in tea that have been found to be responsible for the many health benefits of the drink. The findings were reported at the Experimental Biology 2004 meeting held this year in Washington, DC.
Twenty prostate cancer patients scheduled for radical prostatectomy were administered five cups of green tea, five cups of black tea, or soda containing no polyphenols for five days. Blood was collected before and after the treatment period and serum added to prostate cancer cell line samples. Following the surgeries, polyphenols were detected in all of the prostates excised from men who received black tea, six out of eight of the prostates taken from men who received green tea, and in two out of five of those who received soda (which may have been because they were consuming chocolate or tea before the study). Serum obtained from participants after five days of drinking tea was associated with slower growth when added to the prostate cancer cell cultures compared to serum obtained before the treatment period. No reduction in cancer cell growth was observed when serum from men who drank soda for five days was administered to prostate cells.
Additionally, levels of polyamines, which have been associated with malignancy in humans, were found to be negatively correlated in the prostate with the presence of tea polyphenols .
Lead author Dr Susanne Henning, of the UCLA Center for Human Nutrition, believes that these findings suggest that black and green tea are promising dietary supplements for the prevention of prostate cancer.
Calorie restriction prevents atherosclerosis in humans
In a study to be published this week in the online edition of the Proceedings of the National Academy of Sciences, researchers from Washington University School of Medicine in St Louis, Missouri found that individuals who follow a calorie restricted diet have a lower risk of atherosclerosis, the build-up of fatty plaques in the arteries that can lead to heart attack and stroke, than those who eat an average American diet.
John Holloszy and colleagues studied eighteen members of the Calorie Restriction with Optimal Nutrition (CRON) society, who had been restricting their calorie intake to an average of two-thirds that of the “normal' American diet for three to fifteen years. By comparing them to eighteen individuals who consumed an average diet, the researchers found lower body mass index, percent body fat, blood pressure (systolic and diastolic), total cholesterol, low density lipoprotein cholesterol, total cholesterol to HDL cholesterol, triglycerides, fasting glucose, fasting insulin, serum platelet-derived growth factorAB, and C-reactive protein levels in the calorie restricted group. Additionally, high-density lipoprotein levels were greater in the calorie restricted subjects. Ultrasonographic examination of the carotid arteries of both groups revealed that the calorie restricted group had no thickening of the intima-media (a measure of atherosclerotic plaque). The average carotid artery intima-media thickness of the calorie restricted group was 40 percent less than that of the comparison group.
The study demonstrates that long-term calorie restriction exerts significant beneficial effects on the major risk factors for atherosclerosis. The reduction in C-reactive protein levels observed in calorie-restricted humans also provides evidence that the diet decreases inflammation, a finding previously revealed by several animal studies. In addition, the low plasma insulin and serum platelet-derived growth factor levels exhibited by the calorie restricted group suggest that the diet may provide a decreased stimulus for the cell proliferation involved in atherosclerosis.
Estrogen alone not good either
A study published in the April 14 2004 issue of The Journal of the American Medical Association found that with the exception of decreasing hip fracture risk, estrogen taken alone failed to benefit postmenopausal women who had undergone hysterectomies, and can increase the risk of stroke and deep vein thrombosis. The study was part of the Women's Health Initiative clinical trials which previously found that estrogen in combination with progestin increased the risk of coronary heart disease, stroke and breast cancer in postmenopausal women.
The current double-blind, placebo-controlled trial randomized 10,739 postmenopausal women with prior hysterectomy to receive 0.625 milligrams per day conjugated equine estrogens (CEE, marketed as Premarin) or a placebo. The trial began in 1993 and was to have ended in March 2005 but, like the estrogen-progestin trial, was halted early, due to the increased risk of stroke and the failure of the hormone to prevent coronary heart disease, one of the major questions the current study sought to answer. Estrogen therapy increased the risk of stroke by 39 percent and deep vein thrombosis by 47 percent in this study.
The authors of the report conclude, "Based on these findings, women and their health care professionals now have usable risk estimates for the benefits and harms of CEE alone. Women considering taking CEE should be counseled about an increased risk of stroke but can be reassured about no excess risk of heart disease or breast cancer for at least 6.8 years of use. At present, these data demonstrate no overall benefit of CEE for chronic disease prevention in postmenopausal women and thus argue against its use in this setting. Overall, these data support the current U.S. Food and Drug Administration recommendations for postmenopausal women to use CEE only for menopausal symptoms at the smallest effective dose for the shortest possible time. “
Glucosamine okay for early-stage diabetics
Because animal studies have demonstrated that glucosamine administered by injection can elevate blood glucose levels, The Physician's Desk Reference for Nonprescription Drugs and Dietary Supplements warns against glucosamine use by diabetic patients. A study published in the July 14 2003 issue of the Archives of Internal Medicine found that oral glucosamine supplementation did not result in significant alternations of glucose metabolism in type 2 diabetics, however a letter published in the April 12 2004 issue cautions that the findings may not be valid for late-stage diabetics.
Glucosamine is a popular and effective nonprescription treatment for arthritis that contains a molecule of glucose, the form of sugar found in the blood, which is elevated in patients who have type 2 diabetes .
In a double-blind, randomized trial, researchers provided twenty-two diabetics with 1500 milligrams glucosamine hydrochloride and 1200 milligrams chondroitin sulfate and twelve with a placebo daily for ninety days. Glycosylated hemoglobin, a blood test that reflects glucose control, was measured before and after the treatment period. The team found no significant difference between in glycosylated hemoglobin levels between the two groups, and little in the way of adverse reaction to glucosamine-chondroitin .
The authors of the letter in the current issue of the journal note that 18 percent of the diabetics in the study controlled their diabetes by dietary means, and that the lack of an effect of glucosamine on glycemic control could be explained by an increase in endogenous insulin. Patients whose diabetes has progressed to a later stage may not have the same ability to increase insulin secretion, and may not therefore be able to use glucosamine without some concern over its effect on glycemic control. The authors suggest repeating the experiment across a wider spectrum of diabetic patients in order to validate this osteoarthritis treatment option for individuals with diabetes.
Elevated insulin levels linked with colorectal cancer
Research over the past twenty years has found similar risk factors for both diabetes and colorectal cancer, such as lack of exercise, high body mass index, and diets high in refined carbohydrates and calories. A study published in the April 7 2004 issue of the Journal of the National Cancer Institute has identified yet another risk factor common to both diseases: elevations of the blood indicator of insulin production known as plasma-C-peptide.
Jing Ma, MD, PhD, of the Brigham and Women's Hospital in Boston, and colleagues analyzed the plasma C-peptide levels of 294 healthy men and 176 men with colorectal cancer who took part in the Physician's Health Study. The team discovered that hyperinsulinemia , as indicated by an elevation in C-peptide, was associated with an increase in the incidence of colorectal cancer, independent of other risk factors. Adjusted analysis of the data found that men in the top fifth of C-peptide levels had 3.4 times the risk of developing colorectal cancer than men whose C-peptide levels were in the lowest fifth. The association of C-peptide levels with colorectal cancer risk was stronger among those who drank alcohol frequently than in those who consumed it less frequently, suggesting that alcohol may enhance the insulin sensitivity of colorectal epithelial tissue.
The authors conclude, "Our data not only support the hypothesis that elevated long-term insulin production is one underlying mechanism to link dietary and lifestyle risk factors with colorectal cancer risk but also provide a strong biologic argument that avoiding or reducing the modifiable risk factors, such as being overweight, being physically inactive, and following the Western dietary pattern, could effectively decrease the risk of colorectal cancer and the risk of type 2 diabetes and cardiovascular disease., especially when the global prevalence of obesity is increasing rapidly.” (Ma J et al, “A Prospective study of plasma C-peptide and colorectal cancer risk in men,” JNCI 96:7 p 546-553.)
Zinc supplements improve ADHD treatment
A study published in BioMedCentral Psychiatry this week has revealed that supplementing with zinc may improve drug treatment for attention deficit hyperactivity disorder (ADHD). Attention deficit hyperactivity disorder affects approximately one out of twenty-five school aged children, and is commonly treated with stimulants, such as methylphenidate, otherwise known as Ritalin. To the researchers, knowledge, the current study is the first double-blind placebo controlled clinical trial to evaluate the adjunctive role of zinc in the treatment of ADHD.
Researchers at Tehran University of Medial Sciences in Iran studied forty-four children diagnosed with ADHD at Roozbeh Psychiatric Hospital in Tehran who had not previously received previous drug treatment. Half the group was administered Ritalin along with a placebo, while the other half was treated with Ritalin and 55 milligrams zinc sulfate (containing 15 milligrams elemental zinc) for six weeks. Symptoms of ADHD were rated by the children's parents and teachers at the beginning of the study and at weeks two, four and six.
Over the course of the trial, parent and teacher rating scale scores improved for both groups of children, but more markedly for the children treated with zinc. With the exception of nausea and a metallic taste reported by more children in the group who received zinc sulfate, side effects were similar between the two groups.
Zinc is needed for the production of melatonin which helps to regulate dopamine function. Dopamine signaling plays a role in feelings of pleasure and reward and is believed to be a factor in attention deficit disorder and its treatment. The authors write, "The efficacy of zinc sulphate to increase the rate of improvement in children seems to support the role of zinc deficiency in the pathogenesis of ADHD. “
New study finds aspirin not associated with pancreatic cancer
In contrast with a study published in the January 7 2004 Journal of the National Cancer Institute ( http://jncicancerspectrum.oupjournals.org/ ) which found an association between regular long-term aspirin use and the development of pancreatic cancer in women enrolled in the Nurse's Health Study, a new study published in the JNCI found no association between aspirin use and mortality from the disease.
Eric J. Jacobs, PhD, and colleagues at the American Cancer Society, analyzed data from 987,590 participants in the United States Cancer Prevention Study II (CPS-II). Data obtained from this study had earlier determined a reduced risk of colon, stomach, and esophageal cancer mortality associated with aspirin use among its 1,184,588 participants. Questionnaires administered at the beginning of the study in 1982 provided information concerning frequency and duration of aspirin use as well as behavioral, environmental, occupational and dietary factors. Deaths were ascertained at various points throughout the eighteen-year follow up period, and causes of death verified.
Over the follow-up period, pancreatic cancer claimed the lives of 2,434 male and 2,143 female CPS II participants. No association between aspirin use and pancreatic cancer mortality, either positive or negative, was found among the group, even among those who had used aspirin for two decades or more or for fifteen or more times per month. The results were the similar for both men and women.
The current analysis was significant because of its large size and the results provide important evidence in favor of the lack of an association between pancreatic cancer and aspirin use, which should help reassure those who are taking aspirin on a long term basis.
Reduced vitamin B12 levels correlate with poor memory in those at risk for Alzheimer's disease
In a study published in the April 2004 issue of the American Psychological Association journal, Neuropsychology, healthy individuals who carry the e4 allele version of the gene for apolipoprotein E (e4 ApoE ) were found to perform more poorly on memory tests if their levels of vitamin B12 were low compared to those with higher levels of the vitamin. The genoptype, carried by an estimated 15 percent of the population, is a risk factor for dementia, with 25 percent of carriers with one copy of the allele going on to develop Alzheimer's disease.
David Bunce , PhD, of Goldsmith's College, University of London, Miia Kivipelto, PhD, MD, of the Aging Research Center at the Karolinska Institute in Stockholm, and Åke Wahlin, PhD, of the University of Stockholm, sought to determine how the additional challenge of low levels of vitamin B12 affected carriers of the genotype. The study involved 167 participants in a large project that followed community-dwellers in Stockholm, Sweden, age 75 and older. In the current study, blood samples were analyzed for the gene and for vitamin B12 levels. Half of the participants were found to have low levels of the vitamin. Analysis of the results of the subjects' memory tests revealed that among those who carried the gene, individuals with normal levels of B12 recalled a greater number of words and performed better in other tests related to episodic memory than those who had low levels of the vitamin. In the most demanding test, the genotype plus low levels of vitamin B12 were significantly associated with lower performance.
The authors stated "є4 ApoE carriers may derive relatively greater cognitive benefits from B12 and folate supplements. Supplement treatment is relatively inexpensive and may be required as part of preventive health regimes for older persons."
Calcium from food alone offers little protection against fracture risk
A meta-analysis of studies on the benefit of calcium obtained from one's diet conducted by researchers at the University of Newcastle in Australia has failed to find a benefit for the mineral in reducing the risk of hip fractures. The results were published in the April 2004 issue of the British Journal of Nutrition.
The researchers examined twelve observational studies that evaluated the effect of dietary calcium on hip, spine and forearm fractures in women over thirty-five. Analysis of the data failed to conclude that dietary calcium was related to the risk of hip fracture in the population studied. For forearm fractures, one study showed a protective effect of calcium when intake was greater than 1000 milligrams compared to calcium intake of less than 800 milligrams, while a second study showed no benefit for dietary calcium. The odds of vertebral fracture were doubled in one study for women whose dietary calcium was less than 247 milligrams per day compared to those whose calcium intake was greater than 382 milligrams, but another study did not find that high calcium intake was protective.
In an editorial accompanying the article, Haakon E Meyer of the University of Oslo wrote that “the true impact of dietary calcium intake on fracture rate can only be assessed if vitamin D status is satisfactory.” He noted that a recent meta-analysis of trials involving calcium supplementation found a beneficial effect of the mineral on bone density in women, however the dose ranged from 500 to 2000 milligrams, which is more than the dietary intake in the studies included in the current meta-analysis. The authors of the study concluded that “increasing dietary calcium, short of supplementation, is probably not an effective preventative measure for hip fractures in white women aged greater than 35 years.”