THE OXYGEN CLUB OF CALIFORNIA MEETING: OXIDANTS AND ANTIOXIDANTS IN BIOLOGY
Stephen Lawson, LPI Administrative Officer
The Oxygen Club of California (OCC) held its biennial meeting in Alba, Italy, on June 20-23, co-sponsored, as usual, by the Linus Pauling Institute. Dr. Maret Traber, LPI’s Helen P. Rumbel Professor for Micronutrient Research, is the President of OCC and served as one of the organizers of the meeting.
The meeting, entitled “Cell Signaling and Nutrient-Gene Interactions,” featured 32 speakers—including three from LPI—and covered the following topics: “Nrf2–driven Regulation of Antioxidant Defenses,” “Nutrient-gene Interactions and Epigenetics,” “Novel Roles of Micronutrients,” “Lipid Oxidation and Signaling,” and “Epigenetics, Metabolism, and Aging.” These sessions were followed by a poster session with over 100 posters on relevant topics.
In his keynote lecture, Richard Weindruch noted that studies in rodents and monkeys have demonstrated that caloric restriction leads to an increase in healthspan—the portion of life free from chronic disease and pervasive decline in health and vitality. He and colleagues have been interested in understanding the molecular mechanisms that underlie the increase in healthspan in order to discover substances that could serve as mimics of caloric restriction because chronic caloric restriction is extremely difficult for people to accept. It’s likely that substances that regulate energy metabolism may serve as such mimics.
Nrf2 is a transcription factor (a protein that regulates gene activity by binding to DNA) typically bound to another protein called KEAP in the cell’s cytoplasm. Toxins and reactive oxygen molecules cause Nrf2 to dissociate from KEAP and migrate into the nucleus, where it induces antioxidant and detoxification genes that help protect cells. However, overexpression of Nrf2 may help cancer cells. Speakers noted that Nrf2 also attenuates inflammation and is induced by oxidized lipids and sulforaphane, a phytochemical in cruciferous vegetables like broccoli. Nrf2 has been found to be inhibited in umbilical cord cells in cases of pre-eclampsia and gestational diabetes, which may increase the risk of diabetes and heart disease in those infants when adults. Dietary selenium deficiency may result in increased Nrf2 activity as a compensatory mechanism.
Epigenetics is the study of changes in gene expression that don’t change the underlying DNA sequence. Speakers discussed how chemical modifications of DNA, such as methylation, or of histones, which are proteins that DNA wraps around, affect gene expression. Acetylation (addition of acetyl chemical groups) of histones results in genes being turned on, and the deacetylation of histones causes genes to be turned off. Histone deacetylase (HDAC) inhibitors, therefore, keep genes, including tumor suppressor genes, active. In prostate cancer cells, the phytochemical HDAC inhibitor, sulforaphane, triggers apoptosis (programmed cell death). It was also reported that the B vitamin riboflavin lowers blood pressure in heart disease patients carrying a certain gene, which is prevalent in about 10% of people worldwide. Supplementation with riboflavin may significantly lower the risk for stroke in such people.
New roles for micronutrients and phytochemicals in health continuously emerge. Pomegranate juice has been shown to slow the increase in PSA in men after prostatectomy, and cell studies with pomegranate extract suggest that it is anti-inflammatory. Zinc has an important role in protecting the developing brain from oxidant injury by several mechanisms, and zinc deficiency impairs the synthesis of the endogenous antioxidant glutathione. Studies on vitamin E and the risk for heart disease have been conflicting, but new evidence suggests that some patients, particularly diabetics with the haptoglobin 2-2 genotype, may benefit from supplementation. Coenzyme Q10 may help regulate fat metabolism; supplementation of obese mice lowers body weight and improves metabolic parameters. Lipoic acid and its derivatives induce cellular responses to stress caused by toxins and free radicals. Lipoic acid has also been found to inhibit atherosclerotic lesion development in a mouse model of atherosclerosis, as well as to decrease body weight gain and triglycerides. Through its effect on transcription factors NF-κB (implicated in inflammation) and Nrf2 (regulator of detoxification and antioxidant enzymes), lipoic acid reverses the decline in the antioxidant enzyme superoxide dismutase in the aortas of old rats. Using cigarette smoke as a source of oxidative stress, scientists showed that resveratrol found in red wine or curcumin from the spice turmeric (a major constituent of curry) inhibited inflammation in mice.
Oxidized fats in the body have a wide array of effects. While oxidized fats sometimes serve beneficial functions, they are associated mainly with inflammation and damage to proteins and other biomolecules. Oxidized fats that accumulate in atherosclerotic lesions may contribute to plaque instability and rupture, which could lead to heart attacks or strokes. Lipids in immune cells may control their function and response to inflammatory stimuli. Oxysterols are formed when cholesterol molecules become oxidized and are typically involved in pathological processes like atherosclerosis. In addition to serving as biomarkers of oxidative stress and inflammation, oxysterols help regulate lipid metabolism in the liver.
Aging is characterized by numerous declines in function and increased risk for major diseases. In old mice, Nrf2 activation and supplementation with nicotinamide, which is a derivative of the B vitamin, niacin, and the precursor for the NADH that donates electrons in chemical reactions, improved the survival of neurons and increased the levels of glutathione, an endogenous antioxidant. Oxidative stress and free radical damage have been associated with aging, but some studies correlate oxidative stress more closely with frailty in old age caused by declines in skeletal muscle function and motor neurons. Other studies implicate changes in sex hormones in age-related frailty. Proteasomes are cellular structures that degrade oxidized and damaged proteins. There is an age-related decline in the efficiency of proteasomes, leading to the aggregation of damaged proteins associated with the development of age-related diseases.
Last updated November 2012