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How the world got lost on
the road to an anti-aging pill
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September 22, 2010: by Bill Sardi
For unexplained reasons biologists working in the field of aging fail to explain what causes aging genes to switch on or off, and why genes that accelerate aging begin to progressively exert their influence with advancing age, beginning after full childhood growth is achieved.
There are electrifying studies which assay the gene activation (called gene expression) profiles of animals and humans subjected to calorie-restricted (CR) diets, which is a known practice that prolongs the life of all living organisms.
Also, molecular CR mimetics, or so-called anti-aging pills, comprised of small molecules like resveratrol that can influence genetic machinery inside living cells, have been analyzed for their influence over the human genome.
Molecules similar to resveratrol, such as fisetin, quercetin, ferulic acid, all red wine molecules, and curcumin, a spice molecule, are widely recognized for their anti-aging properties. All of these molecules have one thing in common – they are mineral chelators (key-lay-torz). For example, resveratrol chelates copper. Quercetin chelates iron. Rice bran IP6 is a master mineral chelator. It is no surprise to learn that captopril (Capoten), a drug used to control blood pressure, is, like resveratrol, a copper chelator.
An interesting way to track the effect of small molecules like resveratrol upon aging is to investigate the relationship between aging, metallic minerals, resveratrol and angiotensin II, a hormone-like protein that is secreted within the inner lining of arteries (called the endothelium). Angiotensin, produced via the activity of ACE (angiotensin converting enzyme), causes blood vessels to constrict which then results in elevated blood pressure. ACE inhibiting drugs (Altace, lisinopril, enalapril, ramparil, Zestril, captopril) are prescribed to control blood pressure. A rise in blood pressure is largely an age-related phenomenon, and therefore, ACE inhibitors are sometimes referred to as anti-aging drugs. Small red wine molecules like resveratrol and quercetin are natural enzyme inhibitors and would be expected to inhibit ACE.
It is also no surprise to learn that Sirtuin1, a longevity gene whose gene expression has been shown to be influenced by resveratrol, down-regulates (dims) the production of angiotensin II via dulling the cell wall receptor for this protein.
Iron is a more abundant metallic mineral that slowly accumulates with advancing age, first in males after full growth is achieved (1 milligram per day of life after age 18) and later in females with the onset of menopause (women lose about 30 mg of stored iron in their monthly menstrual flow, thus delaying iron overload). Iron has been called a “malignant spirit of successful aging.”
Once again, it is no surprise to learn that chelation (control or removal) of iron suppresses angiotensin II and also favorably inhibits klotho, a known anti-aging gene.
Angiotensin II causes excess iron to be deposited in the aorta (first blood vessel outside of the heart) and induces iron to be stored in ferritin, the iron-storage protein produced in the liver. Chelation of iron inhibits the storage of iron in ferritin and improves the function of the aorta. Iron chelation also suppresses angiotensin II in the heart.
Excess iron has also been shown to increase transforming growth factor-beta1 (TGF-beta1) which is known to play a crucial role in the development of kidney damage induced by angiotensin II. It is also interesting to note that animals infused with angiotensin II will accumulate cholesterol (lipids) within their kidneys, whereas iron chelators lessen angiotensin II and normalize cholesterol.
So now we have a link between iron accumulation, angiotensin II and aging in the heart, aorta and kidneys.
For whatever reasons, patients with high blood pressure never hear they are iron and copper overloaded, they only hear they need a drug. A major reason why most blood pressure drugs don’t work very well could be the fact that the patient continues to consume highly absorbable iron-rich foods!
Encouragingly, chelation of iron in rodents reduces free radicals and suppresses angiotensin II. Metallic metal chelators favorably regulate oxidation, gene expression and the rate of aging.
A few researchers have begun to connect iron overload with the regulation of genes. However, no clear genetic patterns have been uncovered in relation to iron overload. As researchers at the University of Toronto explain, “an emerging concept is that iron signals through the generation of oxygen free radicals to activate proteins called transcription factors that bind to specific sequences of DNA.” In other words, iron works indirectly upon the genes to generate oxygen free radicals. Contrarily, the removal of iron (chelation) mimics an oxygen-deprived (hypoxic) state which influences gene expression in a more favorable direction.
Having gained this knowledge, let’s take a moment to look at what happens in the aging brain. New evidence clearly shows that iron and copper accumulate with advancing age in regions of the brain, which correlates with breaks in DNA and altered gene expression. The genome (library of genes within each brain cell) becomes unstable due to metal-induced free radical production. Zinc, which is a counterbalancing mineral to copper and iron, counters this problem somewhat. So again, it should be no surprise to learn that a calorie restricted diet decreases accumulation of iron in the brain, favorably influences gene expression, and preserves motor function in animal experiments. CR is just another way to limit the accumulation of metallic minerals and slow the rate of aging. In a similar manner, using a prescription medication, the copper-chelating/ACE-inhibiting drug captopril, mentioned earlier, protects the brain and helps maintain adequate dopamine levels.
The problem here is that George Brewer, a noted researcher at the University of Michigan, shows that even miniscule amounts of unbound (inorganic) copper and iron in drinking water, ten-times lower than what the Environmental Protection Agency allows, accelerates brain aging and memory loss. If the rate of aging is to be successfully slowed, the diet must be addressed. Humans don’t necessarily have to deprive themselves of food, but select foods that provide limited amounts of iron and copper. Limitation of inorganic iron and copper in drinking water and dietary supplements must become part of a successful anti-aging regimen without over-avoidance and subsequent induction of anemia. © 2010 Bill Sardi, ResveratrolNews.com