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How the world got lost on
the road to an anti-aging pill
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February 20, 2011: by Bill Sardi
ResveratrolNews.com – Health news headlines today question whether human growth hormone replacement, used by many Americans to overcome the ravages of aging, is just a misdirection.
It is true that the secretion of human growth hormone diminishes with advancing age. But the just-released results of a 22-year study involving a population of genetically-abnormal individuals in Ecuador who produce low amounts of human growth hormone (GHG) and insulin-like growth factor (IGF) reveals this group exhibit no diabetes, almost no cancer and a very low rate of stroke. Strikingly, the blood serum of these people exhibits a double-protective effect: it protects against oxidative damage and gene mutations and also promotes cellular suicide among highly damaged cells.
Laboratory animals, bred to produce low amounts of these hormones, live on average about 30-40% longer. In human terms, that would thrust human populations toward 100-plus-year life spans. Theoretically, humans who produce an insufficient amount of growth hormones should have what is called a square survival curve where most of life is lived without major illness and then you drop dead, said one of the primary researchers involved in the study.
The dwarfs in Ecuador
But the news headlines need to be re-written. While these short-statured people (~4 feet in height) who live in Ecuador have a genetic advantage like no others on the planet, they don’t live much longer than other human populations because they over-consume alcohol and tend to die of accidental deaths, many related to alcohol abuse.
|Age||Total deaths||Cancer deaths (%)||Total deaths||Cancer deaths|
|10-30 yr||60||3 (5)||5||0|
|30-50 yr||208||46 (22.1)||12||0|
|50-70 yr||370||84 (22.7)||12||0|
|70-90 yr||446||89 (20)||1||0|
GHRD = growth hormone deficient
The human tragedy is that what generations of humanity have long hoped for, healthy longevity, which these Ecuadorians don’t even have to search for, is squandered on a bottle of booze. Mutant human dwarf populations in Ecuador live 75-78 years in generally good health, but could live much longer. The theoretical maximum human lifespan is ~125 years.
Meanwhile, avid longevity seekers who self-administer human growth hormone via injection may be headed in the wrong direction. For some time now researchers have questioned whether growth hormone injections for otherwise healthy aging adults is wise.
It is interesting to learn that a condition called acromegaly, where people grow to be giants due to excessively high growth hormone levels, shortens the life span by about 10 years. This condition can be treated with a pegvisomant (trade name: Somavert), which blocks growth hormones.
Then there are longevity seekers and body builders who pump their bodies with injectable human growth hormone. While hormone treatment in childhood is reported to be beneficial for growth-hormone deficient individuals, dwarf mice deficient in growth hormone actually experience a shortened life span when growth hormone is regularly injected. Growth hormone injections given to long-lived dwarf mice actually hampers their antioxidant defense system.
It is interesting to learn that humans who are deficient in growth hormone due to deletion of their growth hormone gene, or patients with multiple pituitary hormone deficiency due to a gene mutation, as well as patients with insulin-like growth factor (IGF-1) deficiency due to gene mutations (Laron syndrome), will, despite signs of early aging (wrinkled skin, obesity, bone loss, insulin resistance), typically have a long life reaching ages of 80-90 years.
The super-longevity of dwarf mice parallels the recent findings among short-statured humans in Ecuador. Some reports indicate dwarf mice that exhibit suppressed growth hormone levels live 35-70% longer than normal mice. Other reviews show dwarf mice are growth hormone and insulin-growth factor-1 deficient and live 50-64% longer than wild littermates. This is remarkable.
The mutation that produces unusual longevity in dwarf mice was not discovered until 1996. Up till that point, only calorie restriction was known to reliably prolong life.
The inherited genetic trait that results in marginal secretion of growth hormone due to a mutation located on chromosome 16 results in the aforementioned health benefits which surprisingly are also mimicked by a calorie restricted diet.
If growth-hormone deficient dwarf mice receive growth hormone injections twice-daily from a young age, their growth will improve but their IGF-1 levels also rise. Growth hormone injections in young dwarf mice adversely affect the health span and lifespan of these growing animals.
It has long been known that limited-calorie diets prolong the life span of all living organisms ranging from fruit flies, round worms, mice and primate monkeys. Fasting, just another name of calorie restriction outside the laboratory, is known to reduce levels of insulin-like growth factor-I (IGF-1) in mice.
Much like dwarfism, calorie restriction decreases the levels of blood sugar and insulin-like growth factor-1 (IGF-1) and postpones cancer, delays senility and inhibits inflammation. However, while calorie restriction prolongs life in both normal and dwarf mice, it does so by different mechanisms.
Certainly IGF-1 cannot be characterized as troublesome during the growth years, particularly when iron-deficiency anemia is a problem and low IGF-1 levels are common. The reduced demand for iron to produce hemoglobin in red blood cells, experienced once full childhood growth is achieved, may help explain why IGF-1 becomes a nemesis rather than a friendly growth factor.
Insulin-like growth factor-1 (IGF-1) cannot be demonized entirely. In growing rats chemically treated to induce liver disease (cirrhosis), the injection of IGF-1 reduced iron-induced oxidation in the liver. The key factor here was that the laboratory rats were still in their growth years.
Biologists describe a paradox, called the insulin-growth factor-1 (IGF-1) paradox, where IGF-1 enhances necessary growth during the developmental years but can accelerate the aging process. This actually is no paradox. Tissues and organs need to grow and mature during the growth years, but nothing really needs to grow thereafter. After about age 40 or so the body is in a repair mode, not a growth mode.
It is interesting to note that IGF-1 levels are reduced among pre-menopausal Caucasian females who use birth control (estrogen) pills, but not among African-American pre-menopausal users of birth control pills. This may help to explain the much higher rate of breast cancer among African-American women in pre-menopause.
Among women in Japan, the highest consumption of tofu produces an 11% reduction in circulating IFG-1 levels. It is interesting to note that a soy-based diet, rich in isoflavones, has been shown to be beneficial in some (but not all) genetic strains of dwarf mice, lowering their blood sugar levels and further increasing their lifespan. Confusion reigns over which component of soy is most beneficial. Soy isoflavones are really a small constituent of soy, while IP6 phytate, a mineral-controlling molecule, is predominant and controls iron-induced oxidation. This is why we see female dwarf mice outliving their male counterparts. Females control iron via menstruation for long periods of life while male accumulate iron, particularly in the liver, after full childhood growth is achieved.
Whereas a diminution of IGF-1 in aging adults may be beneficial, the opposite is true for growth-hormone deficient humans with hypopituitarism who are at risk for early death. IGF-1 injections may be beneficial for this group. There are also exceptions to this rule. Humans with a particular gene mutation (PROP-1) combined with pituitary hormone deficiency can survive to a very advanced age, longer than other healthy people.
Human studies show resveratrol lower IGF-1 in humans at a 500 milligram dose per day (lowest dose tested). Lower doses may even work better, particularly when synergistic molecules are combined with resveratrol. Current literature points to lower doses of resveratrol being safer and more effective.
It appears vitamin D can help produce health levels of IGF-1 with advancing age without inducing tumors.
Calorie restriction works epigentically, that is, to switch gene-controlled protein-making on or off. Genetic predispositions are inherited mutations, whereas epigenetic changes are controlled by the environment (diet, temperature, radiation, etc) but can also be imprinted and passed on to successive generations, particularly if exposure to environmental factors occurs during conception and early development.
Just how is super-longevity conferred to dwarf mice genetically? There are three ways genes can be switched on or off, either by (a) delivery of B vitamins (folic acid, B12) during conception and early development (called methylation), (b) enzyme inhibition (histone deacetylase) or (c) blockage of genetic codes on messenger RNA via microRNA. Among these three, microRNA is now known as the “guiding hand” of the genome (library of genes). Recently researchers identified microRNA-27a as the key regulator in the dwarf mouse liver tissue that contributes to delayed aging.
Can microRNA-27a be tickled by small molecules to mimic the long life experienced by the dwarf mouse? In a study where researchers compared the microRNA profile of excised mouse hearts subjected to a chemically-induced heart attack, the expression of microRNA27a was 9.3 following a heart attack, 5.5 when resveratrol, a red wine molecule, was employed, and 1.4 when a synergistic combination of small molecules that included resveratrol was given (Longevinex®). There is a strong possibility that resveratrol-based nutriceuticals could mimic the “dwarf mouse effect.”
|MicroRNA differentiation||Control group||Resveratrol||Longevinex®|
Such is the plight of mankind, while experiencing unprecedented longevity due to improved public hygiene, clean foods and pure water, and with access to modern medicines, throws it all away and fails to achieve optimal healthy lifespan due to poor health habits. The Ecuadorian dwarfs are just an example. Their propensity to over-consume alcohol overrides their favorable genetic inheritance.
Whatever antidotes to aging are developed, they will also have to prevail over poor health habits. Tobacco use, over-consumption of alcohol and lack of whole-grain (bran-rich) diets, the inclusion of “obesogens,” chemicals in the food supply that induce hormonal imbalances (example: bisphenol A in tin cans), are undoing the progress of modern civilization.
In this regard, researchers conducted an experiment with laboratory mice, mimicking weekend binge drinking and overeating by adding varying amounts of alcohol and sugar (sucrose) in their diet. Then in one group of mice that consumed the high alcohol/sucrose diet, resveratrol (rez-vair-ah-trol), a red wine molecule, was added to the mix. The alcohol/sucrose/resveratrol-fed mice had reduced markers of circulating blood fats (triglycerides, very-low density cholesterol, and markers of oxidation while exhibiting enhanced good (HDL) cholesterol. Resveratrol overrode the bad health practices.
In another similar experiment, researchers gave laboratory mice (1) a standard diet; (2) a standard diet plus resveratrol added to drinking water; (3) a standard diet plus alcohol added to their drinking water; (4) and a standard diet plus alcohol and resveratrol added to their drinking water. Liver enzymes rose in the alcohol-only group. A marker of inflammation (interleukin-1) was markedly reduced in the alcohol + resveratrol group compared to the alcohol-only group. Remarkably, after 7 weeks, mortality in the alcohol group was 78% versus 22% in the alcohol plus resveratrol group!
Measure of inflammation (interleukin-1) in mice with alcohol or alcohol + resveratrol added to their drinking water.
Survival of mice on standard diet (control -♦-), resveratrol added to drinking water (-■-), alcohol added to drinking water (-▲-)alcohol plus resveratrol added to drinking water (-x-). All animals given alcohol succumbed by 8-weeks whereas 50% of alcohol-fed animals plus resveratrol were still alive.
Researchers wrote: “Resveratrol reduces mortality and liver damage produced by alcohol in mice. If our findings are confirmed by further research, resveratrol could be administered to patients with chronic alcoholism to reduce the mortality and liver damage associated with alcohol abuse. It could even be prophylactically added to alcoholic beverages, in a way similar (10 mg/liter of any alcoholic beverage), similar to how chlorine is added to water to prevent infections.”
It is not likely public health officials or the alcoholic beverage industry will be adding resveratrol to their brews anytime soon. It is also not likely that alcohol abusers are in any way interested in overcoming the deleterious effects of alcohol over-consumption by taking resveratrol pills.
Of course, Big Pharma is posing its candidate growth hormone-blocking drug (Somavert) as the next anti-aging pill. However, its long term efficacy and safety for this drug among healthy individuals with no growth-hormone deficiency disease is yet to be established. While side effects of this drug are tolerated in the face of a high mortality rate among patients with gigantism (acromegaly), these side effects would not be acceptable for healthy individuals seeking to live longer. Somavert is quite expensive, costing between $100-200 per day for 10-20 milligram doses to treat patients with gigantism (acromegaly).
Brian Morris at the Basic & Clinical Genomics Laboratory at the University of Sydney in Australia says: “Current progress bodes well for an ever-increasing length of healthy life for those who adapt emerging knowledge personally (so-called ‘longevitarians’).” Remarkably, relatively few do. Despite the astounding science, there are only an estimated 125,000 regular resveratrol pill users in the U.S. Sales of human growth hormone are 43-times greater than resveratrol pills. – © 2011 Bill Sardi, ResveratrolNews.com