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How the world got lost on
the road to an anti-aging pill
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September 4, 2010: by Bill Sardi
So often, books about super-longevity present a scenario that proposes to deliver an anti-aging pill at some distant time in the future that one wonders if it isn’t science fiction. True, in this era of genetic engineering, biologists are on the cusp of delivering technologies that significantly extend the quality and quantity of human life. Certainly the idea of an anti-aging pill is now on the biological drawing board. But the current science appears to be running in circles. Researchers have their pet genes or organs they study. But who is consolidating all the data into a theory of aging that would be practical and economical for the masses?
Anti-aging researchers can describe age-related changes inside living cells, and in the library of 25,000 human genes, but they often fail to present a framework for what causes those changes. The current fascination with genetic switching is a distraction. Genes don’t switch themselves on or off.
We live with the knowledge that our genes are influenced by environmental factors (diet, radiation, temperature) in what is called epigenetics. Fashioning molecular cocktails to favorably influence the genome is the agenda of the day. Whatever age-defying molecular cocktail is invented must also overcome deleterious factors, such as excessive calorie diets. The building of an anti-aging pill is quite a challenge.
By examination of current published studies, the activation of a sole gene, Sirtuin1, is the holy grail of longevity. But the human body has around 25,000 genes, and aging affects more than a single gene.
How many genes need to be controlled to prolong human life? Well, about half of the human genome (library of genes in human cells) is comprised of either duplicate or defunct genes. So, all the genes don’t need to be switched on or off. The life-long adherence to a limited-calorie diet, considered the unequivocal way to double the life span of living organisms, has been shown to influence 832 genes in the heart of laboratory rats. That number might be the goal of an anti-aging pill.
It is difficult to follow the logic behind the Sirtuin1 gene theory of aging. See if you can make any sense out of it.
An MIT professor was first to note that the Sirtuin1 survival gene is up-regulated (switched on) by a calorie-restricted diet. Then a Harvard professor and a biotech company researcher reported that resveratrol, a red wine molecule, was found to be the best molecular stimulator of Sirtuin1 among many small molecules tested. (Yet even this discovery was later called into question.) But later the MIT professor said, upon re-examination, that Sirtuin1 is not up-regulated in all tissues and organs in animals fed a limited-calorie diet. So exactly which tissue sample is going to be selected to validate Sirtuin1 as an anti-aging gene that mimics the longevity produced by a deprivation diet?
So far, based largely on research conducted in with laboratory rats, what researchers have discovered is that red wine resveratrol pills profoundly improve health but not longevity. But don’t mention this to the online hawker of resveratrol pills who presumptuously claim resveratrol is the fountain of youth. This is not to say resveratrol doesn’t confer longevity, but maybe only in the context of other molecules, such as those provided in red wine.
While the newly released book THE YOUTH PILL by David Stipp (Current Books, division of Penguin, 2010, 308 pages, indexed) is a worthwhile read, particularly because of its ability to background longevity seekers on the evidence for an anti-aging pill, one wonders whether readers are taking a step forward or backward by reading the book.
Stipp, an accomplished science writer, presents the red wine molecule resveratrol (rez-vair-ah-trawl) and an FDA-approved drug under the brand names Sirolimus or Rapamune (rapamycin), the former being a nutriceutical and the latter already an immune-suppressant drug, as longevity pill candidates.
Stipp favors rapamycin, a drug that inhibits the production of a protein called mTOR (target of rapamycin). Resveratrol also inhibits mTOR to a lesser extent.
Stipp says “It makes more sense to focus on drugs that tweak TOR rather than ones that target sirtuin, in the quest for calorie restriction mimetics.”
Calorie restriction is the unequivocal practice that doubles the lifespan of all living organisms tested. Small molecules that can trigger the same genes as a limited calorie diet would be molecular mimics of such a diet.
Stipp prefers rapamycin because it has been shown to prolong the life of laboratory mice, by 9% in males and 14% in females, whereas high-dose resveratrol slightly shortened the lifespan of laboratory mice on a normal 20%-calorie diet (mice on a 60% fat-calorie diet did live longer when their diet was supplemented with resveratrol). While these laboratory animals were profoundly healthier, they did not live longer.
Stipp likes rapamycin’s science, but it falls far short of the doubling of the lifespan as demonstrated in calorie restricted animals. It’s also a $3754-a-year ($10/day) pill (pricing from Drugs.com).
However, resveratrol is still a promising molecule. A gene array study showed that a relatively low dose of resveratrol switches 633 genes in the same direction as a calorie restricted diet.
With calorie restriction, progressive weight gain with advancing age is averted. On a limited calorie diet (~40% less calories) lab animals remain slim throughout life. Only recently was this accomplished with resveratrol in primates (lemurs), but required the human equivalent daily dose of 14,000 milligrams of resveratrol. A more modest dose (100 mg) did not avert age-related weight gain.
What is clear is that rapamycin and resveratrol both have overlapping biological action, and both help to control unbound metallic minerals in the body. Rapamycin is an iron chelator and resveratrol solely a copper chelator. Researchers continue to overlook the progressive accumulation of minerals with advancing age as controllers over genes that regulate aging.
While Stipp offers up rapamycin as a potential anti-aging pill, he is reluctant to personally start taking rapamycin or even resveratrol pills “till the “data on these agents reach actionable levels.”
Stipp wants to see the equivalent of Phase 2 clinical trials which would include lifespan studies of animals. Even Stipp himself doubts whether such studies will ever happen, a position that causes readers to wonder why he wrote his book. With anti-aging pills tantalizingly held before the public like carrots on a stick, the pursuit of a youth pill, by David Stipp’s criteria, becomes a purely intellectual pursuit rather than a practical adventure.
So many authorities write about the prospect of an anti-aging pill while neglecting the fact that the red wine-drinking French have already achieved unprecedented longevity by consuming 3 to 5 glasses of traditionally-made red wine per day. And Stipp, like others, fails to cite a study, even though his book cites 253 references to published scientific studies, showing a nutriceutical mix that parallels the mixed array of red wine solids in wine was able to activate more longevity genes in the short term than adherence to a life-long calorie-restricted diet.
It is difficult to fathom why anyone would advocate use of rapamycin in healthy individuals as an anti-aging pill since this drug is fraught with side effects, namely chronic fatigue, high blood sugar, high cholesterol, diarrhea, swelling in the lower legs, blood abnormalities along with immune suppression and risk for infection.
If for nothing other than the fact that the human body develops resistance to rapamycin over time, it should be shelved as candidate for an anti-aging pill. But it is belatedly moving to center stage as an anti-aging pill. The FDA first approved rapamycin for use in 1997.
But both resveratrol and rapamycin get a shot in the arm by Mikhail Blagosklonny, a tireless researcher at Ordway Research Institute; Albany, New York, who suggests lower-dose resveratrol might be tried in combination with rapamycin.
In laboratory dish studies, Blagosklonny notes that resveratrol slows or completely arrests the cell renewal cycle and therefore should accelerate cellular aging and cell death. But others claim that a pause at S-phase of the cell renewal cycle provides more time for broken DNA to be repaired, demonstrated with resveratrol, and might confer the proposed longevity produced among primitive living organisms such as yeast cells, fruit flies and roundworms.
Blagosklonny points to a recent study which demonstrated that when the cell cycle is blocked, activation of the growth-promoting mTOR pathway accelerates cellular senescence (aging). mTOR protein is needed for cells to grow, multiply, repair, metabolize nutrients (sugar) and cleanse themselves of debris. A diagram presented below attempts to visually present the role of mTOR protein in cellular health.
Blockage of mTOR protein would impair cellular growth, which is why rapamycin, an mTOR inhibitor, is employed as a treatment for cancer. Blocking mTOR protein however impairs wound healing and dulls the immune response, which is why it is also used to blunt organ rejection in transplant patients.
Blagosklonny goes on to show that when the cell renewal cycle is blocked, rapamycin causes cells to become “quiescent” (slow, sluggish) rather than “senescent” (old). So if rapamycin and resveratrol don’t induce cells to age and die off prematurely, then their ability to slow aging can be measured by simple cell counting in a lab dish, he reasons.
In the chart above, untreated cells (A) grow and multiply. When treated with increasing concentrations of resveratrol, the cells die off.
What Blagosklonny is saying is that resveratrol does, at increasing concentration, begin to slow the aging of cells, but such a high concentration is required that near-toxic doses must be employed which leads to cell death. Of course, all of this is demonstrated in a cell dish (in vitro) without all the various antioxidant and protective responses observed in true living systems (in vivo). However, Blagosklonny’s research is instructive. Dosage is critical. He suggests the combination of lower-dose resveratrol with rapamycin as an anti-aging cocktail.
What Blagosklonny demonstrates in his experiments correlates with discoveries by noted resveratrol researcher Dipak Das at the University of Connecticut. Resveratrol at a modest dose (175 mg human equivalent dose, far more than what can be achieved from the diet) protects heart tissue, even pre-conditions heart muscle cells so as to protect them from a heart attack. But at very high doses (1750-3500 mg), resveratrol becomes potentially toxic to heart cells, and 3500 mg (human equivalent dose) kills the rodent heart every time.
So is humanity any closer to an anti-aging pill? Well, as University of Michigan’s Richard Miller notes: “The things we can do in the laboratory to play around with longevity are trivial compared to what nature long ago figured out how to do. By caloric restriction, we can get about a 50% increase in longevity… But nature, even within a specific group of mammals, can do a lot better. The shortest-lived rodents differ by a factor of 10 from the longest-lived rodents. The shortest-lived primates and the longest-lived primates differ by a factor of about 10 or so. If we want to make any real progress in this area, I think we need to figure out how nature does it.”
Doubling the human life span by calorie restriction or a molecular mimic of the same is enough of a challenge, but those who propose a 4-digit human lifespan have come under ridicule. Yet there is an example in nature of an animal living the human equivalent of what the Biblical patriarchs were claimed to have lived.
The naked mole rat, which lives 10 times longer than any other rodent, achieves its super-longevity by controlling mineralization, particularly calcification, over its lifetime. Naked mole rats live about 30 years, other rodents about 3 years, and they retain elastic arteries throughout life and have never exhibited spontaneous tumors in captivity.
Super-longevity is largely achieved by female naked mole rats who make babies throughout life (never enter menopause), therefore continually donating iron and calcium to their offspring. And the naked mole rat burrows underground tunnels with its protruding front teeth which wear away these self-renewing teeth, thus acting as a sink for calcium much like deer shed their antlers to avert over-calcification in their arteries. Of interest, the naked mole rat has been shown to have higher stored iron levels in the liver. For unknown reasons, the naked mole rat does not succumb to iron overload.
I maintain calorie restriction is simply a way to mimic what the naked mole rat does, which is to slow the accumulation of iron, copper and calcium in the human body via limitation of food, thus producing longer lifespan. That is the starting point for the design of an anti-aging pill. – © 2010 Bill Sardi, ResveratrolNews.com