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The Triage Theory of Aging June 10, 2011 BioSyntrx
One of our favorite nutrition researchers, Bruce Ames, PhD and his colleague, Joyce McCann, PhD, at The Nutrition and Metabolism Center, Children Hospital of Oakland, California continue to discoverer how vitamins and minerals may prevent age-related diseases.
Dr. Ames has suggested for some time, "Severe deficiencies of the vitamins and minerals required for life is relatively uncommon in this country, but modest deficiency is very common and too often not taken seriously. Each of the 40 known vitamins and minerals used in metabolism are required for life."
Dr. Ames now famous "triage theory" uses basic principles of the evolutionary theory of aging to highlight the potential importance of vitamin / mineral biology in diseases of aging, including cancer, heart disease, osteoporosis, and dementia.
His theory posits that when the dietary availability of any vitamin or mineral is even moderately inadequate, nature ensures that the vitamin mineral-dependent functions that are essential from an evolutionary perspective (required for short-term survival and/ or reproduction) are protected at the expense of those that are less essential (those whose deficiency does not have acute short-term negative consequences but may have long-term insidious effects that increase risk of diseases associated with aging).
His triage theory does not imply that any particular vitamin mineral deficiency is the only cause of an age-related disease but rather that it is a contributing factor along with the sum of all contributing causal factors.
If the vitamin / mineral "triage theory" is correct it has important implications for public health, particularly in the poor, obese, and elderly who too often consume high calorie, nutrient-deficient. unbalanced diets. Dr. Ames has suggested for years that societal concern about modest nutrient deficiency stays low because it is not accompanied by overt clinical symptoms. His triage theory proposes that insidious changes are occurring that, over the long term, lead to increased risk of diseases of aging and contribute greatly to the cost of health care.
Drs. Ames and McCann's new research published in the June 6 (2011 see abstract below) issue of the prestigious Journal of the Federation of American Societies for Experimental Biology (FASEB) will, hopefully, convince the public to take modest micronutrient deficiency very seriously because it examines modest selenium deficiency to show how damage accumulates over time as a result of vitamin and mineral loss, leading to age-related diseases.
They published a similar and equally impressive study in 2009 in the American Journal of Clinical Nutrition that linked the triage theory of aging to Vitamin K deficiency. In the United States, average intake of vitamin K1 is 70–80 mcg per day, which is well below the currently recommended Adequate Intake of 90–120 mcg. The overuse of blood thinning pharmaceuticals and physician recommendations to avoid most dark green vegetables and supplements that includes vitamin K when taking blood thinners may very well prove to be increasing the risk of many degenerative diseases.
Dr. McCann and Dr. Ames reached their conclusions in this recent selenium study by compiling and assessing several general types of scientific evidence. They tested whether selenium-dependent proteins that are essential from an evolutionary perspective are more resistant to selenium deficiency than those that are less essential. They discovered a highly sophisticated array of mechanisms at cellular and tissue levels that, when selenium is limited, protect essential selenium-dependent proteins at the expense of those that are nonessential.
They also found that mutations in selenium-dependent proteins that are lost on modest selenium deficiency result in characteristics shared by age-related diseases including cancer, heart disease, and loss of immune or brain function.
These results will, hopefully, encourage additional attempts to locate linkages between vitamin or mineral deficiencies and age-related diseases by focusing on the vitamin and mineral-dependent proteins that are nonessential from an evolutionary perspective.
"This paper should settle any debate about the importance of taking a good, complete, multivitamin every day," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "As this report shows, taking a multivitamin that contains selenium is a good way to prevent deficiencies that, over time, can cause harm in ways that we are just beginning to understand."
Ellen Troyer, MT MA, Biosyntrx CEO / Chief Research Officer
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Joyce C. McCann1 and Bruce N. Ames1
Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, California, USA
1 Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute (CHORI), 5700 Martin Luthur King Jr. Way, Oakland, CA 94609, USA. E-mail: B.N.A., bames at chori.org; J.C.M., jmccann at chori.org
The triage theory proposes that modest deficiency of any vitamin or mineral (V/M) could increase age-related diseases. V/M-dependent proteins required for short-term survival and/or reproduction (i.e., “essential”) are predicted to be protected on V/M deficiency over other “nonessential” V/M-dependent proteins needed only for long-term health. The result is accumulation of insidious damage, increasing disease risk. We successfully tested the theory against published evidence on vitamin K. Here, we review about half of the 25 known mammalian selenoproteins; all of those with mouse knockout or human mutant phenotypes that could be used as criteria for a classification of essential or nonessential. Five selenoproteins (Gpx4, Txnrd1, Txnrd2, Dio3, and Sepp1) were classified as essential and 7 (Gpx1, Gpx 2, Gpx 3, Dio1, Dio2, Msrb1, and SelN) nonessential. On modest selenium (Se) deficiency, nonessential selenoprotein activities and concentrations are preferentially lost, with one exception (Dio1 in the thyroid, which we predict is conditionally essential). Mechanisms include the requirement of a special form of tRNA sensitive to Se deficiency for translation of nonessential selenoprotein mRNAs except Dio1. The same set of age-related diseases and conditions, including cancer, heart disease, and immune dysfunction, are prospectively associated with modest Se deficiency and also with genetic dysfunction of nonessential selenoproteins, suggesting that Se deficiency could be a causal factor, a possibility strengthened by mechanistic evidence. Modest Se deficiency is common in many parts of the world; optimal intake could prevent future disease.—McCann, J. C., Ames, B. N. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging.
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- Youtube April 2010 audio by Ames
- Bruce Ames Website
- Website Downloadable Media
- Life Extension® Interview with Dr. Bruce Ames August 2011
By Philip Smith
Dr. Bruce Ames is devoted to uncovering strategies to reverse the aging process, primarily by identifying the underlying mechanisms of degenerative disease. Best known for his groundbreaking research on the mitochondria, Dr. Ames’s lab was the first to document the synergy of lipoic acid and acetyl-L-carnitine for optimizing mitochondrial function.
Following this work, Dr. Ames recently developed the Triage Theory of Aging. His hypothesis centers on the potentially long-term damage of moderate micronutrient deficiencies, including DNA damage leading to cancer. The scope of his research also includes investigations into the mutagenic causes of cancer.
Dr. Ames has authored over 500 research papers. Currently, Dr. Ames is emeritus professor of biochemistry and molecular biology at the University of California, Berkeley and a senior scientist at Children’s Hospital Oakland Research Institute. In this exclusive interview with Life Extension Magazine®, Dr. Ames discusses some of his major areas of research.
Life Extension: One of your best known accomplishments is research into the field of mitochondrial health. You were one of the main investigators to describe the relationship of youthful mitochondria to longevity and disease prevention. Only recently, the idea of mitochondrial vitality has attracted the interest of scientists and the medical profession as an area worthy of significant research. What made you decide to investigate this particular area?
Bruce Ames: Initially, I was curious about cancer prevention and how mutagens damage the human genome. To me it was obvious that cancer was most likely a degenerative disease of aging. Cancer development dramatically increases with age.
The link between my interest in cancer and mitochondria came together because mitochondria were postulated to be important in aging. A tremendous amount of dangerous metabolism occurs in the body’s mitochondria that, if left unchecked, can lead to a host of degenerative diseases. In addition, a first-rate post-doctoral candidate, Tory Hagen, was enthusiastic about tackling the problem.
Normally, to research such a topic you use mice. The problem is that you don’t want to sit around for three years while the mice get older. Instead, we decided to set up numerous functions in mitochondria that were known to decay with age and that we could measure. For example, with age, mitochondria put out more mutagenic oxidant byproducts which are oxygen radicals. In addition, cardiolipin, a key lipid in mitochondrial membrane, declines. Also, the mitochondrial membrane potential declines. We decided to investigate four different functions known to decay in the mitochondria with age. We were looking to understand and optimize metabolic function to prevent mitochondrial decay.
As we were developing these assays in young and old rats, we came across a paper by some Italian researchers who had fed old rats acetyl-L-carnitine. What they found was that mitochondrial transcription improved. Even though this wasn’t one of our initial assays, we became very interested in trying acetyl-L-carnitine. So we fed it to old rats, and as a result, three of the four functions that decayed with age suddenly became more like those of a young rat. Carnitine declines with age, and when we fed high levels to rats, it seemed to alter a number of factors of aging.
While acetyl-L-carnitine provided a great solution to the three functions, we still needed to solve the fourth assay, the increase in mutagenic oxidants, that was not helped by acetyl-L-carnitine. And so we tried a number of things including all the conventional antioxidants—such as vitamin C and vitamin E—but they didn’t work. Lester Packer, at Berkeley, had been saying for years that lipoic acid, which is a normal mitochondrial metabolite, was a terrific antioxidant. Finally, we tried lipoic acid and it worked! We found that together, carnitine and lipoic acid complemented each other and were actually somewhat synergistic. The end result was that the mitochondria of the aging rats appeared to be more like mitochondria of young rats. Jiankang Liu and I had shown that the cognition in these old rats gets better and also in dogs when they are fed these substances. We also have some preliminary evidence that it works in people as well.
Life Extension: The implications of mitochondrial health permeate every aspect of our systemic well-being.
Bruce Ames: Yes, we have enough evidence to demonstrate that mitochondrial decay can contribute to degenerative diseases, including cancer and neurological decline, that are all associated with aging. The impact of mitochondrial decay is far-reaching. Old mitochondria generate increased amounts of mutagenic by-products along with decreased membrane potential and cellular oxygen consumption. All of this decline cascades into DNA and RNA damage and into cells, tissues, and eventually the organs. Our inability to produce ATP as we did when we were younger is also a result of aging mitochondria.
As this article was going to press, the prestigious Journal of the Federation of American Societies for Experimental Biology (FASEB J) published an article authored by Bruce Ames that supports the fundamental philosophy to health and longevity that Life Extension® has promoted for thirty years.
The article builds upon Dr. Ames’s Triage Theory of optimal nutrition, which states that the human body prioritizes the use of vitamins and minerals when it is getting an insufficient amount to keep functioning. While short-term deficiencies are common, they are often not taken seriously by mainstream physicians. Dr. Ames’s research may change all that, as his paper shows how bodily insults accumulated over time as a result of vitamin and mineral loss can lead directly to age-related diseases.
“Understanding how best to define and measure optimum nutrition will make the application of new technologies to allow each person to optimize their own nutrition a much more realistic possibility than it is today,” said Joyce C. McCann, PhD, a co-author of the study from the Nutrition and Metabolism Center at Children’s Hospital Oakland Research Institute in Oakland, California. “If the principles of the theory, as demonstrated for vitamin K and selenium, can be generalized to other vitamins and minerals, this may provide the foundation needed.”
Echoing the importance of this research, Gerald Weissmann, MD, Editor-in-Chief of the FASEB Journal said, “This paper should settle any debate about the importance of taking a good, complete, multivitamin every day. As this report shows, taking a multivitamin that contains selenium is a good way to prevent deficiencies that, over time, can cause harm in ways that we are just beginning to understand.”
Life Extension: The combination of acetyl-L-carnitine and lipoic acid have been cited in the literature as effective caloric restriction mimetics.
Bruce Ames: The work on that concept was done by Tomas Prolla in Wisconsin. Tom had been looking at the array of proteins that get turned on and how they change with age. He was also investigating what changes occur with calorie restriction, which is known to prolong life span. When he looked for small molecules that mimicked the changes created by caloric restriction, he found that both acetyl-L-carnitine and lipoic acid are good mimics. However, one is more effective in the heart and one is more effective in the brain. We were happy with his paper, because it reinforced all our evidence on acetyl-L-carnitine and lipoic acid.
Life Extension: Another area of your research has been the Triage Theory that posits that moderate deficiencies of one of the 40 essential nutrients may lead to DNA damage.
Bruce Ames: Correct. It’s based on a simple analogy. The term “triage” is borrowed from the field of urgent medical care. Triage means deciding which patients to treat when faced with limited resources. When presented with more patients than there are resources to treat them all at the same time, doctors must decide which patients to treat first based on the severity of their condition.
So the patient in cardiac arrest comes first, followed by the patient with a hemorrhaging wound in need of stitches, then the patient with severe influenza, and so on. This provides the best chance for all the patients to survive.
Our bodies evolved to do pretty much the same thing. Faced with limited nutritional resources, the human physiology must “decide” which biological functions to prioritize in order to give the total organism—and the species—the best chance to survive and reproduce.
My work suggests that if you’re even modestly deficient in one of the essential micronutrients, your body has to “ration” them in terms of priority. Under this scenario, the body will always direct nutrients toward short-term health and reproductive capability—and away from regulation and repair of cellular DNA and proteins that increase longevity.
This means that while your body may be providing nutritional support in an effort to sustain system-wide physiological function and reproduction, at the cellular level, the process of decay and death is accelerating. Now let’s look at how this plays out in real-world dietary terms.
To run your metabolism you need the basic macronutrients of fuel, fats, and carbohydrates. But you also need 15 or so vitamins that are co-enzymes and 15 or so minerals that are required in enzymes, and then you need two essential fatty acids, omega-3 and omega-6, and then there are seven or eight essential amino acids, so all together, it’s roughly 40 substances. Virtually every metabolic pathway requires micronutrients. Deficiencies in these micronutrients may not be severe enough to create immediate clinical symptoms, but the long-range implications could lead to an increased risk of diseases associated with aging.
Practically every American is deficient at some level of these nutrients because of our bad diet.
My goal was to explore what could be done in terms of diet to avoid these diseases of aging. The thing that got me going on this was a guy named Jim MacGregor, a scientist who came to my lab on sabbatical. His research had just shown that folic acid deficiency in mice broke chromosomes, just like radiation. He took the experiments further and showed that folic acid deficiency broke chromosomes in people as well, which was quite alarming. According to his research, this was occurring in about 10% of the US population and about half of those that are poor. A significant portion of the American population is experiencing critical DNA damage without realizing it. Very simply, if you don’t eat whole grains or your greens, or take a supplement, it’s like getting irradiated.
Based on this idea, we began to look in the literature and doing experiments. Whenever we made human cells in culture a little deficient in a vitamin or mineral, we started getting DNA damage. I realized that this was an overlooked area of research. It was this fundamental observation that led me to the Triage Theory.
Life Extension: You and Dr. Joyce McCann have done some interesting work on vitamin K. Life Extension readers have been following the latest research on all the benefits of vitamin K with regard to heart disease and cancer.
Bruce Ames: Vitamin K is not a single vitamin but rather a collection of structurally related molecules from different sources. There are K1, MK-4, and MK-7, all with different benefits for the body. We looked at how vitamin K could be used to prevent age-related conditions such as bone fragility, arterial and kidney calcification, cardiovascular disease, and even cancer. In Germany, where vitamin K was discovered, it is known as the “Koagulation” vitamin because it factors so heavily in blood clotting. However, the coagulation factors originate in the liver while other forms of vitamin K are sent to the other tissues in the body. We are beginning to see interesting studies concerning vitamin K deficiencies and mortality from coronary heart disease.
In the United States, the population tends to be fairly low with regards to vitamin K intake, largely due to the fact that we do not consume sufficient greens. In Japan, people obtain healthy amounts of MK-7 from a soy product called natto. We believe that natto consumption may be responsible for the decreased risks of fractures and bone loss among Japanese women. Additionally, natto may be responsible for the lower prevalence of atherosclerosis in Japan.
Life Extension: Additionally, those people taking vitamin K antagonists such as warfarin (Coumadin®) to prevent strokes are experiencing serious vitamin K deficiencies and are at increased risk for osteoporosis and calcification of their arteries.
Bruce Ames: Exactly. There are estimates that more than 30 million prescriptions for warfarin are written each year. Long-term warfarin therapy is linked to increased arterial calcification and bone loss. Additionally, there are observational studies that report associations between aortic valve calcification and long-term anticoagulant therapy. Coumadin® blocks the biosynthesis of MK-4 from vitamin K1.
Life Extension: How does this very basic information about the importance of vitamin K for people taking warfarin get into the hands of doctors prescribing the drug and for patients taking the drug? It seems pretty basic…you’re taking a drug that has a range of highly detrimental side effects. By taking a simple vitamin you can protect your skeletal system and limit atherosclerotic progression.
Bruce Ames: Most doctors don’t know anything about nutrition and have completely abdicated. Medicine is almost useless as far as nutrition goes. The only people interested in nutrition are those alternative medicine docs. When I go to the alternative medicine doc conventions, I’m treated like a rock star. They’ve read all my papers and are passionately into nutrition and preventive medicine.
Life Extension: Based on many facets of your research, if humans ingest optimal levels of nutrients from carnitine and lipoic acid to vitamin K, they could postpone degenerative diseases such as diabetes, cancer, and heart disease in addition to delaying the ravages of aging. As a result of strong nutritional practices and interventions, the doctors might be a little less busy.
Bruce Ames: There will always be a need for doctors. Everybody is going to die of something, we’re just extending the time frame. I’m a firm believer in preventive medicine—it’s much cheaper and you cut out expensive doctors, tests, procedures, and medications. Within about ten years, you’re going to put your finger in a machine, it’ll take a finger prick of blood and you will compare your numbers with some schedule on the Internet and you won’t need a doctor in most instances. Our analytic methods are improving in sensitivity and range every day.
Life Extension: Speaking of people dying, the incidence of obesity is astonishing. It simply did not exist in these proportions 20–30 years ago. Many doctors bemoan the fact that this is the first generation that the parents will outlive the children. Any thoughts?
Bruce Ames: Obese people are hungry all the time because the body is craving missing nutrients such as magnesium. Sixty percent of the American population is too low in magnesium. Instead of whole grains and vegetables, Americans are filling up with junk and are wildly deficient in vitamins and minerals. Even though people are obese and look like they are well fed, they are basically starving for vitamins and minerals.
According to a colleague of mine, Americans aren’t getting enough fiber especially because they need to eat more vegetables and whole grains. On top of which people are consuming vast amounts of simple sugars, which can poke holes in your gut. Bacteria are leaking through, triggering inflammation. The purpose of a balanced diet is to get all your vitamins and minerals, and we’re not doing that. We’re eating calorie-rich refined foods, and what we should be doing is eating more fruits and vegetables, more fish, more whole grains, less red meat, all the things your Mom told you about, and then we’ll be fine.
Life Extension: You’ve done a lot of work in cancer research. What, in your estimation, are the key factors for preventing cancer?
Bruce Ames: Eat a good diet. And then don’t smoke, because smoking takes about 8 or 10 years off your life. And I think bad diets are probably another 8 or 10 years off your life, though we don’t know the exact number. But I suspect it’s going to be even worse than smoking. And the costs are huge. You have to convince people that they’re going to lead miserable lives if they get fat, have years suffering from diabetes and their brain will be all fogged. The choice seems obvious to me.
Life Extension: Dr. Ames, many thanks for all your good work. We all benefit from your innovative research.
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Am J Clin Nutr. 2009 Oct;90(4):889-907. Epub 2009 Aug 19.
McCann JC, Ames BN.
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA. jmccann at chori.org
The triage theory posits that some functions of micronutrients (the approximately 40 essential vitamins, minerals, fatty acids, and amino acids) are restricted during shortage and that functions required for short-term survival take precedence over those that are less essential. Insidious changes accumulate as a consequence of restriction, which increases the risk of diseases of aging. For 16 known vitamin K-dependent (VKD) proteins, we evaluated the relative lethality of 11 known mouse knockout mutants to categorize essentiality. Results indicate that 5 VKD proteins that are required for coagulation had critical functions (knockouts were embryonic lethal), whereas the knockouts of 5 less critical VKD proteins osteocalcin, matrix Gla protein (Mgp), growth arrest specific protein 6, transforming growth factor beta-inducible protein (Tgfbi or betaig-h3), and periostin survived at least through weaning. The VKD gamma-carboxylation of the 5 essential VKD proteins in the liver and the 5 nonessential proteins in nonhepatic tissues sets up a dichotomy that takes advantage of the preferential distribution of dietary vitamin K1 to the liver to preserve coagulation function when vitamin K1 is limiting. Genetic loss of less critical VKD proteins, dietary vitamin K inadequacy, human polymorphisms or mutations, and vitamin K deficiency induced by chronic anticoagulant (warfarin/coumadin) therapy are all linked to age-associated conditions: bone fragility after estrogen loss (osteocalcin) and arterial calcification linked to cardiovascular disease (Mgp). There is increased spontaneous cancer in Tgfbi mouse knockouts, and knockdown of Tgfbi causes mitotic spindle abnormalities. A triage perspective reinforces recommendations of some experts that much of the population and warfarin/coumadin patients may not receive sufficient vitamin K for optimal function of VKD proteins that are important to maintain long-term health.
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