expert opinion

The Triage Theory

February 1, 2011

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Bruce N. Ames, Ph.D., Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland (CA), USA.

“Evolution has equipped us with a triage mechanism (from the French verb ‘trier’ meaning to sort out): When there is a deficiency of micronutrients in our bodies, they are reserved for short-term survival and reproduction at the expense of disabling DNA repair, which increases the risk of developing chronic disease in the long-term. Anytime we do not have enough micronutrients, we are paying a price in long-term DNA damage. If we want maximum life span, our micronutrient needs must be met throughout life. The ‘triage theory’ provides a unifying rationale for a causal link between chronic, modest deficiency of a micronutrient and the many degenerative diseases accompanying aging, such as cancer, immune dysfunction, cognitive decline, cardiovascular disease and strokes. The triage theory predicts that optimizing intake of the roughly 40 essential micronutrients will reduce the risk of chronic diseases associated with aging and increase lifespan. If the theory is correct, incidences of these diseases might be reduced by an inexpensive intervention with micronutrients (1, 2).

The triage theory posits that during evolution, as a result of periods of shortage of micronutrients required by various proteins for function, nature selects organisms capable of rebalancing their metabolism. This rebalancing ensures survival of the organism at the expense of a healthy metabolic state, which results in accumulation of insidious damage leading to longer-term consequences mentioned above including chronic diseases of aging. That nature may have developed such a system is logically consistent with the consensus that natural selection favors short-term survival for reproduction over long-term health. There is, for example, a known triage between organs: If you are short of iron, the body takes it out of the liver before the heart, because if iron is taken from the heart, the body will die. And one of the long-term consequences is DNA damage, which is relatively unimportant when one is starving but can result in cancer after a delay of 20 years. Over the millions of years of evolutionary time up till now, micronutrient shortages were likely to be very common, for example, the 15 essential minerals are not distributed evenly on the earth; dietary sources and availability also fluctuated markedly.

Micronutrient intakes below recommended levels are unusually widespread in poor countries, but also in developed countries in all segments of society, especially the poor, children, adolescents, the obese and the elderly. High consumption of calorie-rich, micronutrient-poor unbalanced diets exacerbates the problem. Over half of the US population has inadequate intakes of magnesium, for instance, and almost all African-Americans have extremely low vitamin D levels. Much of the population suffers a lack in a variety of other micronutrients, such as omega-3 fatty acids, potassium, calcium, vitamin C, vitamin E and vitamin K (3, 4). The results can be damaging to the body. When the supply of vitamin K is limited, as it is in the typical western diet, the body uses what little it can find to protect critical metabolic functions in the liver. Unfortunately, that leaves other vitamin K-dependent proteins, the ones associated with bone building, cancer prevention, and protecting the heart from atherosclerosis, without sufficient vitamin K to function properly. The result leaves the body at risk for developing age-related diseases like cancer, heart disease and osteoporosis.

There is little societal concern because no overt pathologies have been associated with marginal to moderate levels of deficiency. The triage theory predicts that the pathology is insidious, but we believe that it is measurable. We hypothesize that two of the many, possibly measurable consequences of moderate micronutrient deficiency are increased DNA damage (future cancer) and mitochondrial decay (mutagenic oxidant release, future cancer, and cognitive dysfunction), as aspects of a triage response. Risk of diseases, such as cardiovascular disease and immune dysfunction (5), is also increased by micronutrient deficiencies. Likelihood of these consequences is known to increase with age.

It is common for proteins to become deformed with age, for example, membranes become stiffer from oxidation, deforming membrane proteins, particularly in mitochondria. These age-related changes often result in proteins (enzymes) which have a decreased binding affinity for a vitamin-dependent coenzyme or a substrate, resulting in a reduced enzymatic activity. It has been shown that such reduced enzymatic activity can be restored to proximate levels by administering high doses of the vitamin component of the corresponding coenzyme (6). This raises the question of whether high dosages of vitamins may be beneficial to the elderly. These observations also reinforce the importance of considering age when making dietary recommendations.

In addition, it has been shown that several genetic variations (single-nucleotide polymorphisms), in which vitamin-dependent coenzyme binding and thus enzymatic activity is reduced, can be to be compensated for with a high dietary intake of the corresponding vitamin. This dietary remediation illustrates the importance of understanding the effects of polymorphisms on optimal micronutrient requirements. Some appreciable percentage of the population may require a higher level of a particular vitamin or substrate for optimum functioning of the body. We believe that the analysis of binding constants is the beginning of a large field that will make it possible to overcome a large class of deleterious genetic changes by nutritional interventions. The triage hypothesis may facilitate the discovery of sensitive and specific biomarkers of micronutrient insufficiencies that can be used to optimize metabolism at a personal and population level.

Various lines of evidence suggest that healthier lives are to be gained by optimizing our metabolism. More attention to balanced diets and optimizing micronutrient intake could have a major effect on delaying the degenerative diseases of aging. My vision is that this will be done in the future by individuals measuring their own levels of micronutrients from a finger prick of blood in a machine in their local pharmacy, and tuning up their metabolism by adjusting diet or taking supplements – the beginning of an age of true preventive medicine.”

Oakland, USA, 2010

References

  1. Ames B. N. A theory of evolutionary allocation of scarce micronutrients by enzyme triage: adequate micronutrient nutrition to delay the degenerative diseases of aging. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103:17589–17594.
  2. Ames B. N. Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mechanisms of Ageing and Development. 2010; 131(7-8):473–479.
  3. McCann J. C. and Ames B. N. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? American Journal of Clinical Nutrition. 2009; 90(4):889–907.
  4. Moshfegh A. et al. What We Eat in America, NHANES 2001-2002: Usual Nutrient Intakes from Food Compared to Dietary Reference Intakes. U.S. Department of Agriculture, Agricultural Research Service, 2005.
  5. Ames B. N. and McCann J. C. Foreword: prevention of cancer, and the other degenerative diseases of aging, through nutrition. In: Knasmüller S. et al. Chemoprevention of Cancer and DNA Damage by Dietary Factors. Weinheim, Germany: Wiley-VCH; 2009.
  6. Ames B. N. Prevention of Mutation, Cancer, and Other Age-Associated Diseases by Optimizing Micronutrient Intake. J Nucleic Acids. 2010.