Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 14 No. 3 • June-July 2011


The Triage Theory of Aging: Why Modest Inadequacy of Vitamins or Minerals May Increase Diseases of Aging Later

An interesting and potentially important new theory of aging1-3 posits that, while modest inadequacies of vitamins or minerals may not appear to cause short-term negative effects (such as reduced survival), in the long run they may be the basis for insidious effects such as increased risk of age-related diseases. This theory may be important for explaining how the widespread modestly inadequate intake of many vitamins and minerals in the United States and other advanced industrialized countries results, in association with the increasing lifespan in those countries, with more people at risk of age-related diseases. Thus, avoiding those deficiencies in early life can have large benefits that show up in life much later on.

As the latest paper on the triage theory explains,4 “when the dietary availability of a V/M [vitamin/mineral] is moderately inadequate, nature ensures that V/M-dependent functions that are essential from an evolutionary perspective (i.e., required for short-term survival and/or reproduction) are protected at the expense of those that are less essential (i.e., whose lack does not have acute short-term negative consequences but may have long-term insidious effects that increase risk of diseases associated with aging). The triage theory does not imply that any particular V/M 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.” The authors suggest that, if the triage theory is correct, it would have major implications for public health, since as they note (with references cited), most people are modestly deficient in one or more V/Ms and that includes not only poor countries but wealthy countries, especially among the less wealthy, the obese and the elderly.

While this theory is very plausible, there is still a need for significant evidence in order to establish its validity. Hence, the authors have previously published a paper on Vitamin K as an example.3 The new paper4 has analyzed a huge amount of data from published studies to look at selenoproteins from the perspective of triage theory; the paper is 21 pages long and includes 295 references.

As the authors explain in their new paper, the triage theory makes three predictions concerning selenoproteins (SPs): 1. Essential SPs are more resistant than nonessential SPs to Se (selenium) deficiency. 2. Decreased functionality of nonessential SPs increases risk of diseases of aging. 3. There is evidence of a causal relationship between decreased functionality of nonessential SPs and increased risks of diseases of aging. As you can well imagine, to support these hypotheses required the analysis of an immense amount of evidence. We will present a few examples of how the authors assessed the data.

First, it was necessary to determine what selenoproteins (SPs) are “essential” and which ones are “nonessential,” requiring a separate analysis. As the authors explain, they used a model for essentiality in which they looked at mouse KOs (knockouts) for various selenoproteins to determine which ones were either embryonically lethal or where offspring had severely reduced fertility, Those SPs would be “essential” from the perspective of evolution because they would have negative effects on short-term survival and/or negative effects on reproduction. Though the authors recognize that a rodent knockout model is not an ideal or perfect way to identify “essential” uses for vitamins or minerals in humans, it is a reasonable way to begin an inherently complex analysis. In this way, the authors were able to determine, for example, that cytosolic Gpx4 (selenium-containing glutathione peroxidase 4) was essential for embryonic development and another, mitochondrial Gpx4 (selenium-containing glutathione peroxidase 4) was essential for fertility. “The lethality of the cGpx4 KO is consistent with its unique function in protecting against damage from lipid peroxidation and participating in critical lipid peroxide signaling pathways. Severe infertility of mGpx4-KO offspring is also not surprising, given the fact that mGpx4 plays an essential structural role in spermatozoa.”

Prediction 1 proposed that essential SPs would be more resistant than nonessential SPs to selenium deficiency. In other words, when there is only a limited supply of selenium available, it would be expected that the essential selenoproteins would get selenium so as to be able to fulfill their more critical functions before any remaining selenium would be distributed to the nonessential selenoproteins. To determine this, in one example, the authors looked at the relative sensitivities to deficiency of Gpx4 to overall Gpx activity (primarily Gpx1) in rodent models of modest and severe selenium deficiency in liver, kidney, thyroid, muscle, heart, lung, and testis, and (as they report) the essential SP Gpx4 was more resistant to selenium deficiency (either moderate or severe) compared to overall Gpx activity (primarily Gpx1) in all rodent tissues examined. The data for these analyses were obtained from 37 research reports. “... differences between Gpx4 and overall Gpx activity are significant in almost all cases where statistical comparisons were possible (i.e., where >2 experiments were available) ...”

Going on to Predictions 2 and 3, the authors examined the literature to analyze whether decreased functionality of nonessential SPs increase the risk of diseases of aging, and whether there is evidence of a causal relationship. As the authors note, “[i]t is extremely difficult, if not impossible, to test this prediction directly in long-term randomized controlled trials, as we have discussed.” Hence, this analysis used epidemiological studies and other genetic and mechanistic evidence “to ask whether the same diseases or conditions of aging that are prospectively associated with modest Se [selenium] deficiency are also linked to phenotypes of nonessential SP mouse KOs or human mutants, and whether plausible mechanisms suggest a causal connection between these same SPs and diseases.” The authors point out that there is a large body of evidence that links genetic loss of nonessential SP activities to phenotypes similar to those of diseases or conditions of aging associated with modest Se deficiency, suggesting that causal linkages between dysfunction of nonessential SPs and diseases of aging is possible. As they explain, the intent of these data “is not to imply that relationships are necessarily fully established or that causal linkages have been clearly demonstrated” but to establish that enough evidence exists to provide plausibility to the causal relationship.

The authors also note that mutated versions (SNPs, single nucleotide polymorphisms of the selenoprotein gene) of essential SPs are also linked to age-related diseases and point out this is not inconsistent with the triage theory, which “predicts only that modest Se defiency is more likely to impair nonessential SPs than essential SPs.” Moreover, as they also point out, there are many causal factors other than genetic and nutritional ones that may impact the likelihood of disease.

The authors conclude that predictions 1, 2, and 3 were largely borne out by the data. They note, for example, that numerous epidemiological studies “suggest that Se deficiency is prospectively linked to increased cancer risk, and various mutants in mice and humans are also linked to increases in cancer risk. Other diseases or conditions prospectively associated with modest Se deficiency that are similar to nonessential SP mutant phenotypes ... include increased DNA damage, increased cardiovascular disease and related conditions, reduced resistance to infection (primarily viral), and poor cognitive function.” The authors then go on to analyze a variety of mechanisms that might be involved in the increased risk of these diseases.

In summing up, the authors explain that “The most obvious value of the theory is that it provides a rationale for why a particular class of V/M [vitamin-mineral]-dependent proteins (i.e., those that are nonessential) may not be fully functional even at modest levels of V/M [vitamin-mineral] deficiency not accompanied by any obvious clinical signs. The value of this insight is that it suggests a strategy for identifying sensitive biomarkers of V/M [vitamin-mineral] deficiency and candidate proteins mechanistically linked to disease. An important limitation of broadly applying the approach followed here is that mouse KOs are not necessarily reliable predictors of essentiality in humans ... because of many species differences, some known and some as yet unknown.”

We thank the authors both for creating the triage theory1,2 and for the incredible amount of work done in the examination of the evidentiary basis for the triage theory.3,4 The result is truly a valuable contribution to public health. We hope it gets the attention it deserves.

References

  1. Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Natl Acad Sci USA 103:17589-94 (2006).
  2. Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids 725071 (2010).
  3. McCann and Ames. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr 90:889-907 (2009).
  4. McCann and Ames. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J 25:1793-1814 (2011).

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