Adaptive Dysfunction of Selenoproteins From the Perspective of the Triage Theory: Why Modest Selenium Deficiency May Increase Risk of Diseases of Aging

Adaptive Dysfunction of Selenoproteins From the Perspective
of the Triage Theory: Why Modest Selenium Deficiency
May Increase Risk of Diseases of Aging

This section is compiled by Frank M. Painter, D.C.
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FROM:   FASEB J. 2011 (Jun);   25 (6):   1793–1814

McCann JC, Ames BN.

Nutrition and Metabolism Center,
Children's Hospital Oakland Research Institute,
Oakland, California, USA.

Selenium Deficiency May Increase Risk of Chronic Disease

SOURCE:   NUTRA Ingredients ~ March 16, 2011

By analyzing data from hundreds of published articles, Joyce McCann, PhD, and Bruce Ames, PhD, from Children's Hospital Oakland Research Institute (CHORI) report that selenium-dependent proteins considered essential to ensuring an organism survives until it reaches reproductive age are largely more resistant to selenium deficiency than non-essential selenoproteins.

Speaking with NutraIngredients-USA at his office in Oakland, Dr Ames called the new paper a “gorgeous review”, and said it adds to an earlier analysis of triage theory with vitamin K, published in the American Journal of Clinical Nutrition (2009, Vol. 90, pp. 889-907)>

Evolutionary mechanisms

Triage – from the French word trier meaning to sort, separate, or select – works on the battlefield by military doctors prioritizing treatments depending on the probable survival of the wounded.

Dr Ames’ theory works in much the same way: By appreciating that natural selection favors short-term survival over the long-term, Dr Ames’ hypothesized that our short-term survival is achieved by prioritizing the allocation of scarce micronutrients. In other words, to stop us falling over from a lack of iron in the heart, for example, iron is pulled from non-essential sources.

The triage theory is a way of “measuring the insidious damage going on over time”, he said.

The theory was first proposed in 2006 (Proc Natl Acad Sci U S A. 2006 (Nov 21);   103 (47):   17589-94) to explain why age-related diseases like heart disease, cancer, and dementia may be unintended consequences of mechanisms developed during evolution to protect against episodic vitamin/mineral shortages.

New insights

By analyzing the activity and concentrations of 12 selenoproteins, five of which were classified as essential and seven as non-essential, Drs McCann and Ames found that the activity and levels of non-essential selenoproteins were preferentially lost when the organism was moderately selenium deficient.

“Results of the analysis are largely supportive of the theory, suggesting that, among all selenoproteins, dysfunction of those that are nonessential is likely to be the major contributor to increased disease risk due to selenium deficiency,” wrote the Oakland-based scientists.

Indeed, the non-essential selenoprotein Dio2 has previously been linked to a wide range of diseases or conditions, including osteoarthritis, while Gpx1 may protect against DNA damage, and ultimately cancer risk, Gpx2 may exert ant-inflammatory effects, and Gpx3 has been implicated in improved cardiovascular health.

Implications for intakes

Drs McCann and Ames also report that current recommendations for selenium intake – based on maximizing blood activities of the selenium enzyme glutathione peroxidase (GPx) – may be insufficient, given that an essential selenium-dependent protein called Sepp1 was found to be more sensitive to selenium deficiency than Gpx3.

“The fact that Sepp1 is more sensitive to Se deficiency than Gpx3 in human plasma has important implications for estimating the percentage of the population that is modestly selenium deficient,” wrote Drs McCann and Ames.

“Since the current [US] RDA (55 micrograms per day, roughly corresponding to 100 micrograms per liter of plasma selenium) is based on the sensitivity of Gpx3 in plasma, Sepp1 is expected to be at suboptimal levels, even in some individuals meeting current selenium intake recommendations.

“Based on these findings, it recently was suggested that recommended selenium intake levels should be raised from 55 to 75 micrograms per day,” they added.

Speaking with NutraIngredients-USA, Dr Ames Dr Ames added that the vitamin K review had highlighted a ‘protein hierarchy’; while the new selenium review shows that there is also a ‘tissue hierarchy’.

Selenium and cancer

Selenium is a trace element that occurs naturally in the soil and is absorbed by plants and crops, from where it enters the human food chain - either directly or through consumption of meat and other products from grazing animals.

The mineral is included in between 50 and 100 different proteins in the body, with multifarious roles including building heart muscles and healthy sperm. However, cancer prevention remains one of the major benefits of selenium, and it is the only mineral that qualifies for a Food and Drug Administration (FDA)-approved qualified health claim for general cancer reduction incidence.

The Abstract:

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.

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