Moderate Intake of Selenium May Allow Essential Selenium Utilizing Proteins to Function at the Expense of Non-Essential Selenium Proteins: Triage Theory
Abstracted by Susan Sweeny Johnson, PhD, Biochem., from Joyce C. McCann and Bruce N. Ames. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. The FASEB Journal (June 2011) 25:1793-1814. www.fasebj.org/. Posted July 30, 2011.
Dr. Bruce Ames and Dr. Joyce McCann have proposed a triage theory of aging. If there is not an abundance of micronutrient vitamins or minerals in the body, the micronutrients that are available will be used first in protein-associated processes that are essential for the body to survive and successfully accomplish reproduction. Other processes non-essential to viability until successful reproduction that would maintain the body past reproductive age are sacrificed. Thus, when the body contains limited supplies of vitamins and minerals, aging is accelerated.
Previously the authors did a literature review of studies that looked at moderate and severe insufficiencies in Vitamin K (1). They concluded that Vitamin K was indeed preferentially used in essential protein functions. In this paper, the researchers further examined the triage theory via another literature review of studies related to moderate and severe deficiencies in selenium.
Selenium proteins have selenium incorporated into them during protein synthesis where selenium replaces sulfur in the amino acids cysteine and methionine. When selenium replaces sulfur in the active site of an enzyme, reactivity can increase 100 fold (2).
Knock-out studies in mice are commonly used to determine which micronutrient-associated proteins are essential and which are not. If a gene for a given protein is essential for survival or reproduction, then knocking it out (or removing it) will result in mortality or inability to produce viable offspring. In some cases humans may be born completely missing a gene. If the person survives and reproduces, this gene is determined to be non-essential. Five selenoproteins were determined to be essential via mouse knock-out studies while seven other selenoproteins were found to be non-essential.
In each study included, animals, usually mice, were fed various levels of selenium for more than a month. Then enzyme activities of both an essential and non-essential selenoprotein (SP) in a specific tissue were determined in cases where deficiency was moderate, severe and absent. Results for moderate and severe deficiencies in various tissues were reported as a percentage of the activity present when selenium was abundant. When possible, standard deviations and p values* were included.
In the first set of results, glutathione peroxidase 4 (Gpx4) the essential form of the family of Gpx’s, retained significantly more activity during moderate and severe selenium deficiencies in all tissues studied as compared to non-essential overall Gpx activity. These results appear to be statistically relevant with p values* ranging from < 0.0001 to 0.045 for different tissues (3,4).
Secondly, essential thioredoxin reductase 1 (Txnrd 1) activity was preferentially retained as compared to overall Gpx activity in moderately selenium deficient diets but seemed to not be retained in severely deficient diets. In this case, only the liver studies of moderate deficiency yielded statistically significant results (p<0.01)(4,5).
Thirdly, the activity of essential selenium transport protein 1 (Sepp1) was compared to non-essential Gpx3 during moderate and severe selenium deficiency in both mouse and human plasma. Although Sepp1 activity was preferentially retained in mice during moderate (p not determined) and severe deficiency (p=0.0056), in humans, Gpx3 activity was preferentially preserved in severe deficiency (p not determined) (6,7).
In further support of the triage theory, studies of the essential SPs, Gpx4, Txnrd1, and Sepp1, showed that the activity of these proteins rebounded faster that that of non-essential SPs when selenium was reintroduced into the animals (8-10).
Other studies included in this literature review yielded variable results (11-14).
The authors conclude that essential selenoproteins or SPs are in general more resistant than non-essential SPs to selenium deficiency. Further, loss of non-essential SP activities creates symptoms similar to age related disorders (15-17).
If the triage theory for general vitamin/mineral usage is correct, it becomes important to supplement the diet as necessary to prevent even moderate deficiencies that could result in premature aging. Even in the US, moderate deficiencies in certain vitamins and minerals occur particularly in the poor, the obese, or the elderly.
The authors suggest that although selenium deficiency isn’t common in the US, the RDA should be increased to 75micrograms/day to ensure sufficient body levels.
*p is a measure of the statistical significance of a trend. P< 0.05 is considered to be significant.
- McCann, J. C., and Ames, B. N. (2009) Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am. J. Clin. Nutr. 90, 889–907
- Arne´r, E. S. (2010) Selenoproteins – what unique properties can arise with selenocysteine in place of cysteine? Exp. Cell Res. 316, 1296–1303
- Barnes, K. M., Evenson, J. K., Raines, A. M., and Sunde, R. A. (2009) Transcript analysis of the selenoproteome indicates that dietary selenium requirements of rats based on seleniumregulated selenoprotein mRNA levels are uniformly less than those based on glutathione peroxidase activity. J. Nutr. 139, 199–206
- Lei, X. G., Evenson, J. K., Thompson, K. M., and Sunde, R. A. (1995) Glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are differentially regulated in rats by dietary selenium. J. Nutr. 125, 1438–1446
- Wu, Q., and Huang, K. (2004) Effect of long-term SE deficiency on the antioxidant capacities of rat vascular tissue. Biol. Trace Elem. Res. 98, 73–84132. Xia, Y., Hill, K. E., Byrne, D. W., Xu, J., and Burk, R. F. (2005)
- Xia, Y., Hill, K. E., Byrne, D. W., Xu, J., and Burk, R. F. (2005)Effectiveness of selenium supplements in a low-selenium area of China. Am. J. Clin. Nutr. 81, 829–834
- Yang, J. G., Hill, K. E., and Burk, R. F. (1989) Dietary selenium intake controls rat plasma selenoprotein P concentration. J. Nutr. 119, 1010–1012
- Weitzel, F., Ursini, F., and Wendel, A. (1990) Phospholipid hydroperoxide glutathione peroxidase in various mouse organs during selenium deficiency and repletion. Biochim. Biophys. Acta 1036, 88–94
- Bermano, G., Nicol, F., Dyer, J. A., Sunde, R. A., Beckett, G. J., Arthur, J. R., and Hesketh, J. E. (1996) Selenoprotein gene expression during selenium-repletion of selenium-deficient rats. Biol. Trace Elem. Res. 51, 211–223
- Hill, K. E., McCollum, G. W., Boeglin, M. E., and Burk, R. F. (1997) Thioredoxin reductase activity is decreased by selenium deficiency. Biochem. Biophys. Res. Commun. 234, 293–295
- Bermano, G., Nicol, F., Dyer, J. A., Sunde, R. A., Beckett, G. J., Arthur, J. R., and Hesketh, J. E. (1995) Tissue-specific regulation of selenoenzyme gene expression during selenium deficiency in rats. Biochem. J. 311, 425–430
- Mitchell, J. H., Nicol, F., Beckett, G. J., and Arthur, J. R. (1996) Selenoenzyme expression in thyroid and liver of second generation selenium- and iodine-deficient rats. J. Mol. Endocrinol. 16, 259–267
- Uthus, E. O., and Moskovitz, J. (2007) Specific activity ofmethionine sulfoxide reductase in CD-1 mice is significantlyaffected by dietary selenium but not zinc. Biol. Trace. Elem. Res.115, 265–276
- Novoselov, S. V., Calvisi, D. F., Labunskyy, V. M., Factor, V. M.,Carlson, B. A., Fomenko, D. E., Moustafa, M. E., Hatfield, D. L., andGladyshev, V. N. (2005) Selenoprotein deficiency and high levels ofselenium compounds can effectively inhibit hepatocarcinogenesis intransgenic mice. Oncogene 24, 8003–8011
- Bellinger, F. P., Raman, A. V., Reeves, M. A., and Berry, M. J. (2009) Regulation and function of selenoproteins in human disease. Biochem. J. 422, 11–22
- Lu, J., and Holmgren, A. (2009) Selenoproteins. J. Biol. Chem. 284, 723–727
- Brigelius-Flohe´, R., and Kipp, A. (2009) Glutathione peroxidases in different stages of carcinogenesis. Biochim. Biophys. Acta 1790, 1555–1568