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Can ageing be prevented by dietary restriction?
Mechanisms of Ageing and Development 128 (2007) 227–228 www.elsevier.com/locate/mechagedev
Short communication
Can ageing be prevented by dietary restriction? Miklo´s Pe´ter Kalapos * Theoretical Biology Research Group, Da´mvad utca 18, H-1029 Budapest, Hungary Received 6 September 2006; received in revised form 24 October 2006; accepted 8 November 2006 Available online 4 December 2006
Abstract This paper disputes the suggestion of Hipkiss [Hipkiss, A., 2006. On the mechanisms of ageing suppression by dietary restriction—is persistent glycolysis the problem? Mech. Ageing Dev. 127, 8–15], according to which dietary restriction by decreasing methylglyoxal production may prevent ageing. A list of arguments is given to support the refusal of hypothesis: (i) it has never been proven that the main source of methylglyoxal is its formation from triose-phosphate intermediates of glycolysis; (ii) the above note particularly applies to pathological conditions as acetone breakdown and amino acid metabolism also come into picture under these circumstances; (iii) glycolysis is of vital importance, thus its inhibition or a sharp restriction of carbohydrate uptake are unlikely beneficial for those tissues that are exclusively dependent on glycolysis in the regard of their energy production. Taken these concerns into account and considered all the promising attempts to influence the toxic effects of methylglyoxal, it is feared that the theory, as it is, cannot offer benefit to prevent ageing. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Glycolysis; Methylglyoxal; Acetone; Aminoacetone; Dietary restriction
In a recent paper, Hipkiss (2006) claims the introduction of dietary restriction as a possible way of protecting humans from ageing and related pathologies. The idea is that persistent glycolysis leads to a continuous production of glycolytic intermediates that modify macromolecules and are potentially toxic to the cells (Hipkiss, 2006). Particular attention has been paid to methylglyoxal which is, according to Hipkiss (2006), predominantly generated from the glycolytic intermediate triose-phosphates. By listing deleterious effects of methylglyoxal, Hipkiss (2006) argues for the possible impact of a diet and proposes the manipulation of anti-methylglyoxal defences. Having knowledge of concerns about the health problems caused by the overweight of human population, such a proposal would be encouraged, whereas several problems arise that need consideration. At the first look the hypothesis is self-evident. However, after a careful consideration it turns out that the paper obviously misses an important biochemical point. Namely, methylglyoxal is produced not only from glycolytic intermediates, dihydroxyacetone- and glyceraldehyde-3-phosphates, but also from aminoacetone, an offshoot of threonine and glycine metabolism,
* Tel.: +36 1 201 93 24; fax: +36 1 201 93 24. E-mail address: [email protected]. 0047-6374/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2006.11.027
and from acetone (Ray and Ray, 1998; Kalapos, 1999). Though the author truly describes these opportunities in one dependent clause, indeed those are forgotten in the remainder part of the text (Hipkiss, 2006). Moreover, the generation of triose-phosphates is not exclusively dependent on the rate of glycolysis. The alterations of triose-phosphate pool are also linked to other elements such as the flux through pentose-phosphate pathway or the activity of a-glycerophosphate dehydrogenase (EC 1.1.1.8). Probably, under normal conditions the statement that methylglyoxal is predominantly produced from the glycolytic intermediates may be true, even if as yet not proven. But under dietary restriction the aforementioned statement is more than questionable. It has been reported that ketogenic diet, a highfat, low-carbohydrate, low-protein diet causes an increase in the production of ketone bodies, including acetone, too (MusaVeloso, 2004). Acetone is a well-known inducer of CYP2E1 isozymes participating in the conversion of acetone through acetol into methylglyoxal (Gonzalez, 1989). In the most drastic food restriction, in starvation, the serum level of acetone is elevated by several fold and CYP2E1 isozymes are induced, as well (Gonzalez, 1989). Thus, an increased capacity of this route is strongly suggestive in case of food restriction. Hence, we have every reason for the assumption of a role for acetone metabolism in methylglyoxal production during dietary restriction.
228
M.P. Kalapos / Mechanisms of Ageing and Development 128 (2007) 227–228
Furthermore, aminoacetone is also a source of methylglyoxal. L-Threonine dehydrogenase (EC 1.1.1.103) catalyses a NAD+-dependent oxidation of L-threonine to 2-amino-3oxobutyrate, which is then split to glycine and acetyl-coA by the aminoacetone synthase (EC 2.3.1.29), if coA is present (Bird et al., 1984). These two enzymes function in association and glycine production dominates over aminoacetone formation (Bird et al., 1984). When acetyl-coA/coA ratio is high, then 2-amino-3-oxo-butyrate intermediate of these reactions is mainly directed to the production of aminoacetone being oxidized to methylglyoxal by semicarbazide-sensitive amine oxidase (EC 1.4.3.6.) (Bird et al., 1984; Lyles, 1996). On this basis of knowledge, in food restriction, aminoacetone and methylglyoxal formation seem very feasible. Since nobody has so far measured the percentage contribution to methylglyoxal production of potential sources, it cannot be stated that dietary restriction would lead to a decrease of the rate of methylglyoxal formation. Hence, the opposite might also be suggested. Another point needs also to be added. As Vander Jagt et al. (2001) stressed, in the presence of glutathione, aldose reductase (EC 1.1.1.21) functions as a ketone reductase, thus the efficacy of reduction of methylglyoxal by the enzyme to lactaldehyde increases. However, when intracellular glutathione concentration is below normal, the metabolic importance of aldose reductase in the disposal of 1,2-dicarbonyl exceeds that of glyoxalase route and, instead of catalysing lactaldehyde formation, it catalyses the formation of acetol (Vander Jagt et al., 2001). If this is the case, then acetol can be converted back to methylglyoxal by either an oxidation governed by CYP2E1 isozymes or undergoing a disproportionation in the presence of copper ions without any enzyme (Vander Jagt et al., 2001). As in food restriction glutathione levels may drop (Kalapos et al., 1991), acetol formation from methylglyoxal can easily occur and result in an undesirable futile cycle. From medical point of view, an additional and seemingly philosophical aspect has to be addressed that refers to the essence of clinical research. The modification of methylglyoxal formation by food restriction involves complex sequential reactions, that are associated with each other. The inhibition of one of the pathways may lead to changes in the other. In medical interventions, it is always a question whether that particular intervention is beneficial or not. This consideration has to be kept in mind while thinking of the prevention of ageing. In the present time medicine or in the near future, there are or there will be several opportunities to influence methylglyoxal metabolism. For instance, the inhibition of methylglyoxal production from aminoacetone can be prevented with aminoguanidine (Lyles, 1996), the depletion of methylglyoxal by aminoguanidine and other hydrazine drugs seems also to be a fruitful direction even though the by-effects of depleting agents are obvious (Ruggerio-Lopez et al., 1999; Khalifah et al., 1999). Perhaps, L-arginine can be accounted for the most promising agent that limits free carbonyl concentrations (Khalifah et al., 1999). And also, the enhancement of methylglyoxal breakdown by the induction of glyoxalase I would lead to an enhanced anti-carbonyl defence mechanism
(Shinohara et al., 1998). Anti-glycated protein antibodies have already been developed and these can perhaps retard pathological events (Shamai et al., 1998). Living organisms have the ability to form methylglyoxal. Since the description of Embden-Meyerhof scheme of glucose breakdown methylglyoxal has lost its central role in biochemical thinking. But it is beyond doubt that methylglyoxal formation is bound to some degree to an operative glycolysis. Therefore, its production is unavoidable. Glycolysis is an essential biochemical route for energy production. There are several tissues, e.g. some brain regions, red blood cells, for which the biochemical energy is exclusively provided by glycolysis. The above notes rightly propound the real question. To what extent the operation of glycolysis is allowed, if at all, to be inhibited in order to prevent ageing by minimizing methylglyoxal production without influencing normal vital reactions. As mentioned above, there are other opportunities to reach this goal, therefore, it is feared that the suggestion of dietary restriction in its present form raises scruples.
References Bird, M.I., Nunn, P.B., Lord, L.A.J., 1984. Formation of glycine and aminoacetone from L-threonine by rat liver mitochondria. Biochim. Biophys. Acta 802, 229–236. Gonzalez, F.J., 1989. The molecular biology of cytochrome P450s. Pharmacol. Rev. 40, 243–288. Hipkiss, A., 2006. On the mechanism of ageing suppression by dietary restriction—Is persistent glycolysis the problem? Mech. Ageing Dev. 127, 8–15. Kalapos, M.P., 1999. Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications. Toxicol. Lett. 110, 145–175. Kalapos, M.P., Garzo´, T., Antoni, F., Mandl, J., 1991. Effect of methylglyoxal on glucose formation, drug oxidation and glutathione content in isolated murine hepatocytes. Biochim. Biophys. Acta 1092, 284–290. Khalifah, R.G., Baynes, J.W., Hudson, B.G., 1999. Amadorins: novel postAmadori inhibitors of advanced glycation reactions. Biochem. Biophys. Res. Commun. 257, 251–258. Lyles, G.A., 1996. Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspests. Int. J. Biochem. Cell Biol. 28, 259–274. Musa-Veloso, K., 2004. Non-invasive detection of ketosis and its application in refractory epilepsy. Prostagl. Leucotr. Ess. Fatty Acids 70, 329–335. Ray, M., Ray, S., 1998. Methylglyoxal: from a putative intermediate of glucose breakdown to its role in understanding that excessive ATP formation in cell may lead to malignancy. Curr. Sci. 75, 103–113. Ruggerio-Lopez, D., Lecomte, M., Moinet, G., Patereau, G., Lagarde, M., Wiernsperger, N., 1999. Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation. Biochem. Pharmacol. 58, 1765–1773. Shamai, F.A., Partal, A., Sady, C., Glomb, M.A., Nagaraj, R.H., 1998. Immunological evidence for methylglyoxal-derived modifications in vivo. J. Biol. Chem. 273, 6928–6936. Shinohara, M., Thornalley, P.J., Giardion, I., Beisswenger, P., Thorpe, S.R., Onorato, J., Brownlee, M., 1998. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J. Clin. Invest. 101, 1142–1147. Vander Jagt, D.L., Hassenbrook, R.K., Hunsaker, L.A., Brown, W.M., Royer, R.E., 2001. Metabolism of the 2-oxoaldehyde methylglyoxal by aldose reductase and by glyoxalase-I: roles for glutathione in both enzymes and implications for diabetic complications. Chem. Biol. Interact. 130–132, 549–562.
Short communication
Can ageing be prevented by dietary restriction? Miklo´s Pe´ter Kalapos * Theoretical Biology Research Group, Da´mvad utca 18, H-1029 Budapest, Hungary Received 6 September 2006; received in revised form 24 October 2006; accepted 8 November 2006 Available online 4 December 2006
Abstract This paper disputes the suggestion of Hipkiss [Hipkiss, A., 2006. On the mechanisms of ageing suppression by dietary restriction—is persistent glycolysis the problem? Mech. Ageing Dev. 127, 8–15], according to which dietary restriction by decreasing methylglyoxal production may prevent ageing. A list of arguments is given to support the refusal of hypothesis: (i) it has never been proven that the main source of methylglyoxal is its formation from triose-phosphate intermediates of glycolysis; (ii) the above note particularly applies to pathological conditions as acetone breakdown and amino acid metabolism also come into picture under these circumstances; (iii) glycolysis is of vital importance, thus its inhibition or a sharp restriction of carbohydrate uptake are unlikely beneficial for those tissues that are exclusively dependent on glycolysis in the regard of their energy production. Taken these concerns into account and considered all the promising attempts to influence the toxic effects of methylglyoxal, it is feared that the theory, as it is, cannot offer benefit to prevent ageing. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Glycolysis; Methylglyoxal; Acetone; Aminoacetone; Dietary restriction
In a recent paper, Hipkiss (2006) claims the introduction of dietary restriction as a possible way of protecting humans from ageing and related pathologies. The idea is that persistent glycolysis leads to a continuous production of glycolytic intermediates that modify macromolecules and are potentially toxic to the cells (Hipkiss, 2006). Particular attention has been paid to methylglyoxal which is, according to Hipkiss (2006), predominantly generated from the glycolytic intermediate triose-phosphates. By listing deleterious effects of methylglyoxal, Hipkiss (2006) argues for the possible impact of a diet and proposes the manipulation of anti-methylglyoxal defences. Having knowledge of concerns about the health problems caused by the overweight of human population, such a proposal would be encouraged, whereas several problems arise that need consideration. At the first look the hypothesis is self-evident. However, after a careful consideration it turns out that the paper obviously misses an important biochemical point. Namely, methylglyoxal is produced not only from glycolytic intermediates, dihydroxyacetone- and glyceraldehyde-3-phosphates, but also from aminoacetone, an offshoot of threonine and glycine metabolism,
* Tel.: +36 1 201 93 24; fax: +36 1 201 93 24. E-mail address: [email protected]. 0047-6374/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2006.11.027
and from acetone (Ray and Ray, 1998; Kalapos, 1999). Though the author truly describes these opportunities in one dependent clause, indeed those are forgotten in the remainder part of the text (Hipkiss, 2006). Moreover, the generation of triose-phosphates is not exclusively dependent on the rate of glycolysis. The alterations of triose-phosphate pool are also linked to other elements such as the flux through pentose-phosphate pathway or the activity of a-glycerophosphate dehydrogenase (EC 1.1.1.8). Probably, under normal conditions the statement that methylglyoxal is predominantly produced from the glycolytic intermediates may be true, even if as yet not proven. But under dietary restriction the aforementioned statement is more than questionable. It has been reported that ketogenic diet, a highfat, low-carbohydrate, low-protein diet causes an increase in the production of ketone bodies, including acetone, too (MusaVeloso, 2004). Acetone is a well-known inducer of CYP2E1 isozymes participating in the conversion of acetone through acetol into methylglyoxal (Gonzalez, 1989). In the most drastic food restriction, in starvation, the serum level of acetone is elevated by several fold and CYP2E1 isozymes are induced, as well (Gonzalez, 1989). Thus, an increased capacity of this route is strongly suggestive in case of food restriction. Hence, we have every reason for the assumption of a role for acetone metabolism in methylglyoxal production during dietary restriction.
228
M.P. Kalapos / Mechanisms of Ageing and Development 128 (2007) 227–228
Furthermore, aminoacetone is also a source of methylglyoxal. L-Threonine dehydrogenase (EC 1.1.1.103) catalyses a NAD+-dependent oxidation of L-threonine to 2-amino-3oxobutyrate, which is then split to glycine and acetyl-coA by the aminoacetone synthase (EC 2.3.1.29), if coA is present (Bird et al., 1984). These two enzymes function in association and glycine production dominates over aminoacetone formation (Bird et al., 1984). When acetyl-coA/coA ratio is high, then 2-amino-3-oxo-butyrate intermediate of these reactions is mainly directed to the production of aminoacetone being oxidized to methylglyoxal by semicarbazide-sensitive amine oxidase (EC 1.4.3.6.) (Bird et al., 1984; Lyles, 1996). On this basis of knowledge, in food restriction, aminoacetone and methylglyoxal formation seem very feasible. Since nobody has so far measured the percentage contribution to methylglyoxal production of potential sources, it cannot be stated that dietary restriction would lead to a decrease of the rate of methylglyoxal formation. Hence, the opposite might also be suggested. Another point needs also to be added. As Vander Jagt et al. (2001) stressed, in the presence of glutathione, aldose reductase (EC 1.1.1.21) functions as a ketone reductase, thus the efficacy of reduction of methylglyoxal by the enzyme to lactaldehyde increases. However, when intracellular glutathione concentration is below normal, the metabolic importance of aldose reductase in the disposal of 1,2-dicarbonyl exceeds that of glyoxalase route and, instead of catalysing lactaldehyde formation, it catalyses the formation of acetol (Vander Jagt et al., 2001). If this is the case, then acetol can be converted back to methylglyoxal by either an oxidation governed by CYP2E1 isozymes or undergoing a disproportionation in the presence of copper ions without any enzyme (Vander Jagt et al., 2001). As in food restriction glutathione levels may drop (Kalapos et al., 1991), acetol formation from methylglyoxal can easily occur and result in an undesirable futile cycle. From medical point of view, an additional and seemingly philosophical aspect has to be addressed that refers to the essence of clinical research. The modification of methylglyoxal formation by food restriction involves complex sequential reactions, that are associated with each other. The inhibition of one of the pathways may lead to changes in the other. In medical interventions, it is always a question whether that particular intervention is beneficial or not. This consideration has to be kept in mind while thinking of the prevention of ageing. In the present time medicine or in the near future, there are or there will be several opportunities to influence methylglyoxal metabolism. For instance, the inhibition of methylglyoxal production from aminoacetone can be prevented with aminoguanidine (Lyles, 1996), the depletion of methylglyoxal by aminoguanidine and other hydrazine drugs seems also to be a fruitful direction even though the by-effects of depleting agents are obvious (Ruggerio-Lopez et al., 1999; Khalifah et al., 1999). Perhaps, L-arginine can be accounted for the most promising agent that limits free carbonyl concentrations (Khalifah et al., 1999). And also, the enhancement of methylglyoxal breakdown by the induction of glyoxalase I would lead to an enhanced anti-carbonyl defence mechanism
(Shinohara et al., 1998). Anti-glycated protein antibodies have already been developed and these can perhaps retard pathological events (Shamai et al., 1998). Living organisms have the ability to form methylglyoxal. Since the description of Embden-Meyerhof scheme of glucose breakdown methylglyoxal has lost its central role in biochemical thinking. But it is beyond doubt that methylglyoxal formation is bound to some degree to an operative glycolysis. Therefore, its production is unavoidable. Glycolysis is an essential biochemical route for energy production. There are several tissues, e.g. some brain regions, red blood cells, for which the biochemical energy is exclusively provided by glycolysis. The above notes rightly propound the real question. To what extent the operation of glycolysis is allowed, if at all, to be inhibited in order to prevent ageing by minimizing methylglyoxal production without influencing normal vital reactions. As mentioned above, there are other opportunities to reach this goal, therefore, it is feared that the suggestion of dietary restriction in its present form raises scruples.
References Bird, M.I., Nunn, P.B., Lord, L.A.J., 1984. Formation of glycine and aminoacetone from L-threonine by rat liver mitochondria. Biochim. Biophys. Acta 802, 229–236. Gonzalez, F.J., 1989. The molecular biology of cytochrome P450s. Pharmacol. Rev. 40, 243–288. Hipkiss, A., 2006. On the mechanism of ageing suppression by dietary restriction—Is persistent glycolysis the problem? Mech. Ageing Dev. 127, 8–15. Kalapos, M.P., 1999. Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications. Toxicol. Lett. 110, 145–175. Kalapos, M.P., Garzo´, T., Antoni, F., Mandl, J., 1991. Effect of methylglyoxal on glucose formation, drug oxidation and glutathione content in isolated murine hepatocytes. Biochim. Biophys. Acta 1092, 284–290. Khalifah, R.G., Baynes, J.W., Hudson, B.G., 1999. Amadorins: novel postAmadori inhibitors of advanced glycation reactions. Biochem. Biophys. Res. Commun. 257, 251–258. Lyles, G.A., 1996. Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspests. Int. J. Biochem. Cell Biol. 28, 259–274. Musa-Veloso, K., 2004. Non-invasive detection of ketosis and its application in refractory epilepsy. Prostagl. Leucotr. Ess. Fatty Acids 70, 329–335. Ray, M., Ray, S., 1998. Methylglyoxal: from a putative intermediate of glucose breakdown to its role in understanding that excessive ATP formation in cell may lead to malignancy. Curr. Sci. 75, 103–113. Ruggerio-Lopez, D., Lecomte, M., Moinet, G., Patereau, G., Lagarde, M., Wiernsperger, N., 1999. Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation. Biochem. Pharmacol. 58, 1765–1773. Shamai, F.A., Partal, A., Sady, C., Glomb, M.A., Nagaraj, R.H., 1998. Immunological evidence for methylglyoxal-derived modifications in vivo. J. Biol. Chem. 273, 6928–6936. Shinohara, M., Thornalley, P.J., Giardion, I., Beisswenger, P., Thorpe, S.R., Onorato, J., Brownlee, M., 1998. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J. Clin. Invest. 101, 1142–1147. Vander Jagt, D.L., Hassenbrook, R.K., Hunsaker, L.A., Brown, W.M., Royer, R.E., 2001. Metabolism of the 2-oxoaldehyde methylglyoxal by aldose reductase and by glyoxalase-I: roles for glutathione in both enzymes and implications for diabetic complications. Chem. Biol. Interact. 130–132, 549–562.