School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Rejuvenation Res. 2010 Oct;13(5):547-51. doi: 10.1089/rej.2010.1025. Epub 2010 Jul 20.
Because accumulation of altered proteins is the most common biochemical symptom of aging, it is at least possible that such proteotoxicity may cause aging and influence life span. The life span of the nematode worm Caenorhabditis elegans is strongly influenced by changes in the intracellular concentration of methylglyoxal (MG), a putative source of much age-related proteotoxicity and organelle, cellular, and molecular dysfunction. Glycerol has recently been shown to shorten, whereas oxaloacetate has been found to extend, life span in C. elegans. It is suggested here that glycerol and oxaloacetate exert opposing effects on MG formation in C. elegans. It is proposed that, if not secreted by aquaporin, glycerol is converted to glycerol phosphate and then to dihydroxyacetone phosphate (DHAP) via a reaction requiring nicotinamide adenine dinucleotide (NAD(+)). This inhibits operation of the glycerol phosphate cycle in which DHAP is converted into glycerol phosphate, which concomitantly regenerates NAD(+) from NADH, thereby ensuring glycolytic oxidation of glyceraldehyde-3-phosphate (G3P). Because DHAP and G3P spontaneously decompose into MG, and NAD(+) is required for conversion of G3P into phosphoglycerate, the glycerol-induced increased DHAP formation and decreased NAD(+) availability will increase the potential for MG generation. In contrast, oxaloacetate may decrease MG generation by stimulating the operation of the malate-oxaloacetate shuttle, in which oxaloacetate is converted to malate, which regenerates NAD(+) from NADH. By the ensuing G3P oxidation, increased NAD(+) availability will decrease the potential for MG formation. It should be noted that mitochondria are involved in the operation of the above cycle/shuttles and that increased NAD(+) availability also stimulates those sirtuin activities that increase mitogenesis and mitochondrial activity via effects on signal transduction and gene expression, which frequently accompany dietary restriction-induced life span extension.
由于蛋白质的积累是衰老的最常见的生化症状，因此这种蛋白毒性至少可能导致衰老并影响寿命。秀丽隐杆线虫（Caenorhabditis elegans）的寿命受到细胞内甲基乙二醛（MG）浓度变化的强烈影响，MG 是导致与年龄相关的蛋白毒性和细胞器、细胞和分子功能障碍的一个潜在来源。最近已经表明甘油可以缩短，而草酰乙酸可以延长秀丽隐杆线虫的寿命。这里提出甘油和草酰乙酸对秀丽隐杆线虫 MG 形成有相反的影响。建议如果不是通过水通道蛋白分泌的，甘油会被转化为甘油磷酸，然后通过需要烟酰胺腺嘌呤二核苷酸（NAD(+)）的反应转化为二羟丙酮磷酸（DHAP）。这会抑制甘油磷酸循环的运转，其中 DHAP 转化为甘油磷酸，同时将 NADH 再生为 NAD(+)，从而确保甘油醛-3-磷酸（G3P）的糖酵解氧化。因为 DHAP 和 G3P 会自发分解为 MG，并且 NAD(+)是将 G3P 转化为磷酸甘油的必需物质，所以甘油诱导的 DHAP 形成增加和 NAD(+)可用性降低将增加 MG 生成的潜力。相反，草酰乙酸可能通过刺激苹果酸-草酰乙酸穿梭系统的运转来降低 MG 的生成，其中草酰乙酸转化为苹果酸，将 NADH 再生为 NAD(+)。通过随后的 G3P 氧化，增加的 NAD(+)可用性将降低 MG 形成的潜力。应该注意的是，线粒体参与了上述循环/穿梭的运转，增加的 NAD(+)可用性还通过对信号转导和基因表达的影响，刺激那些增加线粒体生成和线粒体活性的 Sirtuin 活性，这经常伴随着饮食限制诱导的寿命延长。
