DO HIGH DOSE B VITAMINS DELAY AGE-RELATED DECAY

描述(申请人提供)：我们提出了三个具体目标：#t)给老年大鼠喂食高剂量的8B维生素，显著提高人类的辅酶水平，以改善衰老的线粒体衰退，从而改善运动、认知和神经肌肉功能，将进行测试，以确定最佳剂量。#2)确定这种喂养是否部分恢复了老年大鼠的线粒体功能障碍，以及老年大鼠的辅酶水平是否真的更高。#3)测试大剂量B族维生素饲喂线粒体代谢产物乙酰肉碱和硫辛酸延缓线粒体衰变的效果。这个项目的基本原理如下。线粒体含有大约1000种蛋白质，它们承载着大量的细胞新陈代谢。线粒体腐烂， 由于氧化剂从电子传递链中泄漏，在衰老和衰老相关的神经退行性疾病中起着重要作用。尽管线粒体不断翻转，但线粒体RNA/DNA、酶和膜脂的氧化作用随着年龄的增长而增加。在老化过程中，这种氧化通过直接的蛋白质氧化、从脂质过氧化中加成的醛，以及在膜蛋白的情况下，氧化膜的流动性降低来改变许多线粒体酶。这些酶的修饰会降低它们与底物或辅酶的亲和力。例如，肉碱乙酰转移酶失去与辅酶A和乙酰肉碱的结合亲和力。随着年龄的增长，许多线粒体酶失去活性，喂食高水平的几种线粒体代谢物可能会逆转一些衰老的衰退。我们在最近的一篇综述中详细记录了给人类喂食高剂量的B维生素，显著提高了各自的辅酶水平，从而刺激了有缺陷的人类酶的活性，降低了辅酶结合亲和力。大约50种由酶缺陷引起的人类遗传病，包括线粒体中的14种，可以通过摄入高水平的相应辅酶的维生素成分来补救。市面上出售的维生素药丸含有25、50或100毫克的B族维生素(即RDA的10到100倍)，但没有令人信服的理由使用如此高剂量的维生素。我们认为，使用大剂量维生素B可能有合理的基础。这一提议在科学上是合理的、新颖的，而且可能会有很高的回报：如果老年人需要高剂量的B族维生素来延缓线粒体腐烂和衰老引起的退行性疾病，公共健康可能会得到重大改善，营养学可能会有一个新的研究方向。

DESCRIPTION (provided by applicant): We propose 3 Specific Aims: #t) To feed old rats high doses of 8 B vitamins, which markedly raise coenzyme levels in humans, to ameliorate the mitochondrial decay of aging and thus improve motor, cognitive and neuromuscular functions, which will be tested to determine the Optimum dose. #2) To determine whether the mitochondrial dysfunction of age is in part restored by this feeding and whether coenzyme levels are indeed higher in the old rats. #3) To test the effect of feeding high-dose B vitamins with mitochondrial metabolites acetyl carnitine and lipoic acid, which we have shown delay mitochondrial decay. The rationale for this project is as follows. Mitochondria contain about 1,000 proteins and they host much cell metabolism. Mitochondrial decay, due to oxidant leakage from the electron transport chain, plays an important role in aging and age-associated neurodegenerative diseases. Oxidation of mitochondrial RNA/DNA, enzymes, and membrane lipid increases with age, despite constant mitochondrial turn over. Such oxidation deforms many mitochonddal enzymes during aging by direct protein oxidation, adduction of aldehydes from lipid peroxidation, and, in the case of membrane proteins, decrease in fluidity of oxidized membranes. These enzyme modifications cause a decrease in their affinity for their substrates or coenzymes. For example, carnitine acetyl transferase loses binding affinity for CoA as well as for acetyl carnitine. Many mitochondrial enzymes lose activity with age and feeding high levels of several mitochondrial metabolites may reverse some of the decay of aging. We have documented in detail in a recent review that feeding high-dose B vitamins to humans, markedly elevates the respective coenzyme levels, and thus stimulates the activity of defective human enzymes with decreased coenzyme-binding affinity. About 50 human genetic diseases due to defective enzymes, including 14 in mitochondria, can be remedied by the ingestion of high levels of the vitamin component of the corresponding coenzyme. Vitamin pills are sold containing 25, 50 or 100 mg of each of the B vitamins (i.e., 10 to 100 times the RDA), yet no convincing reason is available for using such high doses. We suggest that there may be a rational basis for using high-dose B vitamins. This proposal is scientifically plausible, novel, and could have a high pay-off: if old people require high doses of B vitamins to delay mitochondrial decay and the degenerative diseases of aging, there could be a major improvement in public health and a new research direction in nutrition.