Mitochondrial Decay in the Brains of Old Rats: Ameliorating Effect of Alpha-Lipoic Acid and Acetyl-l-carnitine
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To investigate the mitochondrial decay and oxidative damage resulting from aging, the activities/kinetics of the mitochondrial complexes were examined in the brains of young and old rats as well as in old rats fed R-α-lipoic acid plus acetyl-l-carnitine (LA/ALC). The brain mitochondria of old rats, compared with young rats, had significantly decreased endogenous antioxidants and superoxide dismutase activity; more oxidative damage to lipids and proteins; and decreased activities of complex I, IV and V. Complex I showed a decrease in binding affinity (increase in Km) for substrates. Feeding LA/ALC to old rats partially restored age-associated mitochondrial dysfunction to the levels of the young rats. These results indicate that oxidative mitochondrial decay plays an important role in brain aging and that a combination of nutrients targeting mitochondria, such as LA/ALC, could ameliorate mitochondrial decay through preventing mitochondrial oxidative damage.
KeywordsBinding affinity (Km) Brain mitochondria Mitochondrial complex activity Enzyme kinetics Oxidative damage
The authors thank Dr. Afshin Gharib for taking care of the animals. This work was supported by the Ellison Medical Foundation Grants S-0422-99, the National Institute on Aging AG17140, and the National Center for Complementary and Alternative Medicine Research Scientist Award K05 AT001323-4 (B. N. A.), and National Institutes of Health grants NEI EY016101, NIA AG023265, and NCCAM AT01918 (B. N. A. and J. L.) and NIA AG012694 (C. W. C).
- 4.Ames BN, Suh JH, Liu J (2006) Enzymes lose binding affinity for coenzymes and substrates with age: a strategy for remediation. In: Kaput J (ed) Nutrigenomics: concepts and technologies. Wiley, Hoboken, pp 277–291Google Scholar
- 8.Liu J, Killilea DW, Ames BN (2002) Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci USA 99:1876–1881. doi: 10.1073/pnas.261709098 PubMedCrossRefGoogle Scholar
- 12.Alie G, Liu J, Shenk JC et al (2008) Neuronal mitochondrial amelioration by feeding acetyl-l-carnitine and lipoic acid to aged rats. J Cell Mol Med [epub ahead of print]. doi: 10.1111/j.1582-4934.2008.00324.x
- 14.Montgomery SA, Thal LJ, Amrein R (2003) Meta-analysis of double blind randomized controlled clinical trials of acetyl-l-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 18:61–71. doi: 10.1097/00004850-200303000-00001 PubMedCrossRefGoogle Scholar
- 16.McMackin CJ, Widlansky ME, Hamburg NM et al (2007) Effect of combined treatment with alpha-Lipoic acid and acetyl-l-carnitine on vascular function and blood pressure in patients with coronary artery disease. J Clin Hypertens (Greenwich) 9:249–255Google Scholar
- 25.Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM (2004) Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 94:53–59. doi: 10.1161/01.RES.0000109416.56608.64 PubMedCrossRefGoogle Scholar
- 33.Abdul HM, Butterfield DA (2007) Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-l-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med 42:371–384. doi: 10.1016/j.freeradbiomed.2006.11.006 PubMedCrossRefGoogle Scholar