Feeding acetyl- l -carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress

Abstract

Mitochondrial-supported bioenergetics decline and oxidative stress increases during aging. To address whether the dietary addition of acetyl-L-carnitine [ALCAR, 1.5% (wt͞vol) in the drinking water] and͞or (R)-␣-lipoic acid [LA, 0.5% (wt͞wt) in the chow] improved these endpoints, young (2-4 mo) and old (24 -28 mo) F344 rats were supplemented for up to 1 mo before death and hepatocyte isolation. ALCAR؉LA partially reversed the age-related decline in average mitochondrial membrane potential and significantly increased (P ‫؍‬ 0.02) hepatocellular O 2 consumption, indicating that mitochondrial-supported cellular metabolism was markedly improved by this feeding regimen. ALCAR؉LA also increased ambulatory activity in both young and old rats; moreover, the improvement was significantly greater (P ‫؍‬ 0.03) in old versus young animals and also greater when compared with old rats fed ALCAR or LA alone. To determine whether ALCAR؉LA also affected indices of oxidative stress, ascorbic acid and markers of lipid peroxidation (malondialdehyde) were monitored. The hepatocellular ascorbate level markedly declined with age (P ‫؍‬ 0.003) but was restored to the level seen in young rats when ALCAR؉LA was given. The level of malondialdehyde, which was significantly higher (P ‫؍‬ 0.0001) in old versus young rats, also declined after ALCAR؉LA supplementation and was not significantly different from that of young unsupplemented rats. Feeding ALCAR in combination with LA increased metabolism and lowered oxidative stress more than either compound alone. H armon, Miguel, and others (1, 2) postulated that mitochondrial decay is a significant factor in aging, caused, in part, by the release of reactive oxygen species (ROS) as by-products of mitochondrial electron transport. Mitochondria are targets of their own oxidant by-products. The steady-state oxidative damage in mitochondria is high relative to other organelles, and the percentage of oxygen converted to superoxide increases with age (3-6). This leads to a vicious cycle of increasing mitochondrial damage, which adversely affects cell function (7), and results in a loss of ATP-generating capacity, especially in times of greater energy demand, thereby compromising vital ATP-dependent reactions. Cellular processes affected by mitochondrial decay include detoxification, repair systems, DNA replication, osmotic balance, and higher-order processes (7), such as cognitive function (7-9). Thus, preservation of mitochondrial function is important for maintaining overall health during aging (7). This theory is buttressed by the observation that caloric restriction, the only known regimen to increase mean life span in animals, maintains mitochondrial function and lowers oxidant production (7,8,(10)(11)(12). A spartan diet of calorie restriction appears to be too unappealing to be widely adopted in humans, and thus other alternative regimens to improve or maintain normal mitochondrial activities have been sought.Several dietary supplements, including the mitochondrial cofactor and antioxidant lipoi...

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…Additionally, acetyl L-carnitine attenuated ketamine-induced behavioral alterations and body weight decrements in preweaning rats (Boctor et al, 2008) and was found to exert efficient preventive effects in a cellular model of Parkinson's disease (Zhang et al, 2010). Beneficial effects of acetyl L-carnitine on cognitive and mitochondrial dysfunction have been shown in aging rats (Hagen et al, 2002a;Liu et al, 2002), as well. In our earlier study, we speculated that acetyl L-carnitine's reversal of ketamine-induced decrease in heart rate and ERK/MAPK activity could be mediated by calcium-modulated signaling (Kanungo et al, 2012).…”

“…Another important property of the carnitines is their ability to neutralize toxic acyl-CoA production in the mitochondria (Stumpf et al, 1985), which correlates with numerous diseases of the CNS including neurodegenerative diseases (Makar et al, 1995;Orth and Schapira, 2002;Rubio et al, 1998). Acetyl L-carnitine is also reportedly effective in reducing age-dependent mitochondria functional decay and in restoring mitochondrial membrane potential, cardiolipin content, metabolic oxygen (O2) consumption, and β-oxidation of fatty acids (Gadaleta et al, 1998;Hagen et al, 1998Hagen et al, , 2002a. For neurons at early developmental stages, co-administration of L-carnitine significantly diminished ROS (reactive oxygen species) generation and provided near complete protection of neurons from ketamineinduced neurodegeneration .…”

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

“…The complementary effect of LA and ALC on cognitive and mitochondrial dysfunction has been shown in ageing rats [27,28,40]. One reason is that LA+ALC act on different pathways necessary for mitochondria: LA is a mitochondrial antioxidant and cofactor of pyruvate dehydrogenase, while ALC is an energy enhancer [25,41].…”

L‐carnitine inhibits hepatocarcinogenesis via protection of mitochondria

“…21,22 Furthermore, carnitine strongly inhibited the destruction of the mitochondrial membrane and mitochondrial dysfunction-induced injury in various types of cells. [22][23][24][25] These findings indicate that oxidative stress elicited from abnormally accumulated copper increased the amount of free fatty acids, thereby inducing mitochondrial dysfunction, resulting in cell death and enhanced secondary generation of ROS, which are significantly inhibited by carnitine treatment. Consistent with this notion is a report indicating that administration of carnitine decreased free fatty acids in serum and tissues and prevented tissue injury in juvenile visceral steatosis (JVS) mice that lack a carnitine transporter.…”

“…21 In fact, there are also several reports showing that carnitine effectively inhibited mitochondrial injury induced by oxidative stress and mitochondriadependent apoptosis. [22][23][24][25] It is thought that carnitine shows its protective effects on mitochondria and on whole cells by inhibiting free fatty acid-induced mitochondrial membrane damage and/or its secondary effects. 22,26,27 Using the hypothesis that oxidative injury induced during the process of hepatocarcinogenesis in LEC rats might be inhibited by carnitine, we investigated whether this agent could prevent inflammatory damage and hepatocarcinogenesis in LEC rats.…”