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L-Carnitine (ß-hydroxy-gammatrimethylammonium butylate) —
(CH3)3N+-CH2-CH(OH)-CH2-COO-
— is a nutrient normally obtained in the diet from meat (muscle). It is synthesized in the
liver from lysine and methionine. Carnitine promotes fatty acid oxidation (fat metabolism) in
muscle, thereby promoting efficient energy production.
Fats (fatty acids) cannot be metabolized unless they are transported into mitochondria by carnitine. Fat is a primary source of energy in muscle, notably in heart muscle. Once in the mitochondria fatty acid chains are broken into two-carbon acetyl-CoA units (a process known as ß-oxidation). (A modified ß-oxidation also occurs in peroxisomes.) Acetyl-CoA can then be converted to ATP via the citric acid cycle and oxidative phosphorylation.
The acetylated version of carnitine, Actyl-L-Carnitine (ALCAR) is absorbed by the gastrointestinal tract, enters cells and crosses the blood-brain barrier more readily than unacetylated carnitine, and is therefore more suitable as a nutritional supplement.
Carnitine acetyltransferase is the enzyme catalyst which reversibly converts acetyl-CoA and carnitine to acetylcarnitine and CoEnzyme A (CoA) — thus allowing peroxisomal ß-oxidation and the transport of fatty acid acetyl groups into the mitochondria for ß-oxidation. Carnitine acetyltransferase binding-affinity and activity decreases with age due to protein modification by aldehydes from lipid peroxidation. Supplementation of old rats with ALCAR and/or lipoic acid restored carnitine acetyltransferase binding-affinity and activity to levels observed in young rats [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Liu, J; 99(4):1876-1881 (2002)].
L-Carnitine stabilizes membranes by interaction with cytoskeletal protein and the phospholipid bilayer, by protecting cysteine residues from oxidation in membrane-bound enzymes and by direct action agaiinst lipid peroxidation [JOURNAL OF ANTI-AGING MEDICINE; Rani,JP; 4(2):145-153 (2001)]. In addition to its anti-oxidant properties, ALCAR is neuroprotective by inhibition of excitotoxicity and by providing a source of acetyl-CoA to the Tricarboxylic Acid Cycle (TCA) to promote aerobic metabolism [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1053:153-161 (2005)].
L-Carnitine administered to aged (over 22 months old) rats for 21 days reduced DNA-protein cross-links by about half, and reduced nuclear DNA oxidative damage (8−OHdG) by about a third in the striatum, hippocampus and cerebral cortex. For the whole brain, 21 days of L−carnitine reduced mitochondrial DNA oxidative damage (8−OHdG) by about one quarter [EXPERIMENTAL GERONTOLOGY; Haripriya,D; 40(2):129-135 (2005)]. A similar experiment showed carnitine to protect rat brain DNA from oxidative damage associated with decline of antioxidant enzymes with age [EXPERIMENTAL NEUROLOGY; Juliet,PAR; 191(1):33-40 (2005)].
Experiments show that the content of carnitine in rat heart muscle declines with age, but can be restored with ALCAR. Cardiolipin (diphosphatidyl glycerol) is a key component in mitochondrial inner membranes. Cardiolipin reduces proton permeability while serving as a transport cofactor. Cardiolipin declines with age in liver & heart mitochondrial membranes, but ALCAR supplementation restores cardiolipin to youthful levels (by an unknown mechanism) [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 959:491-507 (2002)]. ALCAR supplementation also can restore mitochondrial rRNA & mRNA to youthful levels in rat brains & hearts [EUROPEAN JOURNAL OF BIOCHEMISTRY 187:501-506 (1990)]. ALCAR supplementation reverses the age-related loss of mitochondrial cristae and, in combination with lipoic acid (LA), substantially restored spatial memory capacity in experimental rats [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Liu,J; 99(4):2356-2361 (2002)]. The ALCAR/LA combination has been shown to partially or completely restore brain mitochondrial function of old rats to the level of young rats [NEUROCHEMICAL RESEARCH; Long,J; 34(4):755-763 (2009)]. The ALCAR/LA combination has significantly improved complex object discrimination and spatial learning in aged beagle dogs [THE FASEB JOURNAL; Milgram,NW; 21(13):3756-3762 (2007)].
In addition to its actions on fat metabolism, L-carnitine can reduce muscle apoptosis (cell suicide) through actions on gene expression and actions on apoptosis-related proteins or cytokines. Congestive heart failure is associated with myopathy (death of heart muscle cells, often due to apoptosis). L-carnitine increases gene expression of Bcl-2 protein and reduces gene expression of caspases, thereby reducing apoptosis. Chronic inflammation associated with heart failure leads to high levels of the cytokine Tumor Necrosis Factor-alpha (TNF−α), which promotes apoptosis. L-carnitine results in reduced serum TNF−α levels [AMERICAN JOURNAL OF PHYSIOLOGY, CELL PHYSIOLOGY; Vescovo,G; 283:C802-C810 (2002)].
ALCAR protects against ischemia-reperfusion injury in both the heart [PROGRESS IN CARDIOVASCULAR DISEASES 40(3):265-286 (1997)] and brain [ANNALS OF EMERGENCY MEDICINE 29(6):758-765 (1997)]. The neuroprotective properties of ALCAR are partly associated with its ability to reduce brain dependence upon glucose metabolism [BRAIN RESEARCH 526:108-112 (1990)]. ALCAR supplementation can maintain NMDA receptors in the hippocampus at youthful levels [EXPERIMENTAL GERONTOLOGY 28:537-548 (1993)].
ALCAR protects against the neurotoxic effects of the Alzeimer' Disease-associated protein amyloid beta by acting both as an anti-oxidant and by maintaining ATP synthesis [NEUROCHEMICAL RESEARCH; Dhitavat,S; 27(6):501-505 (2002)].
At the same time as ALCAR supplementation improves mitochondrial function in rat livers, it increases free radical damage due to increased energy production through oxidative phosphorylation. But supplementation with both ALCAR and lipoic acid can provide the benefits of both improved metabolic function and reduced oxidative stress. Moreover, ALCAR has been shown to enhance the ability of lipoic acid to reverse oxidative stress arising from iron overload in human fibroblasts [REDOX REPORT; Lal,A; 13(1):2-10 (2008)]. An age-dependent accumulation of iron has been demonstrated in the cerebral cortex of rats [REDOX REPORT; Suh,JH; 10(1):52-60 (2005)].