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A number of studies have shown that carnitine supplementation – alone or in conjunction with supplemental lipoic acid - promotes mitochondrial biogenesis (MB) in skeletal, muscle, and brain of aging rodents; no such effect is seen in younger animals. These findings parallel clinical studies in which supplemental carnitine improves physical and mental energy in elderly humans, while decreasing body fat and increasing lean mass – effects that have not been achieved with carnitine in younger people. The age dependence of these phenomena appears to reflect the fact that tissue carnitine levels, especially those in muscle, decline during aging; carnitine supplementation restores higher, more youthful tissues carnitine levels in aging animals, but has relatively little impact in this regard on younger ones. The effect of supplemental carnitine on MB in aging animals appears to be mediated, in whole or in part, by increased expression of PPARγ-coactivator-1α (PGC-1α), a key driver of MB. There is recent evidence that, in low millimolar intracellular concentrations such as those seen in skeletal muscle, carnitine functions as an inhibitor of type 1 histone deacetylases (HDACs). Moreover, it has been reported that drug inhibitors of these deacetylases boost mRNA and protein expression of PGC-1α, presumably by promoting transcription of the PGC-1a gene; these drugs also amplify MB. It is therefore proposed that intracellular carnitine provides a moderate tonic inhibition of type 1 HDACs that supports PGC1α transcription and that diminishes with age as tissue carnitine levels decline; hence, carnitine supplementation in the elderly restores youthful expression of PGC-1α and promotes MB. The complementary impact of lipoic acid on MB may reflect the fact that the promoter of the gene coding for nuclear respiratory factor-1 (NRF-1) contains antioxidant response elements; hence, NRF-1 transcription is promoted by phase 2 inducers such as lipoic acid. PGC-1α and NRF-1 collaborate in driving the expression of mitochondrial proteins. Additional nutraceutical measures which may likewise support MB – citrulline, taurine, N-acetylcysteine, high-dose biotin, and astaxanthin – are discussed. The adverse impact of metabolic syndrome on MB in skeletal muscle may be mediated by toll-like receptor 4 (TLR4) signaling stimulated by saturated fatty acids; antagonists of TLR4 signaling, possibly including ferulic acid and phycocyanobilin, may therefore promote MB in the context of metabolic syndrome. Restoration of youthful MB in the elderly may have favorable impacts on physical capacity and cognitive function, body composition, insulin sensitivity, and oxidative stress.
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