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, 95 (16), 9562-6

Acetyl-L-carnitine Fed to Old Rats Partially Restores Mitochondrial Function and Ambulatory Activity

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Acetyl-L-carnitine Fed to Old Rats Partially Restores Mitochondrial Function and Ambulatory Activity

T M Hagen et al. Proc Natl Acad Sci U S A.

Abstract

Mitochondrial function and ambulatory activity were monitored after feeding old rats acetyl-L-carnitine (ALCAR). Young (3-5 mo) and old (22-28 mo) rats were given a 1.5% (wt/vol) solution of ALCAR in their drinking water for 1 mo, were sacrificed, and their liver parenchymal cells were isolated. ALCAR supplementation significantly reverses the age-associated decline of mitochondrial membrane potential, as assessed by rhodamine 123 staining. Cardiolipin, which declines significantly with age, is also restored. ALCAR increases cellular oxygen consumption, which declines with age, to the level of young rats. However, the oxidant production per oxygen consumed, as measured by 2',7'-dichlorofluorescin fluorescence levels, is approximately 30% higher than in untreated old rats. Cellular glutathione and ascorbate levels were nearly 30% and 50% lower, respectively, in cells from ALCAR-supplemented old rats than in untreated old rats, further indicating that ALCAR supplementation might increase oxidative stress. Ambulatory activity in young and old rats was quantified as a general measure of metabolic activity. Ambulatory activity, defined as mean total distance traveled, in old rats is almost 3-fold lower than in young animals. ALCAR supplementation increases ambulatory activity significantly in both young and old rats, with the increase being larger in old rats. Thus, ALCAR supplementation to old rats markedly reverses the age-associated decline in many indices of mitochondrial function and general metabolic activity, but may increase oxidative stress.

Figures

Figure 1
Figure 1
ALCAR reverses the age-associated decline in R123 fluorescence. Hepatocytes isolated from rats either supplemented with 1.5% (wt/vol) ALCAR for 1 mo or unsupplemented were incubated with R123 30 min before analysis by flow cytometry. Results show that ALCAR supplementation significantly reverses the age-associated decline in mitochondrial membrane potential and abolishes the appearance of mitochondrial heterogeneity with age. Shown is a fluorogram typical of that seen in at least six experiments.
Figure 2
Figure 2
Cardiolipin, a key phospholipid necessary for mitochondrial substrate transport, was extracted from hepatocytes and the levels were assessed by HPLC. Results show that mitochondria in cells from old rats have significantly lower cardiolipin when compared with cells isolated from young rats. ALCAR supplementation restores this level to that of young rats.
Figure 3
Figure 3
DCFH was used as a probe to determine the rate of oxidant production in cells isolated from animals (with or without ALCAR). ALCAR supplementation causes an enhanced rate of oxidant production. These results indicate that ALCAR may improve mitochondrial function but may also increase the amount of oxidants produced as by-products in mitochondrial electron transport.
Figure 4
Figure 4
Distance traveled by young and old rats. Each bar represents the mean distance traveled (cm/h) ± SEM from 8 h of quantification, as described in the text. Distance was determined from the same young (n = 5) and old (n = 5) rats before and after ALCAR treatment. ∗∗, P = 0.0005 when comparing pre-ALCAR old and post-ALCAR old. ∗, P = 0.0011 when comparing pre-ALCAR young and post-ALCAR young. P = 0.0610 when comparing post-ALCAR old and pre-ALCAR young (by using the two-tailed Student’s t test).

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