Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid -- Liu et al. 99 (4): 2356 -- Proceedings of the National Academy of Sciences
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 4, 2356-2361, February 19,
2002
Memory loss in old rats is associated with brain mitochondrial
decay and RNA/DNA oxidation: Partial reversal by feeding
acetyl-L-carnitine and/or R--lipoic acid
[names and research institutes cut for brevity, see URL above]
Accumulation of oxidative damage to mitochondria, protein, and
nucleic acid in the brain may lead to neuronal and cognitive
dysfunction. The effects on cognitive function, brain
mitochondrial structure, and biomarkers of oxidative damage were
studied after feeding old rats two mitochondrial ****bolites,
acetyl-L-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking
water], and/or R--lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet].
Spatial memory was assessed by using the Morris water maze;
temporal memory was tested by using the peak procedure (a time-
discrimination procedure). Dietary supplementation with ALCAR
and/or LA improved memory, the combination being the most
effective for two different tests of spatial memory (P < 0.05;
P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical
analysis showed that oxidative damage to nucleic acids (8-
hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with
age in the hippocampus, a region important for memory. Oxidative
damage to nucleic acids occurred predominantly in RNA. Dietary
administration of ALCAR and/or LA significantly reduced the
extent of oxidized RNA, the combination being the most effective.
Electron microscopic studies in the hippocampus showed that ALCAR
and/or LA reversed age-associated mitochondrial structural decay.
These results suggest that feeding ALCAR and LA to old rats
improves performance on memory tasks by lowering oxidative damage
and improving mitochondrial function.
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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 -- Liu et al. 99 (4): 1876 -- Proceedings of
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 4, 1876-1881, February 19,
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--lipoic acid
[names and research institutes cut for brevity, see URL]
We test whether the dysfunction with age of carnitine
acetyltransferase (CAT), a key mitochondrial enzyme for fuel
utilization, is due to decreased binding affinity for substrate
and whether this substrate, fed to old rats, restores CAT
activity. The kinetics of CAT were analyzed by using the brains
of young and old rats and of old rats supplemented for 7 weeks
with the CAT substrate acetyl-L-carnitine (ALCAR) and/or the
mitochondrial antioxidant precursor R--lipoic acid (LA). Old
rats, compared with young rats, showed a decrease in CAT activity
and in CAT-binding affinity for both substrates, ALCAR and CoA.
Feeding ALCAR or ALCAR plus LA to old rats significantly restored
CAT-binding affinity for ALCAR and CoA, and CAT activity. To
explore the underlying mechanism, lipid peroxidation and total
iron and copper levels were assayed; all increased in old rats.
Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation
but did not decrease iron and copper levels. Ex vivo oxidation of
young-rat brain with Fe(II) caused loss of CAT activity and
binding affinity. In vitro oxidation of purified CAT with Fe(II)
inactivated the enzyme but did not alter binding affinity. However,
in vitro treatment of CAT with the lipid peroxidation
products malondialdehyde or 4-hydroxy-nonenal caused a decrease
in CAT-binding affinity and activity, thus mimicking age-related
change. Preincubation of CAT with ALCAR or CoA prevented
malondialdehyde-induced dysfunction. Thus, feeding old rats high
levels of key mitochondrial ****bolites can ameliorate oxidative
damage, enzyme activity, substrate-binding affinity, and
mitochondrial dysfunction.
**************************************** ********** **************
Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves ****bolic function while decreasing oxidative stress -- Hagen et al. 99 (4): 1870 -- Proceedings of the National Academy of Sciences
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 4, 1870-1875, February 19,
2002
Feeding acetyl-L-carnitine and lipoic acid to old rats significantly
improves ****bolic function while decreasing oxidative stress
[names and research institutes cut for brevity, see URL above]
Mitochondrial-supported bioenergetics decline and oxidative stress
increases during aging. To address whether the dietary addition of
acetyl-L-carnitine [ALCAR, 1.5% (wt/vol) in the drinking water]
and/or (R)--lipoic acid [LA, 0.5% (wt/wt) 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 O2 consumption, indicating that mitochondrial-
supported cellular ****bolism 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 ****bolism and
lowered oxidative stress more than either compound alone.
