Alterations
to cardiac metabolism with advancing age
Ger J. van der Vusse
Department of Physiology, Cardiovascular Research Institute Maastricht
(CARIM),Maastricht University, Maastricht, the Netherlands
Correspondence: Professor Ger J. van der Vusse, Department of
Physiology, Cardiovascular Research Institute Maastricht (CARIM),
Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands.
Tel: +31 43 3881086, fax: +31 433884166 , e-mail:
vandervusse@fys.unimaas.nl
Because of the rapidly growing number of elderly
people in Western societies, cardiac malfunction due to age-related
changes in the cardiovascular system is becoming a major health
problem. As thoroughly discussed in an excellent review by Lakatta,[1]
there is no straightforward answer to the question whether aging
itself is inherently associated with impaired cardiac performance,
since other factors such as lifestyle and diseases may interact
with the normal physiological aging process. On the one hand,
the detrimental effects of, for example, sedentariness accumulate
with advancing age, and on the other, diseases such as hypertension
and myocardial ischemia are more often seen in the elderly.
Although pump activity of the physiologically aged heart seems
not to be affected under resting conditions, cardiac performance
is depressed when the heart is energetically challenged.[1]
Moreover, profound changes at the cellular and subcellular level
have been reported: b-adrenergic responsiveness of the cardiac
system is significantly reduced,[1] calcium
handling is altered,[2] and the composition
of contractile proteins changed, exemplified by a shift from the
a to the b form of the myosin heavy chain.[3]
It is of interest to note that the latter change is thought to
improve the efficiency of the aging heart.[1]
Prompted by the pioneering studies of Abu-Erreish et al[4]
in the late 1970s, demonstrating a decline in fatty acid oxidation
with a concomitant increase in glycolytic activity in the aged
rat heart, a plethora of studies has been performed to disclose
the effect of aging on cardiac energy metabolism. In general,
these studies point to substantial changes in the activity of
the enzymes that play a key role in cardiac energy metabolism,
and to alterations in the tissue content of cofactors required
for substrate oxidation, and in mitochondrial functioning. The
pathophysiological significance of these changes for mechanical
performance of the aging heart is, however, incompletely understood
and a matter of continuous debate.
Cardiac metabolism
Proper cardiac electromechanical performance requires unimpeded
delivery of molecular oxygen and oxidizable substrates. The heart
relies mainly on fatty acids and glucose for intracellular ATP
production.[5] Under normal conditions, lactate
and ketone bodies are used to a lesser extent.[6]
Healthy coronary vessels guarantee a sufficient supply of substrates
to the energy-converting myocytes. As indicated in Figure 1, glucose
transport into the cardiomyocyte is facilitated by GLUT4.
Figure 1. Schematic representation of substrate uptake
and metabolism in the cardiac muscle cell. FAT, fatty acid translocase;
FABP, sarcoplasmic fatty acid-binding protein; NAD, nicotinamide
adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide.
The latter protein is a glucose transporter that
can be recruited from its intracellular storage site to enhance
the sarcolemmal capacity to translocate glucose. Glucose is subsequently
degraded to pyruvate in a stepwise fashion in the cytoplasm of
the cardiac muscle cell. This process, glycolysis, yields two
molecules of ATP per molecule of glucose. Under aerobic conditions,
pyruvate is converted to acetyl-CoA by pyruvate dehydrogenase,
an enzyme complex associated with the mitochondrial inner membrane.
Acetyl-CoA reacts with oxaloacetate, an intermediate of the citric
acid cycle, yielding citrate. During one turn of the citric acid
cycle, citrate is metabolized to oxaloacetate. In concerted action
with the mitochondrial respiratory chain, 36 molecules of ATP
are produced when one molecule of glucose is oxidized to CO2 and
H2O. Recent investigations have revealed that, analogous to glucose,
fatty acid uptake by the cardiac muscle cell is also facilitated
by a sarcolemma-associated transport protein.[7]
This protein, designated fatty acid translocase, augments the
capacity of the cardiomyocyte to extract fatty acids from the
extracellular compartment by increasing its sarcolemmal content
through translocation from an intracellular site to the cell membrane.[8]
Transport of fatty acids from the sarcolemma to the mitochondrial
outer membrane is facilitated by cytoplasmic fatty acid-binding
protein. After conversion to fatty acyl-CoA, a reaction step catalyzed
by acyl-CoA synthetase, the acyl moiety is transferred across
the mitochondrial inner membrane as acylcarnitine (Figure 2).
Figure 2. Detailed description of mitochondrial fatty acid
uptake and degradation. Numbers 1, 2, 3, 4, and 5 refer to fatty
acyl synthetase, carnitine palmitoyl transferase-1, carnitine-acylcarnitine
translocase, carnitine palmitoyl transferase-2, and 3-hydroxyacyl-CoA
dehydrogenase, respectively; fp, flavoprotein; NAD+, oxidized
nicotinamide adenine dinucleotide; NADH, reduced nicotinamide
adenine dinucleotide.
Inside the mitochondrion, carnitine is replaced
by CoA, and acyl-CoA is stepwise degraded to acetyl-CoA in a metabolic
pathway termed b-oxidation. As described above, the acetyl moiety
of acetyl-CoA is oxidized by concerted action of the citric acid
cycle and the respiratory chain. Oxidation of fatty acids yields
approximately 130 molecules of ATP per molecule of substrate.
Energy conversion in the aging heart
Animal studies have clearly shown that substrate metabolism in
the aging heart is different to that in the young adult heart.
The capacity to oxidize fatty acids declines, while glycolytic
degradation of glucose increases.[4] Collected
data point to a multifactorial cause of the decrease in fatty
acid oxidation. First, the cardiac tissue content of carnitine,
indispensable for mitochondrial uptake of fatty acyl moieties,
is significantly reduced in the aged myocardium.[4,9]
The maximal activity of carnitine palmitoyl transferase-1 and
carnitine-acylcarnitine translocase was also found to be decreased
in mitochondria isolated from the aged heart (Figure 2).[10–12]
The combined findings indicate therefore that both the enzyme
and transporter, and the cofactor required for mitochondrial fatty
acyl uptake, are affected in the aged myocardium. Interestingly,
the tissue content of CoA, required for fatty acid activation
at the mitochondrial outer membrane (Figure 2), is unaffected
by aging.[4] By contrast, the maximal activity
of the enzyme catalyzing the activation step, acyl-CoA synthetase,
declines significantly with advancing age.[13]
The same holds for one of the key enzymes in the b-oxidation pathway,
3-hydroxyacyl-CoA dehydrogenase.[13]
The impact of the decline in enzyme activity and content of cofactors
involved in fatty acid handling has been established in studies
on intact mitochondria isolated from rat myocardium, ie, the oxidation
rate of palmitoyl carnitine declines by 40%.[13]
It is noteworthy that in conjunction with the relative increase
in cardiac glucose utilization, substantial alterations have been
observed in the tissue content of transport proteins and activity
of enzymes involved in carbohydrate handling in the aged heart.
GLUT4 content significantly declined in the hearts of 25-month-old
rats compared with animals 3.5 months of age.[14]
These seemingly conflicting findings of increased glycolytic flux
and decreased total GLUT4 content suggest that a relatively higher
proportion of GLUT4 is permanently present in the sarcolemma of
aged cardiomyocytes. The total activity of pyruvate dehydrogenase,
controlling the mitochondrial conversion of pyruvate into acetyl-CoA,
does not change in the aged heart. However, the percentage of
the enzyme complex in its active form significantly decreases
during aging.[15] The decline in proportion
of pyruvate dehydrogenase in the active form might indicate that
in the aged heart, pyruvate is preferentially converted to lactate
rather than oxidized in the mitochondrial matrix (Figure 1)
Recent studies also indicate that the activity of some components
of the respiratory chain, such as cytochrome c oxidase, is depressed
in the aged heart. It is, however, unknown whether this decline
affects the maximum capacity of the aged cardiac mitochondrion
to utilize molecular oxygen and to regenerate ATP from ADP. Despite
this uncertainty, current data point towards the mitochondrion
as one of the main cellular compartments in which cardiac energy
metabolism becomes affected during advancing age.
Evidence is accumulating that alterations in the phospholipid
composition of the aged cardiac mitochondria are, at least in
part, responsible for the decline in mitochondrial metabolic functioning.
Cardiolipin, a phospholipid species that is specifically incorporated
in mitochondrial membranes, shows a significant decline in
the aging myocardium.[12,16]
It is generally accepted that cardiolipin is an essential phospholipid
moiety in the mitochondrial membrane that is required to optimize
the activity of enzymes constituting the respiratory chain.
The cause of the age-related decline in mitochondrial cardiolipin
content is unknown, but the relatively high proportion of polyunsaturated
fatty acids in this particular phospholipid points to the damaging
effect of oxygen free radicals. In this respect it is noteworthy
that the production of oxygen free radicals, with their main site
of production being the mitochondrion itself, is more prominent
in the aged than in the young adult heart.[17]
Alternatively, exposure to oxygen free radicals may be enhanced
due to a decline in capacity to scavenge the active oxygen species
in the aged heart. This notion, however, has been challenged by
the observation that, as a compensatory reaction, the activities
of the main oxygen radical scavenger enzymes are stimulated in
the mitochondria of the aged heart.[18] In
addition to cardiolipin, mitochondrial DNA is a ready target for
oxygen free radicals.[19,20] Oxidative damage
of cardiac mitochondrial DNA was found to be inversely related
to maximum lifespan of the mammals under investigation.[19]
Mitochondrial DNA is relatively more sensitive to oxygen free
radicals than is nuclear DNA, which may explain the fact that
in particular mitochondrial proteins and, hence, proteins involved
in cardiac energy conversion are compromised with increasing age.
Dietary and therapeutic strategies
Since energy metabolism has been identified as one of the processes
affected in the aging heart, multiple strategies have been developed
to restore cardiac substrate handling and energy production to
the juvenile level. These therapeutic strategies mostly relate
to dietary interventions. Since epidemiological and laboratory
evidence points to oxidative injury caused by oxygen free radicals
as an important factor in the major diseases of older age, fruit
and vegetables, rich in antioxidant vitamins such as vitamin E
and C, have been strongly recommended.[21]
In vitro studies on mitochondria isolated from the aged heart
have shown that restoration of the mitochondrial cardiolipin content
to young adult levels promptly restores the activity of enzymes
involved in the respiratory chain. At present, no strategies,
however, have been developed to prevent or restore the decline
in mitochondrial cardiolipin content in the intact heart in situ
during advancing age by dietary supplementation of cardiolipin.
Studies on rats have provided solid evidence that chronic administration
of acetylcholine via drinking water completely restores cardiac
carnitine levels in aged animals to that seen in rats 5 months
of age.[9] More recently, it was shown that acetylcarnitine treatment
of rats prevented the age-related decline in activity of carnitine-acylcarnitine
translocase in cardiac mitochondria. Unfortunately, information
is lacking on the beneficial effect of carnitine supplementation
in cardiac mechanical performance. Moreover, until now, the potentially
beneficial effect of carnitine supplementation has not been explored
in the aging human heart.
In addition to dietary strategies, molecular biology may provide
powerful tools to restore cardiac metabolism in the aging heart.
When most details of the expression of genes coding for metabolic
proteins are known, one may envisage that the administration of
ligands specifically interacting with nuclear factors, regulating
the expression and, hence, tissue content of proteins or enzymes
involved in cardiac substrate handling and conversion, will result
in improved cardiac energy metabolism in the elderly.
REFERENCES
-
Cardiovascular regulatory mechanisms in advanced
age.
Lakatta EG.
Laboratory of Cardiovascular Science, National Institute on
Aging, Baltimore, Maryland.
Publication Types:
PMID: 8475195 [PubMed - indexed for MEDLINE]
-
Intracellular calcium transients and developed
tension in rat heart muscle. A mechanism for the negative interval-strength
relationship.
Orchard CH, Lakatta EG.
The purposes of the present study were to determine (a) whether
changes of intracellular [Ca2+] (Cai) can account for the decrease
of developed tension observed in rat heart muscle when stimulation
rate is increased, and (b) whether the effect of stimulation
rate on Cai is altered in conditions in which the rate of repriming
of the sarcoplasmic reticulum (SR) is altered, as when perfusate
[Ca2+] (Cao) is increased, and in heart muscle from senescent
animals. The photoprotein aequorin was used to monitor Cai in
rat papillary muscles. In muscles from 6-mo-old rats, increasing
the stimulation rate in the range 0.2-0.66 Hz led to parallel
decreases of both the aequorin light transient and developed
tension when Cao was 2 mM. When Cao was increased to 4 mM, changes
in the stimulation rate had less effect on both the light transient
and tension. At 8 mM Cao, changing the stimulation rate had
no effect on either the light transient or developed tension.
Papillary muscles from 24-mo-old rats, in which SR function
is likely to be depressed, exhibited a prolonged Ca2+ transient
and twitch. At a Cao of 4 or 8 mM, increasing the stimulation
rate from 0.33 to 0.66 Hz still led to decreases in the size
of the aequorin light transient and developed tension in these
muscles. Developed tension and aequorin light responded to increases
of Cao in the same way in both groups of muscles. We conclude
that under the conditions of our experiments, developed tension
is determined by Cai. The negative interval-strength relationship
observed when Cao is in the physiological range can be accounted
for by a time-dependent recycling of Ca2+ by the SR. The effects
of increasing Cao and the age-related differences observed at
high Cao can also be accounted for using this model.
PMID: 4067571 [PubMed - indexed for MEDLINE]
-
Changes in myosin isoenzymes, ATPase activity,
and contraction duration in rat cardiac muscle with aging can
be modulated by thyroxine.
Effron MB, Bhatnagar GM, Spurgeon HA, Ruano-Arroyo G, Lakatta
EG.
To determine whether the relative decline in cardiac myosin
isoenzyme V1 with maturation continues progressively into senescence
and whether thyroxine could reverse age-associated changes in
the myosin isoenzyme profile and contraction, rats 2, 8, and
24 months old were treated with thyroxine, 6.4 mg/kg, for 7
days. Myosin isoenzymes, Ca2+-myosin ATPase activities, and
isometric contractile function were measured in cardiac preparations
from thyroxine-treated animals and age-matched controls. Right
ventricular hypertrophy did not occur with aging in controls.
Thyroxine increased right ventricular weight in each age group
compared to the control group. Body weight decreased by 10%
in all thyroxine-treated rats. The relative right ventricular
V1 isoenzyme content progressively decreased from 75 +/- 1%
to 54 +/- 1% and 14 +/- 1% in controls at 2, 8, and 24 months,
respectively, and was associated with a reciprocal increase
in V3 myosin isoenzyme. Ca2+-myosin ATPase activity also progressively
declined monotonically with age in the control rats from 854
+/- 28 nmol Pi/mg prot/min at 2 months to 529 +/- 28 nmol Pi/mg
prot/min at 24 months. Thyroxine administration increased right
ventricular V1 at each age to 97 +/- 2%, 73 +/- 2%, and 59 +/-
2% at 2, 8, and 24 months, respectively. A thyroxine induced
increase in the Ca2+-myosin ATPase activity could be detected
only in the 24-month-old animals.(ABSTRACT TRUNCATED AT 250
WORDS)
PMID: 2952364 [PubMed - indexed for MEDLINE]
-
Fatty acid oxidation by isolated perfused
working hearts of aged rats.
Abu-Erreish GM, Neely JR, Whitmer JT, Whitman V, Sanadi DR.
It has been reported that mitochondria isolated from hearts of
old rats have lower respiratory activity than mitochondria
from young rats. In order to determine the physiological
correlates of these changes, the metabolism of hearts from
young and old rats has been compared in a perfused working
heart preparation. The oxidation of [14C]palmitate to 14CO2,
oxygen consumption, and nucleotide levels were measured under
different cardiac workloads. The hearts from old animals
performed less cardiac work and utilized less oxygen and
palmitate in proportion to tissue mass, but the ratio of
oxygen consumed to pressure developed was unaltered. There was
a small but significant decrease in cardiac efficiency
expressed as the ratio between the rate of oxygen consumed and
ventricular pressure development. Tissue levels of total
carnitine and long-chain acylcarnitine derivatives were
greatly reduced in the older heart without significant change
in free CoA, acetyl-CoA, or long-chain acyl-CoA. The adenine
nucleotide levels were not significantly different in the two
groups. The results appear consistent with the in vitro
studies on isolated mitochondria.
PMID: 842660 [PubMed - indexed for MEDLINE]
5. van
der Vusse GJ, Glatz JFC, Stam HC, Reneman RS. Fatty acid homeostasis
in the normoxic and ischemic heart. Physiol Rev. 1992;72:881–940.
link not found
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Energy metabolism of the heart: from basic
concepts to clinical applications.
Taegtmeyer H.
Division of Cardiology, University of Texas-Houston Medical
School.
Publication Types:
PMID: 8174388 [PubMed - indexed for MEDLINE]
-
Uptake and metabolism of palmitate by isolated
cardiac myocytes from adult rats: involvement of sarcolemmal
proteins.
Luiken JJ, van Nieuwenhoven FA, America G, van der Vusse
GJ, Glatz JF.
Department of Physiology, Cardiovascular Research Institute
Maastricht (CARIM), Maastricht University, The Netherlands.
The precise mechanism of uptake of long-chain fatty acids (FA)
by cardiac myocytes is incompletely understood. We examined
the involvement of sarcolemmal proteins in the initial uptake
of FA by isolated rat cardiac myocytes, and the relation between
initial uptake and metabolism. Cardiac myocytes were incubated
in the presence of 90 microns [1-14C]palmitate complexed to
300 microns bovine serum albumin (BSA), presenting a physiologically
relevant condition. During initial palmitate uptake (3 min),
56% of the intracellularly sequestered palmitate was esterified,
and an additional 21% converted into oxidation intermediates.
Varying the palmitate/BSA molar ratio revealed saturation kinetics
with the apparent Km for cellular palmitate uptake (435 micro
M) to be comparable to those for esterification (465 micro M)
and oxidation (222 micro M). Varying the BSA concentration at
a fixed palmitate/BSA molar ratio also showed saturation of
uptake at increasing concentrations, with an apparent Km for
BSA of 23 micro M. Changes in palmitate metabolism induced by
changes in glucose utilization were accompanied by identical
effects on palmitate uptake. Addition of lactate also inhibited
both oxidation and uptake of palmitate, but had no effect on
esterification. Virtually complete inhibition of palmitate oxidation
by etomoxir inhibited palmitate uptake for 50%, while decreasing
esterification by 33%. In the presence of phloretin and trypsin,
palmitate uptake and metabolism were inhibited 76-88%, and in
the presence of sulfo-N-succinimidyloleate by 53%. It is concluded
that a) the bulk of sarcolemmal palmitate translocation occurs
by membrane-associated FA-binding proteins, most likely assisted
by albumin binding proteins without regulatory function, and
b) palmitate uptake is most likely driven by its rapid intracellular
metabolic conversion.
PMID: 9144089 [PubMed - indexed for MEDLINE].
-
Acute regulation of fatty acid uptake involves
the cellular redistribution of fatty acid translocase.
Bonen A, Luiken JJ, Arumugam Y, Glatz JF, Tandon NN.
Department of Kinesiology, University of Waterloo, Waterloo,
Ontario N2L 3G1, Canada. abonen@healthy.uwaterloo.ca
We used muscle contraction, which increases fatty acid oxidation,
as a model to determine whether fatty acid transport is acutely
regulated by fatty acid translocase (FAT/CD36). Palmitate uptake
by giant vesicles, obtained from skeletal muscle, was increased
by muscle contraction. Kinetic studies indicated that muscle
contraction increased V(max), but K(m) remained unaltered. Sulfo-N-succinimidyl
oleate, a specific inhibitor of FAT/CD36, fully blocked the
contraction-induced increase in palmitate uptake. In giant vesicles
from contracting muscles, plasma membrane FAT/CD36 was also
increased in parallel with the increase in long chain fatty
acid uptake. Further studies showed that like GLUT-4, FAT/CD36
is located in both the plasma membrane and intracellularly (endosomally).
With muscle contraction, FAT/CD36 at the surface of the muscle
was increased, while concomitantly, FAT/CD36 in the intracellular
pool was reduced. Similar responses were observed for GLUT-4.
We conclude that fatty acid uptake is subject to short term
regulation by muscle contraction and involves the translocation
of FAT/CD36 from intracellular stores to the sarcolemma, analogous
to the regulation of glucose uptake by GLUT-4.
PMID: 10799533 [PubMed - indexed for MEDLINE]
-
Levels of carnitines in brain and other tissues
of rats of different ages: effect of acetyl-L-carnitine administration.
Maccari F, Arseni A, Chiodi P, Ramacci MT, Angelucci L.
Institute for Research on Senescence, Sigma-Tau S.p.A., Pomezia,
Rome, Italy.
Male Sprague-Dawley rats, aged 2, 5, 16, 20 and 30 months and
normally fed, were used for determination of carnitines in the
brain, serum, heart, tibial muscle, liver and urine. With respect
to 5-month-old animals, those aged 30 months exhibited a statistically
significant decrement of total carnitine levels in the brain,
serum, heart and tibial muscle, accompanied by a dramatic increment
in the liver. This suggests impaired net transport of carnitines
from the liver to the blood in old age. Urinary excretion was
similar in the two age groups. One group received from 5 months
on daily 75 mg/kg acetyl-L-carnitine in drinking water. At 20
months, the treated animals showed levels of brain, heart and
serum carnitines similar to those of 5-month-old animals. The
recovery of brain, heart and serum carnitines in the old animals
treated with acetyl-L-carnitine indicates that intestinal absorption
and tissue uptake remain sufficiently efficient in the course
of aging. The lower level of brain lipofuscins due to acetyl-L-carnitine
treatment may be related to the effect of the compound on acetylcholine
metabolism.
PMID: 2369927 [PubMed - indexed for MEDLINE]
-
Mitochondrial metabolism and substrate competition
in the aging Fischer rat heart.
McMillin JB, Taffet GE, Taegtmeyer H, Hudson EK, Tate CA.
Department of Pathology and Laboratory Medicine, University
of Texas Medical School at Houston.
OBJECTIVE: The objective was to examine mitochondrial oxidative
metabolism of long chain fatty acids and to compare it with
glucose uptake and the generation of pressure-volume work in
hearts from mature and aged rats. METHODS: Hearts from mature
(8 to 15 months of age) and old (28 to 30 months) Fischer 344
rats were perfused as working hearts with either 10 mM glucose
or glucose plus 1 mM oleic acid (2% bovine serum albumin) and
rates of glucose extraction were determined. Hearts were subjected
to a stepwise increase in work load. In separate experiments,
mitochondria were isolated from mature and old rat hearts and
assayed for respiratory function, carnitine exchange, carnitine
palmitoyltransferase activities, and phospholipid content. RESULTS:
Although there were no differences in peak work attained between
the mature and old rats in the presence of either glucose alone
or glucose plus oleic acid, glucose utilisation was significantly
decreased by oleate in the mature animals only. No significant
changes in either glutamate or succinate (+rotenone) supported
respiration were found in heart mitochondria isolated from old
rats compared with mature animals. In agreement with prior studies
with the Wistar rat model of aging, significant decrements in
the rates of palmitoylcarnitine oxidation and carnitine exchange
were apparent in the old Fischer animals. A significant lowering
of heart mitochondrial carnitine palmitoyltransferase I activity
was also found in the old animals. A decrease in the amounts
of carnitine loaded in mitochondria from old animals is consistent
with reduced carnitine content in both mitochondria and whole
hearts from aged Wistar and Fischer rats. A significant (23%)
reduction in heart mitochondrial cardiolipin content from 30
month old Fischer rats suggests that this phospholipid may also
contribute to the lower rates of carnitine and acylcarnitine
transport across the mitochondrial inner membrane. CONCLUSION:
The limitation in the delivery of fatty acyl units to beta oxidation
as measured in isolated heart mitochondria from old rats has
a physiological correlate in the intact heart. The well documented
suppression of glucose oxidation by fatty acids seen in the
adult rat heart is not seen in old hearts, supporting the in
vitro finding of decreased oxidation of palmitoylcarnitine with
senescence.
PMID: 8313432 [PubMed - indexed for MEDLINE]
-
Carnitine palmitoyl transferase-I activity
in the aging mouse heart.
Odiet JA, Boerrigter ME, Wei JY.
Division on Aging, Harvard Medical School, Beth Israel Hospital,
Boston, MA 02215, USA.
We investigated the influence of age on carnitine palmitoyl
transferase-I (CPT-I, EC 2.3.1.21) activity in the mouse heart.
There was an age-associated decrease in CPT-I activity from
2 to 26 months (P = 0.006). We studied the effect of oxygen-derived
radicals on CPT-I activity. Mitochondria from 2-month-old mouse
hearts exposed to different concentrations of hydrogen peroxide
(H2O2) showed a dose-related decrease in CPT-I activity (P <
0.002). To determine the possible reversibility of the age change
in CPT-I activity, we studied the effect of oral administration
of propionyl-L-carnitine (PLC). Oral pretreatment of middle-aged
(18-month-old) mice with PLC resulted in a 37% increase of basal
CPT-I activity (P < 0.05) compared to age-matched untreated
animals, and restored it to a level similar to that of 2-month-old
mice. Pretreatment of senescent (26-month-old) mice with PLC,
however, showed no significant change in basal CPT-I activity.
It is possible that the age-related decrease in CPT-I activity
may result from an in vivo accumulation of oxygen-derived radical
damage. It appears that the age change in CPT-I activity in
18- but not in the 26-month-old mice is reversible with PLC.
PMID: 7616763 [PubMed - indexed for MEDLINE]
-
Carnitine-acylcarnitine translocase activity
in cardiac mitochondria from aged rats: the effect of acetyl-L-carnitine.
Paradies G, Ruggiero FM, Petrosillo G, Gadaleta MN, Quagliariello
E.
Department of Biochemistry and Molecular Biology, University
of Bari, Italy.
Age-related changes in mitochondrial fatty acids metabolism
may underlie the progressive decline in cardiac function. The
effect of aging and acute treatment with acetyl-L-carnitine
on fatty acids oxidation and on carnitine-acylcarnitine translocase
activity in rat heart mitochondria was studied. Rates of palmitoylcarnitine
supported respiration as well as carnitine-carnitine and carnitine-palmitoylcarnitine
exchange reactions were all depressed (approx. 35%) in heart
mitochondria from aged rats. These effects were almost completely
reversed following treatment of aged rats with acetyl-L-carnitine.
Heart mitochondrial cardiolipin content was significantly reduced
(approx. 38%) in aged rats. Treatment of aged rats with acetyl-L-carnitine
restored the level of cardiolipin to that of young rats. It
is suggested that acetyl-L-carnitine is able to reverse age-related
decrement in mitochondrial carnitine-acylcarnitine exchange
activity by restoring the normal cardiolipin content.
PMID: 8788238 [PubMed - indexed for MEDLINE]
-
Lipid oxidation by heart mitochondria from
young adult and senescent rats.
Hansford RG.
PMID: 637843 [PubMed - indexed for MEDLINE]
-
Myocardial GLUT-4 glucose transporter
protein levels of rats decline with advancing age.
Cartee GD.
Biodynamics Laboratory, University of Wisconsin-Madison.
Age-related changes in glucose metabolism and glucose
transporter protein content have been described in adipose
tissue and skeletal muscle, two tissues that express the
GLUT-4 isoform of the glucose transporter protein. I studied
the effect of age on the levels of GLUT-4 protein in a third
insulin-sensitive tissue: the heart. Cardiac ventricles were
sampled from male Fischer 344/Brown Norway F1 hybrid (F344/BNNia)
rats. The total protein concentration of the left ventricle
did not change with age. GLUT-4 levels per mg of protein
declined by 15% between 3.5 and 13 months of age, and by
another 12% during adulthood (between 13 and 25 months of age);
when expressed per g wet weight, the decreases were 13% and
17%, respectively. Linear regression analysis revealed a
significant (p < .0001) relationship (r2 = .634) between
age and myocardial GLUT-4. These results demonstrate that the
GLUT-4 levels in the left ventricle decrease in an age-related
fashion and suggest that the capacity for glucose transport
might also be reduced.
PMID: 8315221 [PubMed - indexed for MEDLINE]
15. Nakai
N, Sato Y, Oshida Y, et al. Effects of aging on the activities
of pyruvate dehydrogenase complex and its kinase in rat heart.
Life Sci. 1997;60:2309–2314. link not found
-
Age-dependent decline in the cytochrome c
oxidase activity in rat heart mitochondria: role of cardiolipin.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
Department of Biochemistry and Molecular Biology, University
of Bari, Italy.
Cardiolipin is a major mitochondrial membrane lipid and plays
a pivotal role in mitochondrial function. We have recently suggested
a possible involvement of this phospholipid in the age-linked
decline of cytochrome c oxidase activity in rat heart mitochondria
[G. Paradies et al. (1993) Arch. Gerontol. Geriatr. 16, 263-272].
The aim of this work was to test our earlier proposal. We have
investigated whether addition of exogenous cardiolipin to mitochondria
is able to reverse, in situ, the age-linked decrease in the
cytochrome oxidase activity. The method of fusion of liposomes
with mitochondria developed by Hackenbrock [Hackenbrock and
Chazotte (1986) Methods Enzymol. 125, 35-45] was employed in
order to enrich the mitochondria cardiolipin content. We demonstrate
that the lower cytochrome c oxidase activity in heart mitochondria
from aged rats can be fully restored to the level of young control
rats by exogenously added cardiolipin. No restoration was obtained
with other phospholipids or with peroxidized cardiolipin. Our
data support a key role for cardiolipin in the age-linked decline
of rat heart mitochondrial cytochrome c oxidase activity.
PMID: 9109403 [PubMed - indexed for MEDLINE]
-
Mitochondrial production of pro-oxidants
and cellular senescence.
Sohal RS, Brunk UT.
Department of Biological Sciences, Southern Methodist University,
Dallas, TX 75275.
Mitochondria are the major intracellular producers of O2- and
H2O2. The level of oxidative stress in cells, as indicated by
the in vivo exhalation of alkanes and the concentration of molecular
products of oxy-radical reactions, increases during aging in
mammals as well as insects. In this paper, we discuss the relationship
between mitochondrial generation of O2- and H2O2, and the aging
process. The rate of mitochondrial O2- and H2O2 generation increases
with age in houseflies and the brain, heart and liver of rat.
This rate has been found to correspond to the life expectancy
of flies and to the maximum life span potential (MLSP) of six
different mammalian species, namely, mouse, rat, guinea pig,
rabbit, pig and cow. In contrast, the level of antioxidant defenses
provided by activities of superoxide dismutase, catalase, glutathione
peroxidase and glutathione concentration neither uniformly declines
with age nor corresponds to variations in MLSP of different
mammalian species. It is argued that the rate of mitochondrial
O2- and H2O2 generation rather than the antioxidant level may
act as a longevity determinant.
Publication Types:
PMID: 1383771 [PubMed - indexed for MEDLINE]
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Mitochondrial production of pro-oxidants
and cellular senescence.
Sohal RS, Brunk UT.
Department of Biological Sciences, Southern Methodist University,
Dallas, TX 75275.
Mitochondria are the major intracellular producers of O2- and
H2O2. The level of oxidative stress in cells, as indicated by
the in vivo exhalation of alkanes and the concentration of molecular
products of oxy-radical reactions, increases during aging in
mammals as well as insects. In this paper, we discuss the relationship
between mitochondrial generation of O2- and H2O2, and the aging
process. The rate of mitochondrial O2- and H2O2 generation increases
with age in houseflies and the brain, heart and liver of rat.
This rate has been found to correspond to the life expectancy
of flies and to the maximum life span potential (MLSP) of six
different mammalian species, namely, mouse, rat, guinea pig,
rabbit, pig and cow. In contrast, the level of antioxidant defenses
provided by activities of superoxide dismutase, catalase, glutathione
peroxidase and glutathione concentration neither uniformly declines
with age nor corresponds to variations in MLSP of different
mammalian species. It is argued that the rate of mitochondrial
O2- and H2O2 generation rather than the antioxidant level may
act as a longevity determinant.
Publication Types:
PMID: 1383771 [PubMed - indexed for MEDLINE]
-
Oxidative damage to mitochondrial DNA is
inversely related to maximum life span in the heart and brain
of mammals.
Barja G, Herrero A.
Department of Animal Biology-II (Animal Physiology), Faculty
of Biology, Complutense University, Madrid 28040, Spain.
DNA damage is considered of paramount importance in aging. Among
causes of this damage, free radical attack, particularly from
mitochondrial origin, is receiving special attention. If oxidative
damage to DNA is involved in aging, long-lived animals (which
age slowly) should show lower levels of markers of this kind
of damage than short-lived ones. However, this possibility has
not heretofore been investigated. In this study, steady-state
levels of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) referred
to deoxyguanosine (dG) were measured by high performance liquid
chromatography (HPLC) in the mitochondrial (mtDNA) and nuclear
(nDNA) DNA from the heart of eight and the brain of six mammalian
species ranging in maximum life span (MLSP) from 3.5 to 46 years.
Exactly the same digestion of DNA to deoxynucleosides and HPLC
protocols was used for mtDNA and nDNA. Significantly higher
(three- to ninefold) 8-oxodG/dG values were found in mtDNA than
in nDNA in all the species studied in both tissues. 8-oxodG/dG
in nDNA did not correlate with MLSP across species either in
the heart (r=-0.68; P<0.06) or brain (r = 0.53; P<0.27).
However, 8-oxodG/dG in mtDNA was inversely correlated with MLSP
both in heart (r=-0.92; P<0.001) and brain (r=-0.88; P<0.016)
tissues following the power function y = a(.)x(b), where y is
8-oxodG/dG and x is the MLSP. This agrees with the consistent
observation that mitochondrial free radical generation is also
lower in long-lived than in short-lived species. The results
obtained agree with the notion that oxygen radicals of mitochondrial
origin oxidatively damage mtDNA in a way related to the aging
rate of each species.-Barja, G., Herrero, A. Oxidative damage
to mitochondrial DNA is inversely related to maximum life span
in the heart and brain of mammals.
PMID: 10657987 [PubMed - indexed for MEDLINE]
-
Mitochondrial DNA alterations as ageing-associated
molecular events.
Wei YH.
Department of Biochemistry, National Yang-Ming Medical College,
Taipei, Taiwan.
Mitochondrial DNA (mtDNA) is a naked double-stranded circular
extrachromosomal genetic element continuously exposed to the
matrix that contains great amounts of reactive oxygen species
and free radicals. The age-dependent decline in the capability
and capacity of mitochondria to dispose these oxy-radicals will
render mtDNA more vulnerable to mutations during the ageing
process. During the past 3 years, more than 10 different types
of deletions have been identified in the mtDNA of various tissues
of old humans. Some of them were found only in a certain tissue
but some others appeared in more than one organ or tissue. The
4977-bp deletion is the most prevalent and abundant one among
these deletions. Skeletal muscle is the target tissue of most
ageing-associated mtDNA deletions and has often been found to
carry multiple deletions. The onset age of the various deletions
in mtDNA varies greatly with individual and type of the deletion.
The 4977-bp deletion has been independently demonstrated to
occur in the mtDNA of various tissues of the human in the early
third decade of life. However, the 7436-bp deletion was only
detected in the heart mtDNA of human subjects in their late
thirties. The others appeared only in older humans over 40 years
old. No apparent sex difference was found in the onset age of
these ageing-associated mtDNA deletions. The various ageing-associated
deletions could be classified into two groups. Most of the deletions
belong to the first group, in which the 5'- and 3'-end breakpoints
of the deletion are flanked by 4-bp or longer direct repeats.
The deletion in the second group occurs less frequently and
shows no distinct repeat sequences flanking the deletion sites.
These two groups of mtDNA deletions may occur by different mechanisms.
The first group is most probably caused by internal recombination
or slippage mispairing during replication of mtDNA by the D-loop
mechanism. The deleted mtDNA and the deleted DNA fragment may
be further degraded or escape from the mitochondria and get
translocated into the nucleus. The latter route has been substantiated
by many observations of inserted mtDNA sequences in the nuclear
DNA. Thus, the fragments of migrating mtDNA may change the information
content and expression level of certain nuclear genes and thereby
promote the ageing process or cause cancer. Similar ageing-associated
alterations of mtDNA have also been observed in aged animals
and plants. I suggest that mtDNA deletions and other mutations
to be discovered are molecular events generally associated with
the ageing process.
Publication Types:
PMID: 1383757 [PubMed - indexed for MEDLINE]
-
Should antioxidant vitamins be routinely
recommended for older people?
Ward JA.
Royal South Sydney Hospital, Zetland, New South Wales, Australia.
The hypothesis that oxidative damage due to free radicals is
an important cause of aging is the subject of much research
and even more interest among the public and lay media. An increasing
number of older people are asking whether they should be taking
antioxidant vitamins, despite their considerable cost. Epidemiological
and laboratory evidence indicates that oxidative damage caused
by oxygen free radicals is important in many of the major diseases
of older age. It is also clear that a diet high in antioxidants
protects against these diseases, including many cancers and
ischaemic heart disease. However, it has not been proven whether
antioxidant vitamins, taken as dietary supplements, provide
the same level of protection as a diet that is rich in fruit
and vegetables. Although there appears to be no reason to discourage
older people from taking vitamin E (tocopherols) and ascorbic
acid (vitamin C), the best advice to give them is to reduce
their intake of xenobiotics, to drink tea instead of coffee,
and to eat liberal amounts of fruit, vegetables, nuts, soya
beans and lentils. The use of beta-carotene as a dietary supplement
should be discouraged.
Publication Types:
PMID: 9534018 [PubMed - indexed for MEDLINE]
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