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Regional differences in the response of cardiac cells to triiodothyronine administration across the left ventricle free wall of rat heart.
No full textWe have studied the effect of T3 administration (50 micrograms/Kg/day) on the
phenotype expression of several glucose-metabolizing enzymes (hexokinase, HK,
glucose-6-phosphate dehydrogenase, G6P-DH, aldolase, ALD, phosphofructokinase,
PFK, lactate dehydrogenase, LDH) in the different myocardial layers of the left
ventricle wall. In the control rats, most of these enzyme activities are
uniformly distributed across the left ventricle wall, G6P-DH being the only
exception. In the rats given T3 for 14 days, the mean levels of PFK, HK and ALD
activities increased significantly. With regard to the transmural distribution
patterns, that of PFK was unchanged, unlike those of HK and ALD which exhibited
their maximum increase in activity in the midmyocardium or in the mid- and
subepicardial myocardium. With LDH, a significant increase in activity was found
in the subepicardial layers which escaped detection on the whole homogenate. It
is concluded that the administration of thyroid hormone has different effects on
enzyme phenotype expression of cardiomyocytes in different regions of the cardiac
wall
Changes in 5'-nucleotidase and adenosine deaminase distribution across the rat left ventricle wall during growth and aging.
No full textThe concentrations of the adenosine-generating enzyme 5'-nucleotidase (5'-N) and
of the adenosine-degrading enzyme adenosine deaminase (ADA) in the rat left
ventricle change as a function of the age of the animal. The enzyme distribution
across the left ventricle wall is non-uniform in adult or old rats (in the case
of 5'-N) or in all age-groups (in the case of ADA). In the oldest rats, 5'-N
activity exhibited a significant increase in the mid-myocardium and in the inner
myocardial layers as compared with the young adult controls
Transmural distribution of hexokinase, glucose-6-phosphate dehydrogenase and glutamate-oxalacetate transaminase in the left ventricle of the rat
No full textThe changes in hexokinase (HK), glucose-6-phosphate dehydrogenase (G6P-DH) and glutamate aspertate aminotransferase (GOT) activities with the location of tissue within the left ventricle wall have been explored in the rat myocardium. The hearts were cut in 100 micron thick serial sections (see 4) and all sections spectrophotometric procedures (5). No significant transmural gradient in HK activity was observed but the levels of G6P-DH and of GOT activities were significantly higher in the subepicardial tissue and were at their lowest levels in the midmyocardial layers. Our data and previous observations (3,6) indicate that adptions to regional differences in the cardiac work load occurred in the left ventricle wall but that the transmural patterns of enzyme distribution may change with the different animal specie
Changes in the transmural distribution of glucose-metabolizing enzymes across the left and right ventricular wall of rat heart during growth and ageing.
No full textThe age-related changes in the activities of five glucose-metabolizing enzymes
(hexokinase, HK; glucose-6-phosphate dehydrogenase, G6P-DH; aldolase, ALD;
phosphofructokinase, PFK; and lactate dehydrogenase, LDH) were investigated in
the walls of left and right ventricles of rats of various age-groups (1-24
months). Age-related changes were found in the activities of all of the enzymes
in both ventricles during growth (with significant decreases between 2 and 6
months of age) and in the levels of PFK and LDH in the left ventricle during
ageing (with a significant increase between 12 and 24 months of age). The
distribution of the enzyme activities across the wall of both ventricles was
quite uniform in young, adult and mature rats (the distribution of G6P-DH
activity in the left ventricle wall at 2 months of age was the only notable
exception) but became non-uniform in the old rats with regard to G6P-DH, PFK, LDH
and probably HK in the left ventricle and G6P-DH and HK in the right ventricle.
These data support the hypothesis that alterations connected with ageing do not
lead to a generalized decline of cardiac metabolic capacity, and that they are
also the result of specific adaptive modifications, perhaps related to alteration
in the distribution of the work load and/or of nutrition across the ventricular
wall
Il controllo della dieta è il mezzo più efficace per ritardare l’invecchiamento e la comparsa delle malattie associate con l’età anziana
No full textInsulin, food restriction and the extension of lifespan: the mechanism of longevity
No full textDo ̈tsch et al. reported in this journal (1) on Blu ̈ her and
co-worker’s evaluation of the 18% increase in the lifespan of fat-specific insulin receptor knockout (FIRKO)
mouse (2). As early as 3 months of age, these mice maintained a body weight approximately 20% below the body
weight of their control littermates. The reduction in
body weight was caused by an approximately 60%
reduction of fat tissue. Interestingly, their appetite was
not reduced, resulting in the food intake being equivalent to that of the control animals. As a consequence,
food intake related to body weight exceeded that of the
controls by more than 50% (3). The conclusion was
that a reduction of fat mass without caloric restriction
can be associated with increased longevity in mice,
possibly through effects on insulin signalling.
Do ̈ tsch et al. highlighted that Blu ̈ her et al. fell short of
explaining the mechanism of longevity in their FIRKO
mice, because they speculated about a reduction in
the generation of oxygen-free radicals (4, 5) or a mechanism involving insulin-like growth factor-I (IGF-I) signalling but unfortunately they did not provide any data
regarding that hypothesis. We would like to mention
here that a possible explanation of prolongation of lifespan by caloric restriction or defective insulin signalling
has already been published (see ref. 6, Fig. 3): lower
insulin levels or activity may increase autophagy and
lysosomal proteolysis (7, 8), the anti-ageing cell repair
mechanism which improves disposal of altered membranes and cellular organelles, and cell housekeeping
(6, 9). This explanation is in line with recent genetic
findings which demonstrate that autophagy genes are
required for normal dauer morphogenesis and lifespan
extension in Caenorhabditis elegans (10).
The good news is that the beneficial effect on longevity could be obtained by drugs, without any genetic
manipulation: a decrease in free fatty acid (FFA)
plasma levels by the lifelong administration of antilipolytic drugs to fasted rats may retard the age-related
changes in biomarkers of ageing that are known to
correlate with life expectancy (11, 12).
It is conceivable that in the FIRKO mice, the 50–70%
reduction in fat mass throughout life might be associated with a decrease in the production and plasma
levels of FFA.
The antilipolytic drug for the purpose of the Pharmacological Intensification of Suppression of Ageing
(PISA) (this name was kindly suggested by Dr George
Martin, Seattle, WA, USA) is licensed for human use
as a hypolipidaemic agent (Acipimox). From a practical
point of view, the treatment might open a way to make
more people likely to adhere to an anti-ageing regimen
of dietary restriction otherwise too intensive to be
endurable over an extended period involving much of
human life (13
The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases
No full textMacroautophagy is a degradation/recycling system ubiquitous in eukariotic cells,
which generates nutrients during fasting under the control of amino acids and
hormones, and contributes to the turnover and rejuvenation of cellular components
(long-lived proteins, cytomembranes and organelles). Tight coupling between these
two functions may be the weak point in cell housekeeping. Ageing denotes a
post-maturational deterioration of tissues and organs with the passage of time,
due to the progressive accumulation of the misfunctioning cell components because
of oxidative damage and an age-dependent decline of turnover rate and
housekeeping. Caloric restriction (CR) and lower insulin levels may slow down
many age-dependent processes and extend lifespan. Recent evidence is reviewed
showing that autophagy is involved in ageing and in the anti-ageing action of
anti-ageing calorie restriction: function of autophagy declines during adulthood
and is almost negligible at older age; CR prevents the age-dependent decline of
autophagic proteolysis and improves the sensitivity of liver cells to stimulation
of lysosomal degradation; protection of autophagic proteolysis from the
age-related decline co-varies with the duration and level of anti-ageing food
restriction like the effects of CR extending lifespan; the pharmacological
stimulation of macroautophagy has anti-ageing effects. Besides the involvement in
ageing, macroautophagy may have an essential role in the pathogenesis of many
age-associated diseases. Higher protein turnover may not fully account for the
anti-ageing effects of macroautophagy, and effects of macroautophagy on
housekeeping of the cell organelles, antioxidant machinery of cell membranes and
transmembrane cell signaling should also be considered
The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction
No full textRestricting caloric intake (CR) well below that of ad libitum (AL) fed animals
retards and/or delays many characteristics of ageing and the occurrence and
progression of age-associated diseases, efficacy depending on duration. The
hypothesis that the anti-ageing effect of CR might involve stimulation of the
cell-repair mechanism autophagy was tested. The effects of ageing and duration of
anti-ageing CR on liver autophagic proteolysis (AP) were explored in male AL
Sprague-Dawley rats aged 2-, 6-, 12- and 24-months; and 24-month-old rats on a CR
diet initiated at 2-, 6- and 12-month of age or initiated at age 2-months and
interrupted at age 18 months. The age-related changes in the regulation of AP
were studied by monitoring the rate of valine release in the incubation medium
from isolated liver cells by an HPLC procedure. Results show that the maximum
attainable rate and the regulation of AP decline with increasing age; that
changes are prevented by anti-ageing CR initiated at young age, that the
protective effects of CR change with the duration of diet. It is concluded that
the data are compatible with the hypothesis that AP and improved membrane
maintenance might be involved in the antiageing mechanism of CR
The anti-ageing effects of caloric restriction may involve stimulation of macro autophagy and lysosomal degradation, and can be intensified pharmacologically
No full textCaloric restriction (CR) and a reduced growth hormone (GH)-insulin-like growth
factor (IGF-1) axis are associated with an extension of lifespan across taxa.
Evidence is reviewed showing that CR and reduced insulin of GH-IGF-1 axis may
exhibit their effects at least partly by their common stimulatory action on
autophagy, the cell repair mechanism responsible for the housekeeping of cell
membranes and organelles including the free radical generators peroxisomes and
mitochondria. It is shown that the life-long weekly administration of an
anti-lipolytic drug may decrease glucose and insulin levels and stimulate
autophagy and intensify anti-ageing effects of submaximal CR
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