Age-related changes of serotonin and its metabolites content in the visual system of the rat

Measurements have been taken of the serotonin and its metabolites (tryptophan, 5-hydroxytryptophan, 5-hydroxy-3-indolacetic acid and 5-hydroxytryptophol) in each structure of the geniculate and extrageniculate visual system of rats aged between 3 and 30 months. The concentration of tryptophan was the highest of all compounds studied. Its increase during ageing is statistically significant in the lateral geniculate and posterior thalamus. 5-HTP concentration was very low and in some cases not detectable. 5-HT concentrations and its principal metabolite, 5-HIAA, showed a different profile in each brain structure. The lateral geniculate and visual cortex showed statistically significant changes, but with opposite results. In the lateral geniculate the 5-HT and 5-HIAA concentrations were increased during the ageing period. However, in the visual cortex the 5-HT and 5-HIAA concentrations decreased in the same period. These age-related changes were not seen in the superior colliculus and posterior thalamus as in the 5-HT levels as in the 5-HIAA. 5-hydroxytryptophol was always found in low concentration. These results suggest age-related changes in the geniculate visual system.     

Age-related changes in adrenaline content of rat splanchnic blood vessels

The influence of ageing on the adrenaline content of the superior mesenteric artery and vein, renal artery and vein and portal vein was studied in 3-month- (young), 12-month- (adult) and 24-month-old (old) male Wistar rats using radioenzymatic assay for the measurement of catecholamine levels. Adrenaline concentrations were unchanged in the vascular wall of the blood vessels examined in adult rats, but were significantly decreased in the vascular wall of the superior mesenteric, renal and portal veins of old rats. In contrast, no age-dependent changes of adrenaline levels were found in the vascular wall of the superior mesenteric or renal arteries. The possibility that the loss of adrenaline concentrations in the venous vascular wall may be in some way related to the cardiovascular impairment occurring with age is discussed.     

Age-related changes in serotonin content and its release reaction of rat platelets

The serotonin content of platelets, serum and plasma from rats of various ages was examined. In male rats, platelet serotonin content, which was about 0.65 nmol/10(8) platelets at young age (6-7 months), increased slightly at middle age (12-14 months) but decreased markedly at old age (25-26 months). Significant difference (P less than 0.05) was observed between young and old rats, and between middle-aged and old rats. In female rats, on the other hand, no age-related change in the platelet serotonin content was found. In both sexes, the serotonin content of rat sera changed with age in the same pattern as that of the platelets. No plasma serotonin was detected in rats of either sex and at any ages examined. Serotonin release from rat platelets was also studied using collagen and thrombin as stimulants. In males, the responsiveness of platelets to these two stimulants showed almost the same age-dependent changes. It was lower in middle-aged rats than in young rats but increased greatly in old rats. Significant difference (P less than 0.05) was observed between middle-aged and old rats. In females, collagen and thrombin had the opposite effect on the sensitivity of the platelets as age increased. The amount of serotonin released in response to collagen was low until middle age but increased markedly at old age, while the content of serotonin released by thrombin remained high until middle age and decreased greatly at old age. These results imply that age-related changes in the serotonin release reaction in rat platelets differed according to the stimulants used.     

Age-related changes in the galactose recognition system in rat liver cells

In the present report, the galactose recognition system in 3- and 24-month-old rat livers has been studied with in vitro and with in situ binding experiments and in vivo ligand uptake. The galactose-specific receptors were visualized by using colloidal gold particles of different sizes (5 nm, 17 nm and 50 nm mean diameter), coated with lactosylated bovine serum albumin (LacBSA) as electron dense ligands. The data show that aging affects the expression of galactose-specific receptors and the rate of endocytosis. In the in vitro and in situ experiments hepatocytes and liver macrophages from old rats on the plasma membrane express a decreased number of binding sites with respect to those present on the adult rat liver cells. Approximately 80% of the total number of liver macrophages from aged rats show a binding distribution which is very different from the typical clustered receptor arrangement: the binding sites appear as single or small clusters of gold granules. As a direct consequence of the altered pattern of the receptor distribution, the capacity of liver macrophages from 24-month-old rats to internalize the larger ligands (17 nm and 50 nm) is decreased, as compared with adult rats. Aging, therefore, influences the galactose recognition system in two ways: (i) by decreasing the number of binding sites expressed on the liver cell surfaces; and (ii) by modifying the receptor distribution on liver macrophages and consequently affecting the internalization of galactose exposing particles.     

Age-related changes in the kinetic properties of the acetyl-CoA carboxylase and phospholipid content of rat liver

Age-related changes in the activity of rat liver acetyl-CoA carboxylase and the phospholipid content have been investigated in detail between birth and the age of 2.5 years. During postnatal development and ageing the enzyme shows varying kinetic properties as well as different specific activities. During the first days of postnatal life the activity declines. A minimum of 20% from adult levels is found 4 days after birth. Thereafter the specific activity rapidly increases. The highest specific activities are found in old animals. Major changes can be found in the kinetics of the activation of the enzyme by citrate. The influence of ATP concentration shows minor age-related alterations. The phospholipid composition of the rat liver is age-dependent, too. The coincidence of modifications in the phospholipid composition and correlated variations of the acetyl-CoA carboxylase activity as well as developmental increase of the endoplasmic reticulum in the liver and the growth rate of the rat brain are discussed.     

Age-related changes in sleep in the rat

Human sleep in old age is characterized by a number of changes, including reductions in sleep efficiency, amounts of visually scored slow-wave and REM sleep, and amplitude of the diurnal sleep/wake rhythm. In older rats, some, but not all, of these traits have been reported, including a decrease in the mean duration of sleep bouts, an increase in the number of sleep bouts, and a modest reduction of REM sleep. Studies of the diurnal rhythm of total sleep have had varied results. There are, however, virtually no data indicating at what point across the rat's lifetime the changes seen in old age begin to occur. In order to more fully characterize sleep in older rats, and to develop data on when they first appear, we have examined sleep in young adult (3 months), middle-aged (12 months), and older (24 months) rats during 24 hours under constant dim light. Analyses of variance revealed no age-related changes in total sleep, NREM or REM sleep, wake time after sleep onset, or three different measures of the amplitude of the sleep/wake circadian rhythm. There were, however, significant age-related reductions in high-voltage NREM sleep ("HS2"), the mean length of sleep bouts, and REM-onset duration. These were seen in the 1-year-old rats, indicating that the changes seen in the older animals were evident by midlife.     

Age-related changes in the redox status of rat muscle cells and their role in enzyme-aging

The redox status of three biological components capable of undergoing oxidation-reduction reactions, glutathione, NAD and NADP, were determined in muscle tissues of young and old rats. A considerable increase in the relative concentration of the oxidized form, at the expense of the reduced one was found in the old tissue reflecting a significantly less reducing environment than in young cells. The effects of varying the ratio of reduced/oxidized glutathione in vitro on the activity of the enzyme glyceraldehyde-3-phosphate dehydrogenase extracted from young and old animals were compared. It was found that concentrations of GSSG as found in old muscle tissue do not affect enzyme samples extracted from young muscle. The accumulation of oxidized glutathione observed in old cells does not, therefore, directly cause the age-related activity loss of this enzyme.     

Redox aspects of signaling by catecholamines and their metabolites

This review covers certain novel aspects of catecholamine signaling in neurons that involve redox systems and synaptic plasticity. The redox hypothesis suggests that one important factor in neurocomputation is the formation of new synapses and the removal of old ones (synaptic plasticity), which is modulated in part by the redox balance at the synapse between reactive oxygen species (ROS) (such as hydrogen peroxide and the nitric oxide radical) and neuroprotective antioxidants (such as ascorbate, glutathione, and catecholamines). Catecholamines, in particular dopamine, which signals positive reinforcement, may play a key role in this activity. Dopamine has powerful antioxidant properties by several separate mechanisms-direct ROS scavenging, activation of the synthesis of antioxidant proteins, and possibly via dismuting complexes with iron inside endosomes or in catecholaminergic synaptic vesicles. This may contribute to synaptic growth and reinforcement-directed learning. On the other hand, catecholamines are easily oxidized to toxic quinones on the neuromelanin pathway. This might contribute under certain circumstances to synaptic deletion. Evidence is presented that abnormalities in this system may contribute to the pathogenesis of Parkinson's disease and schizophrenia.     

Age-related changes of thymalin content in human epidermis

Immunomorphological analysis revealed the presence of thymalin in human epidermis and in fetal reticuloepithelium. These structures are developed from the common embryonic primordium ectoderm. In embryos and adult humans thymalin is present only in young epidermal cells, which undergo age-related involution. By the age of 70 years, the layer of thymalin-containing cells looks thinned and discontinuous. The content of thymalin, a thymic factor, decreases with age.     

Age-related changes in rat brain capillaries

We have measured several morphological parameters by electron microscopy of frontal cortex (FC) and hippocampal CA1 (HC) capillaries in male Fischer 344 rat 3-, 9- and 24-months old. The results indicate that with increasing age there is an increase in the cross-sectional area of the basement membrane, increase in the friction of endothelial cell and pericyte cytoplasmic area occupied by mitochondria in the FC, increase in the size of the pericyte mitochondria in both the FC and HC, increased capillary lumen area in the FC and decreased capillary lumen area in the HC. Also, the cytoplasmic area occupied by mitochondria in capillary pericytes is larger than in the endothelial cells of both FC and HC. These results suggest that there is regional variation in the age-associated changes in capillary morphometrics.     

Age-related epigenetic changes and the immune system

The role of DNA methylation in immune function is discussed extensively in other papers in this issue. Many of these discussions assume that DNA methylation, a major mediator of epigenetic information, is fairly immutable and uniform in adult cells and tissues. There is, however, growing evidence that DNA methylation changes subtly with age. Normal aging cells and tissues show a progressive loss of 5-methylcytosine content, primarily within DNA repeated sequences, but also in potential gene regulatory areas. In parallel, selected genes show progressive age-related increases in promoter methylation, which, once a critical methylation density is reached, have the potential to permanently silence gene expression. These changes are highly mosaic within a given tissue and introduce a high degree of epigenetic variability in aging cells. Such epigenetic phenomena could impact immune response through masking/unmasking potential tissue antigens as well as by modulating the differentiation and response of immune effector cells. The contribution of epigenetic changes to the altered immune function observed in aging humans deserves careful investigation.     

Age-related changes in arginine and its metabolites in memory-associated brain structures

l-arginine is metabolised by nitric oxide synthase (NOS) and arginase to form l-citrulline and nitric oxide, and l-ornithine and urea, respectively. The present study investigated NOS and arginase activities, and the levels of l-arginine, l-citrulline and l-ornithine, as well as glutamate and γ-aminobutyric acid (GABA), in memory-related brain structures in 4, 12 and 24 months old rats. Significantly increased NOS and arginase activities with age were found across the CA1, CA2/3 and dentate gyrus (DG) sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, postrhinal and temporal cortices in a region-specific manner. For l-arginine, there were age-related increases in CA1 and the perirhinal and temporal cortices, and decreases in the entorhinal and postrhinal cortices. l-citrulline levels were decreased with age in the prefrontal, postrhinal and temporal cortices. There were age-related decreases in l-citrulline/l-arginine molar ratio in CA1 and CA2/3 and the prefrontal and temporal cortices, but an increase in the entorhinal cortex (EC). Increased l-ornithine levels and l-ornithine/l-arginine molar ratios with age were found in most of the brain regions examined. Glutamate levels were significantly decreased with age in the prefrontal, entorhinal, perirhinal and temporal cortices, whereas GABA level was largely unchanged except for age-related increase in CA1. There were significantly decreased glutamate/GABA molar ratios with age in six brain regions. Correlational analyses revealed no inverse relationship between NOS and arginase activities, and no positive correlations between the activities of the two enzymes and the tissue concentrations of their products. Interestingly, there were significant positive correlations between glutamate and GABA, and l-arginine and its metabolites in many brain regions. These results demonstrate that the aging process has dramatic effects on the NOS and arginase metabolic pathways of l-arginine and the glutamatergic neurotransmitter system. Since l-arginine metabolism is complex, there is a need to determine its metabolomic profile in vivo in the future.     

Age-related changes of exercise-induced plasma catecholamines and neuropeptide Y responses in normal human subjects

Age-related plasma noradrenaline and neuropeptide Y were evaluated in seven young (mean ± SD, 28 ± 3 years) and seven elderly (64 ± 8 years) normal subjects during rest and different work loads on a cycle ergometer. In the supine and the sitting position plasma noradrenaline and neuropeptide Y were almost identical in the two groups. Plasma neuropeptide Y did not increase during exercise at 100 W for 15 min. At this load plasma noradrenaline levels were higher in the older subjects (mean ± SEM, 0.97 ± 0.12 vs. 0.60 ± 0.09 ng ml^-l). There was a significant correlation between plasma noradrenaline and the relative work load at 100 W (r = 0. 794 , P = 0.0007). At 75% of maximal work load plasma noradrenaline and neuropeptide Y were higher in the young group (1.84 ± 0.16 vs. 1.26 ± 0.13 ng ml^-l (noradrenaline) and 38 ± 4 vs. 22 ± 5 pmol 1^-1 (neuropeptide Y)). In the elderly group plasma neuropeptide Y did not increase during exercise and showed a tendency to fall below basal level 5 min post-exercise. It is concluded, that plasma noradrenaline does not increase more in older subjects during exercise when correcting for the generally lower physical fitness in this group compared to younger subjects, and that plasma neuropeptide Y does not increase during exercise in older subjects, suggesting an age-reduced capacity in this system.     

Age-related changes in visual recognition memory during infancy and early childhood

Age-related changes in long-term memory during infancy and early childhood were examined using the Visual Recognition Memory (VRM) procedure. Independent groups of 1-, 2-, 3-, and 4-year-olds were familiarized with a visual stimulus and were tested either immediately or after a delay that ranged from 24 hr to 6 months. Although all age groups exhibited a significant novelty preference when tested immediately after familiarization, clear age-related differences emerged over longer retention intervals. We conclude that age-related increases in basic retention are a fundamental aspect of mammalian memory development and, in humans, these increases may play a vital role in the offset of childhood amnesia.     

Age-related changes in dopaminergic and serotonergic indices in the rat forebrain

Age-related changes in the content of dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in anterior cerebral cortex, hippocampus and striatum of the rat have been investigated using HPLC with electrochemical detection. A significant decrease in HVA was observed in the striatum and hippocampus of the aged (27 months) animals, as compared to the controls (2.4 to 2.6 months). A significant decrease in DA levels was also observed in the hippocampus but not in the striatum. In contrast, the level of DA in the cerebral cortex was markedly increased in the aged animals. A concomitant increase in 3-MT level was observed. Finally the level of 5-HIAA was significantly increased in striatum and hippocampus.     

Age-related changes of exercise-induced plasma catecholamines and neuropeptide Y responses in normal human subjects.

Age-related plasma noradrenaline and neuropeptide Y were evaluated in seven young (mean +/- SD, 28 +/- 3 years) and seven elderly (64 +/- 8 years) normal subjects during rest and different work loads on a cycle ergometer. In the supine and the sitting position plasma noradrenaline and neuropeptide Y were almost identical in the two groups. Plasma neuropeptide Y did not increase during exercise at 100 W for 15 min. At this load plasma noradrenaline levels were higher in the older subjects (mean +/- SEM, 0.97 +/- 0.12 vs. 0.60 +/- 0.09 ng ml-1). There was a significant correlation between plasma noradrenaline and the relative work load at 100 W (r = 0.794, P = 0.0007). At 75% of maximal work load plasma noradrenaline and neuropeptide Y were higher in the young group (1.84 +/- 0.16 vs. 1.26 +/- 0.13 ng ml-1 (noradrenaline) and 38 +/- 4 vs. 22 +/- 5 pmol l-1 (neuropeptide Y)). In the elderly group plasma neuropeptide Y did not increase during exercise and showed a tendency to fall below basal level 5 min post-exercise. It is concluded, that plasma noradrenaline does not increase more in older subjects during exercise when correcting for the generally lower physical fitness in this group compared to younger subjects, and that plasma neuropeptide Y does not increase during exercise in older subjects, suggesting an age-reduced capacity in this system.     

Age-related changes in expression of metallothionein-III in rat brain

Metallothionein (MT)-III is a metal binding protein, called growth inhibitory factor, and is mainly expressed in the central nervous system. Since MT-III decreases in the brain of Alzheimer's disease (AD), a growing interest has been focused on its relationship to neurodegenerative diseases. To clarify age-related changes in the MT-III expression and its inducibility against oxidative stress, we analyzed the expression of MT-III and its mRNA in the brain of lipopolysaccharide (LPS)-treated aged rats. In the frontal cortex, basal expression of MT-III mRNA was significantly increased with aging, while it was observed no induction of MT-III mRNA against LPS administration in the aged rat brain. MT-III immunopositive cells were increased in the frontal, parietal and piriform cortices, hypothalamus and amygdaloid nucleus with aging. The LPS treatment induced MT-III expression in the brain of young-adult rats, but not in the aged rat brain. Furthermore, the MT-III induction with LPS treatment was mainly observed in oligodendrocyte and microglia. In the present study, we showed that inducibility of brain MT-III against oxidative stress may be reduced with aging. Since it has been reported that MT-III has neuroprotective roles as an antioxidant, present results suggest that MT-III is closely related to the neurodegeneration in the aged animals.     

Age-related GABAA receptor changes in rat auditory cortex

Auditory cortex (AI) shows age-related decreases in pre-synaptic markers for gamma-aminobutyric acid (GABA) and degraded AI neuronal response properties. Previous studies find age-related increases in spontaneous and driven activity, decreased spectral and directional sensitivity, and impaired novelty detection. The present study examined expression of GABA_A receptor (GABA_AR) subunit message, protein, and quantitative GABA_AR binding in young, middle-aged, and aged rat AI, with comparisons with adjoining parietal cortex. Significant loss of GABA_AR α₁ subunit message across AI layers was observed in middle-aged and aged rats and α₁ subunit protein levels declined in layers II and III. Age-related increases in GABA_AR α₃ subunit message and protein levels were observed in certain AI layers. GABA_AR subunits, including β₁, β₂, γ₁, γ_2s, and γ_2L, primarily, but not exclusively, showed age-related declines at the message and protein levels. The ability of GABA to modulate [³H]t-butylbicycloorthobenzoate binding in the chloride channel showed age-related decreases in peak binding and changes in desensitization kinetics. Collectively, age-related changes in GABA_AR subunit composition would alter the magnitude and temporal properties of inhibitory synaptic transmission and could underpin observed age-related functional changes seen in the elderly.     

Age-related changes in brain proDynorphin gene expression in the rat

Dynorphin has a well-established role in feeding and gustation. Alterations in taste perception and feeding behavior are common with age. We hypothesized that proDynorphin gene expression in brain areas involved in taste and feeding declines with age. Male Sprague-Dawley rats were housed individually with ad libitum access to food and water. Brain punches of the selected regions were dissected out in groups of rats aged 4–6, 12–14 and 18–21 months. ProDynorphin mRNA (measured using a cDNA probe) decreased significantly with age in arcuate nucleus and amygdala; increased significantly with age in hippocampus; and was not significantly affected in nucleus of the solitary tract, cortex, caudate putamen or hypothalamic paraventricular nucleus. These data suggest an age-related decrease in the synthesis of dynorphin in two brain regions strongly associated with feeding behavior, and an increase in dynorphin synthesis in a brain region associated with learning and memory.