Enzyme activities, gene function and ageing in mammals. (Review).
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Aging↗
Biomedical subjects
C E Finch
Publications and source records attributed to C E Finch.
Regulation of liver tyrosine aminotransferase by endogenous factors in the mouse.
The levels of mouse liver tyrosine aminotransferase (TAT) are shown to increase rapidly and transiently during and after various challenges (e.g., exposure to cold or shaking) to the homeostatic machinery of the fasted mouse. The increase of TAT is dependent on gene activity. Recent feeding and adrenalectomy are shown to inhibit the induction of TAT during the challenge of cold.
Adrenal Glands↗
Ageing and the regulation of cell activities during exposure to cold.
The inability to maintain body temperature and a selective pattern of changes in the regulation of cell activities were revealed by briefly exposing ageing C57B1/6J male mice to cold (10 degrees C). The induction of liver tyrosine aminotransferase (TAT) during exposure to cold (a gene-dependent process) was markedly delayed in senescent mice (26 months old) as compared with younger mice (3-16 months old); after the delay, the rate of increase of TAT was similar to that prevailing in younger mice. Direct challenge of the liver with injections of corticosterone or insulin elicited the induction of TAT on an identical time course in young and senescent mice. These experiments provide an example of an age change in a gene-dependent cell process (the delayed induction of TAT in senescent mice during exposure to cold) which is not due to a change in the potential of the genome for responding when exogenous stimulae are supplied (injection of hormones). In contrast to the age-related change in liver cell activities, no significant changes were found in the secretion of corticosterone during exposure to cold. Although the seat of these selective age-related changes in the regulation of cell activities remains unclear, it is argued that generalized damage to the genome of cells throughout the body is not involved. The results of this and other studies showing the selective effect of age on cell activities are considered in terms of the concept that many cellular age changes represent the response of cells to primary age-related changes in humoral factors in the internal environment of the body.
Adrenal Glands↗
Changes in alpha-macroglobulin during malaria in the duckling.
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Alpha-Globulins↗
LHRH neurons in the female C57BL/6J mouse brain during reproductive aging: no loss up to middle age.
The numbers of neurons containing luteinizing hormone releasing hormone (LHRH) were examined with specific immunocytochemical techniques in C57BL/6J mice at 5-6 months and 15-16 months of age, the latter being the time of transition to the loss of estrous cycles. No changes were found in the organization, morphology, or numbers of LHRH neurons.
Animals↗
Divergent changes in D-1 and D-2 dopamine binding sites in human brain during aging.
The density of D-1 and D-2 dopamine receptors in human caudate nucleus and putamen, obtained postmortem, were studied throughout the adult lifespan using [3H]fluphenazine as the dopamine receptor ligand. The D-1 subtype increased progressively with age in both regions, while the D-2 subtype declined in caudate nucleus. The ratio of D-1/D-2 Bmax in both regions increased from approximately 1 at age 20 to 2 by age 75. The dopamine content in putamen declined with age and was inversely correlated with D-1 receptor density. We suggest that D-1 receptor density is up-regulated by loss of dopamine during aging. The D-2 receptor density in caudate nucleus was positively correlated with choline acetyltransferase activity, suggesting that loss of intrastriatal neurons with age may contribute to the decrease in D-2 sites. These divergent changes in dopamine receptor subtypes with age result in an altered complement of dopamine receptors in older humans and may provide a basis for selective pharmacotherapy in disorders of the basal ganglia.
Adolescent↗
Compartmentalization of calmodulin and tubulin in the male C57BL/6J mouse brain: heterogeneity of age changes in calmodulin compartments.
Calmodulin (CaM) and tubulin were analyzed by radioimmunoassay in subcellular fractions prepared from cerebral cortex and striatum of aging male C57BL/6J mice. Three fractions were prepared by a new procedure: cytosol (soluble); EGTA-releasable, membrane-bound; and detergent-extractable (Triton X-100), membrane-bound fractions. CaM concentration in all three fractions prepared from striatum showed small (10-15%, p less than 0.05) decreases with age (3-31 months). Cortical CaM concentrations were less affected by age, and only the EGTA-releasable fraction decreased. To compare functional activity and immunoreactivity of CaM, soluble CaM was also assayed by the activation of cyclic nucleotide phosphodiesterase (PDE). The radioimmunoassay and PDE activation assays gave equivalent results, suggesting that no alteration occurred with age in biological activity of CaM, via post-translational modification or other mechanisms. Soluble and particulate tubulin concentration did not change significantly with age in either brain region. The changes observed in striatal CaM, particularly in membrane-bound compartments, could contribute to the age-related decline in mammalian basal ganglial function.
Aging↗
Spontaneous tumors in aging female mice are more prevalent in the lateral pituitary zones.
The localization of gross and microscopic spontaneous pituitary tumors was examined in aging female C57BL/6J mice. These tumors were lactotroph adenomas, by morphological and immunocytochemical criteria. Each lobe of the pars distalis was divided into three zones of approximately equal size and the number of tumors in each zone was counted. Twelve out of 30 tumors were located entirely within the most lateral zone. An additional 14 tumors occurred in both the most lateral and the interjacent zones. Thus, almost 90% of the observed tumors were localized in more lateral zones of the pars distalis (Chi-squared test, p less than 0.01). These findings support a hypothesis that lower portal blood dopamine levels reaching lateral portions of the pars distalis are a factor in the higher incidence of lactotroph adenomas in these zones.
Adenoma↗
APP-695 transcript prevalence is selectively reduced during Alzheimer's disease in cortex and hippocampus but not in cerebellum.
We previously found a selective loss of the brain specific APP-695 transcript in Alzheimer's disease (AD) cortex, which results in a 2.5-fold increase in the APP-751/APP-695 transcript ratio in AD (9). Here we report a similar increase in APP-751/APP-695 mRNA ratio in AD hippocampus. However, the cerebellum had a 6-fold lower ratio, which does not change in AD. The APP-695 mRNA species is greatly decreased (3-4-fold) in mRNA from AD cortex and hippocampus, whereas the APP-751 mRNA species is essentially unchanged. Considering hippocampal neuron loss and cortical neuron loss and atrophy, the data presented may be compatible with increased APP-751 mRNA and decreased APP-695 mRNA prevalence in remaining neurons in AD. A possible relationship between a high APP-751/APP-695 ratio and amyloid pathology is discussed.
Adult↗
Middle age: an evolving frontier in gerontology.
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Aging↗
Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain.
Several RNA sequences were tested for age-related changes in prevalence levels in the mouse cerebral cortex, hippocampus, and cerebellum. In all three regions, there were increased levels of RNA for glial fibrillary acidic protein, an astrocyte-specific protein, by RNA gel-blot analysis and by a solution hybridization assay. There was no change in glutamine synthetase mRNA level, another glial protein. The only other mRNA sequence which changed was Thy-1 antigen, a neuronal protein, which decreased slightly in the hippocampus. We conclude that with age there is an age-related increase in glial fibrillary acidic protein RNA prevalence potentially reflecting an increase in the size, number, and/or fibrous character of astrocytes.
Aging↗
New models for new perspectives in the biology of senescence.
This essay presents examples of life history patterns that are not often discussed. Life spans range nearly a million-fold between different species of higher animals and plants and must be species characteristics under considerable genetic control. A comparative approach to senescence reveals a vast variety in temporal organization, both among species as well as between and within populations that may vary over as large ranges of scale and qualitative characteristics as do morphological and biochemical variations. Species comparisons across many levels of biological organization involving the life histories of many species besides the usual few mammals, insects, and nematodes importantly expand the view of mechanisms that limit life spans. The presumption that age-correlated changes are all adverse to some degree and that most components of an organism should decay as the life span is approached is reevaluated.
Aging↗
Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning.
This study describes evidence in the adult human and rat brain for mRNAs that encode two complement (C) proteins, C1qB and C4. C proteins are important effectors of humoral immunity and inflammation in peripheral tissues but have not been considered as normally present in brain. Previous immunocytochemical studies showed that C proteins are associated with plaques, tangles, and dystrophic neurites in Alzheimer's disease (AD), but their source is unknown. Combined immunocytochemistry and in situ hybridization techniques show C4 mRNA in pyramidal neurons and C1qB mRNA in microglia. Primary rat neuron cultures also show C1qB mRNA. In the cortex from AD brains, there were two- to threefold increases of C1qB mRNA and C4 mRNA, and increased C1qB mRNA prevalence was in part associated with microglia. As a model for AD, we examined entorhinal cortex perforant path transection in the rat brain, which caused rapid increases of C1qB mRNA in the ipsilateral, but not contralateral, hippocampus and entorhinal cortex. The role of brain-derived acute and chronic C induction during AD and experimental lesions can now be considered in relation to functions of C proteins that pertain to cell degeneration and/or cell preservation and synaptic plasticity.
Aged↗
Failure of dietary restriction to retard age-related neurochemical changes in mice.
Age-sensitive neurochemical measures and estrous cyclicity were studied in female mice from the long-lived C3B10F1 strain fed either a control diet or subjected to dietary restriction (DR) from 3 weeks of age. Striatal dopaminergic D2 receptor density decreased by 25% from 9-10 months to 28-30 months of age in the control group. This decline was uninfluenced by DR. Anterior pituitary dopamine + dihydroxyphenylacetic acid content increased by 2.5 fold with age in the control group but DR failed to oppose this age-related change. In contrast to DR's lack of influence on these two neurochemical measures were findings on estrous cyclicity. Although mice on DR did not display estrous cycles, cyclicity was rapidly initiated when these mice were switched to the control diet at 12 and even at 22 months of age. Thus, limited aspects of neuroendocrine aging were retarded by DR in this long-lived mouse model.
Aging↗
BDNF and trkB mRNA expression in the hippocampal formation of aging rats.
Quantitative in situ hybridization and northern blot analysis techniques were used to determine the topographical distribution and levels of mRNA coding for brain-derived neurotrophic factor (BDNF) and the tyrosine receptor kinase (trkB) mRNA in the hippocampal formation of two strains of male rat during aging. Age did not change the prevalence or regional distribution patterns of BDNF or trkB mRNA in the hippocampal formation throughout the lifespan of male Sprague-Dawley rats. There also were no significant differences in the prevalence or topographical distribution patterns of trkB mRNA transcripts during aging. Northern blot analysis of hippocampal RNA from male Fischer 344 confirmed that neither BDNF mRNA nor trkB mRNA levels changed with age. These findings suggest that age-related neurodegenerative changes, including the atrophy of the cholinergic septo-hippocampal pathway, are not the result of changes in hippocampal BDNF or trkB mRNA expression. Moreover, the prevalence and distribution of synaptosomal-associated protein 25 (SNAP-25), a neuron-specific protein located in synaptic terminals and a putative marker of synaptic integrity, did not change with age. These findings indicate that altered hippocampal synaptic plasticity which occurs in the aged rat brain is not a reflection of changes in the expression of BDNF or trkB receptor mRNA.
Aging↗
GFAP mRNA increases with age in rat and human brain.
Glial fibrillary acidic protein (GFAP) mRNA was examined by RNA blot hybridization in three age groups of two cohorts of male F-344 rats and in 47 human postmortem brain samples. GFAP mRNA increased in the hippocampus and striatum of 24 versus 6- to 7-month-old rats. Another astrocytic molecular marker, glutamine synthetase mRNA, did not change with age in rat brain. Rat GFAP mRNA prevalence was inversely correlated with serum testosterone but not correlated with serum corticosterone. In human hippocampus, frontal and temporal cortex, GFAP mRNA also increased in older (60-79 years) compared with middle-aged (25-59 years) individuals. In contrast, mitochondrial cytochrome oxidase subunit 1 mRNA did not change between age groups in any region. By combining the three regions for further analysis, GFAP mRNA increased with age irregardless of gender, alcoholism in the middle-aged group, or whether brains were classified as normal or neuropathologic (excluding Alzheimer's disease pathology). These data indicate that increased GFAP protein or GFAP-immunoreactive astrocytes in rats and humans may result from transcriptional or post-transcriptional regulation and extend the number to three species (including mouse) showing an increase in GFAP mRNA with age. Factors that are known to regulate GFAP mRNA expression in young brains are considered as possible causes of age-related increases.
Adult↗
Increases of glial fibrillary acidic protein in the aging female mouse brain.
Age-related increases of the astrocyte marker, glial fibrillary acidic protein (GFAP), were further resolved by in situ hybridization and immunocytochemistry in female C57BL/6J mice. The age groups represented the major stages of reproductive aging: young (5 months), middle-age (18 months), and old (23 and 26 months). GFAP mRNA and protein showed generalized increases in old mice. Major white fiber tracts, such as the corpus callosum, fimbria, stria terminalis, and optic tract, showed increased GFAP immunostaining and mRNA. Gray matter showed robust > or = twofold increases in GFAP mRNA with age, especially in the thalamus and hypothalamus, areas that expressed little GFAP in the young. These generalized age-related increases of GFAP in many brain regions imply the existence of a widespread stimulus for increased activity of astrocytes during aging.
Aging↗
Food restriction delays the age-related increase in GFAP mRNA in rat hypothalamus.
Astrogliosis with advancing age is correlated with increased expression of glial fibrillary acidic protein (GFAP). Hypothalamic GFAP mRNA prevalence was determined in male F344 rats of different ages that were fed ad lib (AL) and compared with that of rats that were food-restricted (FR) to 60% of AL levels. Hypothalamic GFAP mRNA increased 3-fold at 24 to 25 months in AL rats compared with 3 and 6 month groups. There were no differences in GFAP mRNA levels between AL and FR rats from 3 to 18 months. However, GFAP mRNA was significantly lower in FR than in AL rats at 24 to 25 months; FR rats reached the level of GFAP mRNA in 24 to 25 months AL rats by 33 months. Hypothalamic glutamine synthetase mRNA also increased with age in both dietary groups but did not differ between dietary groups at any age. The observation that FR delays the increased expression of GFAP in the hypothalamus during aging lends support to the hypothesis that upregulation of GFAP mRNA is a biomarker of brain aging.
Aging↗