Age-dependent Changes In Function Research Articles

S100A8, which increases with age, induces cellular senescence-like changes in bovine oviduct epithelial cells.

The oviduct is an essential component in reproduction and oviduct epithelial cells (OECs) secrete various types of cytokine. However, mechanisms of aging and inflammation of OECs are unknown. We previously reported the age-dependent functional changes of bovine OECs such that aged OECs expressed higher levels of inflammatory cytokines. We selected S100A8 and S100A9 as molecules expressed more highly in aged OECs, as candidates to induce age-related changes, and investigated using bovine OECs. The OECs were isolated from bovine oviductal tissues (Aged, more than 120months; Young, between 30 and 50months) and cultured. Aged OECs exhibited higher senescence-associated (SA)-β-gal staining (a biomarker of cellular senescence) and mRNA expression of SA-inflammatory cytokines than young OECs. Cellular senescence occurred in both young and aged OECs upon passaging the cells. Treatment with S100A8, but not S100A9, resulted in the induction of cellular senescence in bovine OECs. Both S100A8 and S100A9 stimulated the secretion of the inflammatory cytokine IL-8 from bovine OECs. S100A8-induced IL-8 secretion was dependent on receptor RAGE, AP-1 activation, and reactive oxygen species production. In addition, S100A8 reduced the content of collagen while inducing the expression of matrix metalloproteinases, suggesting the induction of dysregulation of the extracellular matrix in OECs. We suggest that bovine OECs recognize an excessive increase in age-associated DAMPs, such as S100A8 and S100A9, and that these signals may contribute to chronic oviductal inflammation, resulting in infertility associated with oviductal dysfunction.

Sensitivity of GABAergic Tonic Currents to Acute Ethanol in Cerebellar Granule Neurons is Not Age- or δ Subunit-Dependent in Developing Rats.

The age of first exposure to ethanol (EtOH), as well as reduced sensitivity to its motor-impairing effects, are associated with a future predisposition to abuse EtOH. In adolescence, acute EtOH potentiates GABA transmission, including tonic inhibition mediated by δ-containing extrasynaptic GABAA receptors (GABAA Rs) in cerebellar granule neurons (CGNs), an effect that likely contributes to EtOH-induced motor impairment. Prenatal EtOH exposure is strikingly prevalent and is associated with increased EtOH abuse later in life; however, the acute effects of EtOH on GABA transmission in developing CGNs are unknown. Using whole-cell patch-clamp electrophysiological techniques in acute brain slices, we examined the acute effects of EtOH on GABA transmission and functionally assessed the role of δ-containing GABAA Rs in CGNs of preweanling (postnatal day [P] 12 to 14) and postweanling (P28 to 30) male Sprague-Dawley rats. The magnitude of basal tonic currents were similar at both ages. However, 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride, an agonist with preferential affinity for δ-containing GABAA Rs, significantly potentiated tonic currents to a larger magnitude in CGNs from postweanlings compared to preweanlings. Conversely, acute application of EtOH (80mM) significantly increased tonic currents and the frequency of spontaneous inhibitory postsynaptic currents to a similar extent in CGNs from pre- and postweanlings. These findings highlight the sensitivity of the developing cerebellum to EtOH. Furthermore, this study demonstrates age-dependent functional changes in a well-characterized circuitry that may contribute to the short- and long-term effects of prenatal exposure to EtOH.

Advances in hematopoietic stem cell research through mouse genetics

Successful bone marrow transplantation involves migration of hematopoietic stem cells through the blood, entering the extravascular hematopoietic cords, lodging in the proper niche, and expanding and differentiating to produce large numbers of mature cells -- all without depletion of the stem cell pool. An additional variable in these processes is the age of both the donor bone marrow and the recipient. Basic stem cell biology and transplant biology aim to uncover the molecular mechanisms controlling these processes. Mouse genetics is a frequently used tool that allows dissection of individual pathways that influence properties of hematopoietic stem cells. Recently, the conception of a niche has been expanded to include evidence for a vascular and an endosteal niche. Additionally, hematopoietic stem cell interactions within the niche have been further defined, documenting the importance of cell cycle, cell adhesion, response to cytokine stimulation and age-dependent functional changes. A new model for hematopoietic stem cell aging was proposed that supports the hypothesis that stem cell aging is at least partially due to an accumulation of DNA damage leading to exhaustion. This review focuses on the last year's progress using mouse genetics as a tool to study intrinsic mechanisms of hematopoietic stem cell biology.

Drug dosage in the elderly. Is it rational?

Pharmacotherapy in the elderly requires an understanding of the age-dependent changes in function and composition of the body. Aging is characterised by a progressive loss of functional capacities of most if not all organs, a reduction in response to receptor stimulation and homeostatic mechanisms, and a loss of water content and an increase of fat content in the body. The most important pharmacokinetic change in old age is a decrease in the excretory capacity of the kidney; in this regard, the elderly should be considered as renally insufficient patients. The decline in the rate of drug metabolism with advancing age is less marked. In addition, the volume of distribution and the oral bioavailability of drugs may be changed in the elderly compared with younger individuals. Average dosage adjustments for the aged can be derived from simple equations and mean pharmacokinetic parameters from older and younger adults. However, these average dose adjustment factors neglect the large variation in the decline in organ functions among the elderly. Individual dose adjustment factors can be obtained from the drug clearance in a particular patient, where clearance/fractional bioavailability (CL/f) may be calculated from the area under the plasma concentration-time curve (AUC) of the drug in question. Using pharmacokinetic guidelines for dose adjustments, the same plasma drug concentrations result in elderly as in younger adults. However, we are frequently confronted with pharmacodynamic changes in old age which alter the sensitivity to drugs, irrespective of changes in drug disposition. For instance, the sensitivity of the cardiovascular system to beta-adrenergic agonists and antagonists decreases in old age and the incidence of orthostatic episodes in response to drugs that lower blood pressure is increased. The CNS is especially vulnerable in the elderly; agents that affect brain function (anaesthetics, opioids, anticonvulsants, psychotropic drugs) must be used very cautiously in this age group. The increased responsiveness to drugs in the elderly renders the measurement of drug plasma concentrations an attractive method to monitor pharmacotherapy in this age group. Sensitive technology to quantitatively determine plasma drug concentrations is available. However, optimal therapeutic plasma concentrations have not been established for most drugs in the elderly. Investigations concerning drug pharmacokinetic-pharmacodynamic relationships in the aged are an important area of future work in clinical pharmacology.

In vivo electrochemical studies of dopamine diffusion and clearance in the striatum of young and aged Fischer-344 rats

Dopaminergic neurons are vulnerable to the degenerative effects of the aging process. Age-dependent functional changes which occur in nigrostriatal and mesolimbic DA pathways may decrease the ability of these systems to effectively communicate with postsynaptic targets, thereby impairing the normal flow of motor information through the basal ganglia. In order to overcome these effects, the brain relies on homeostatic mechanisms which act to balance neurochemical changes. In this study we have tested the hypothesis that dopamine neurons compensate for age-related decreases in depolarization-induced transmitter overflow by altering the rate of DA clearance from the extracellular space. The diffusion and clearance of DA was directly measured in urethane anesthetized Fischer 344 rats using high-speed (5 Hz) in vivo electrochemical recordings and local drug application techniques. The results show that aged rats (24 and 30 months old) are as effective in removing exogenously applied dopamine from the striatum as young rats (6 months old). However, the uptake sites in the aged animals were less responsive to nomifensine, a competitive inhibitor of DA uptake. This drug did not modulate the amplitude of DA signals in the dorsal striatum of 30-month-old rats nor in the ventral striatum of 24-and 30-month-old rats. We can conclude that there are changes in the high affinity uptake carrier based on the different pharmacological actions of nomifensine in the young and aged striatum. If this is the case, then more studies are necessary to determine if drugs used in the treatment of depression (which have the same mechanism of action as nomifensine) are less effective in elderly patients. This research may also lead to the understanding of mechanisms which compensate for age-related deficits in chemical signalling.

Age-dependent decrease in the affinity of muscarinic M1 receptors in neocortex of rhesus monkeys.

In vitro autoradiography on tissue sections and receptor assay in cortical membrane homogenates revealed that pirenzepine high-affinity muscarinic sites (M1) decrease in affinity in the prefrontal cortex and in other cortical areas of aged rhesus monkey (Macaca mulatta). Carbachol competition experiments detected only a single, low-affinity class of sites in old monkeys, while two classes of sites (low and high affinity) were observed in young adults. The change in affinity in the aged monkeys is not accompanied by a decrease in the density of these sites and, further, the age-related decline in the affinity of the M1 site is reversible. In the presence of Mg2+, the M1 muscarinic receptors in the aged monkeys were capable of forming carbachol high-affinity sites. These results provide evidence for age-dependent functional changes in receptor activity in cerebral cortex and indicate that these receptors maintain a degree of plasticity that could be a strategic target for research aimed at treatment of memory disorders in aged humans.

635 AGE-DEPENDENT CHANGES IN BILIARY MOTILITY AND STRUCTURE

Age-dependent changes of the biliary tract may predispose to developing biliary tract disease. The purpose of this study was to determine the effects of aging on biliary motility and structure of male guinea pigs. Bile flow rates declined with increasing age and were greater when measured by volume of bile collected from the ampulla vs bile duct cannula: Flow Rates(μl/min/kg) While fasting, intravital microscopy measured bile flow rates and documented rhythmic contractions of the sphincter ductus choledochi(SDC) at 4-6/min with associated narrowing of the proximal duct and filling of the ampulla until milking constrictions of the ampulla at 1-2/min emptied its contents into the duodenum. The newborn had incomplete closure of the SDC and a fold in the ampulla prevented filling of the distal ampulla until the entire duct was distended. Ten ml/kg of Ensure in the duodenum caused relaxation of the SDC and tonic contractions of the ampulla. Methylmeth-acrylate casts of the biliary system correlated structures with these functional components. In conclusion, bile flow rates decreased with aging and the sphincter of Oddi was propulsive with age-dependent changes in function and structure.

Lymphocyte subpopulation changes by aging

Peripheral blood lymphocyte suspensions of healthy young and aged subjects were tested for the percentage of (1) E-rosetting cells by three different modifications of the rosette technique; (2) α-naphthylacetate esterase positive cells of different staining patterns; (3) IgG-Fe receptor positive cells; (4) C3 receptor positive cells; (5) labile and stable bound surface immunoglobulin positive cells; and (6) cells bearing different classes of immunoglobulins on their surface or intracytoplasmically. Age dependent changes were registered both within the T-cell and the B-cell subpopulations, some of which may be due to in vivo activation of lymphocytes. Attention is called to some technical aspects of lymphocyte subpopulation determinations and to the significance of quantitative changes in the proportions of lymphocyte subpopulations in respect to the age dependent functional changes of lymphocytes.

Comparative bone morphometric analysis of mandibles and iliac crests

A comparative analysis of bone mass in the mandible and the iliac crest has been carried out in autopsy specimens from 30 subjects aged 23-84 years. Microradiograms of standardized 100-micrometer-thick sections of the undemineralized plastic embedded material from the two locations were used for quantitation. The following measurements were carried out by electronic point-counting: 1) the percentage of cortical bone mass in the subperiosteal and subendosteal layers, 2) mean cortical width, and 3) the percentage of trabecular bone mass in the iliac crest. Positive correlations were found in the expressions of bone mass within the mandible; the values were significantly higher in the 200-micrometer-thick subperiosteal layer than in the remaining part of the mandibular cortex. Only a poor or no correlation was found in the expressions of bone mass from the two sites. The investigation, therefore, shows that bone mass and cortical width in the mandible cannot be predicted from a biopsy from the iliac crest. This finding may partly be due to different age-dependent functional changes of the two bones.