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Biomedical subjects

G S Roth

Publications and source records attributed to G S Roth.

At least 73 records · Page 4Linked to original sources
PubMed1997

Effect of aging on vulnerability of striatal D1 and D2 dopamine receptor-containing neurons to kainic acid.

Kainic acid lesions elicit reductions in ligand binding to both D1 and D2 striata dopamine receptors in young and old rats. Relative reductions are greatest for both receptors in young animals than old. In addition, D1 receptor binding is reduced more than D2 at both ages. These findings support the idea that those dopamine receptor neurons lost during aging may reside in a kainic acid sensitive population.

Aging↗
PubMed1997

Processing of Alzheimer's amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells.

The processing of Alzheimer's amyloid precursor protein was studied by Western blotting during H2O2 induced apoptosis in cultures of human neuroblastoma cells. A new 5.5 kDa fragment putatively containing intact A beta was detected and found to be highly associated with apoptosis. The results suggest a possible vicious cycle involving H2O2, A beta and apoptosis which may contribute to the neuronal death mechanism in Alzheimer's Disease.

Alzheimer Disease↗
PubMed1997

Dopamine induces apoptosis in cultured rat striatal neurons; possible mechanism of D2-dopamine receptor neuron loss during aging.

We examined D2-dopamine receptor containing neurons in cultures of neonatal rat striatum for apoptosis following dopamine treatment. Exposure to cultures to micromolar concentrations of dopamine resulted in 60-70% killing of D2-dopamine receptor neurons within 24 hr. We also utilized a double labeling procedure to determine that treatment with dopamine induced apoptosis in D2-dopamine receptor containing neurons. These results suggest that loss of D2-dopamine receptor containing neurons during aging could be due to an apoptotic effect of dopamine.

Animals↗
PubMed1997

Dietary restriction in rhesus monkeys: lymphopenia and reduced mitogen-induced proliferation in peripheral blood mononuclear cells.

Dietary restriction (DR) markedly extends mean and maximal life span, and retards the rate of biological aging in rodent models; however, it is unknown if these results occur in primate species. The purpose of the current study was to investigate selected immunologic outcomes in Rhesus monkeys subjected to DR for a period of seven years. Similar to observations in mice on DR, lymphopenia occurred in the restricted monkeys. Compared to normally fed controls, the mitogen-induced proliferative responses of peripheral blood mononuclear cells (PBMC) were reduced in monkeys subjected to DR very early in life (up to 1 year), but not in others restricted in young adulthood (3-5 years). These data indicate that lymphopenia is a shared occurrence in rodents and primates on DR. However, the mitogen-induced proliferative data accumulated in rodents and primates cannot now be compared because PBMC have not been studied long enough or in comparable detail in primates fed restricted diets.

Aging↗
PubMed1997

Activity measures in rhesus monkeys on long-term calorie restriction.

Calorie restriction (CR), undernutrition without malnutrition, extends the mean and maximal lifespan of several ecologically diverse species. Rodents on CR demonstrate increased activity measured as spontaneous locomotion, wheel running, open field behavior or movement. Activity measures were recorded from 19 male rhesus monkeys (Macaca mulatta) as either controls (C) which were fed a nutritious diet to approximate ad libitum levels, or as experimentals (E) which were fed 30% less than age- and weight-matched controls. Within each diet group, some monkeys (n = 10) began CR at 2.3 years of age (range 2.2-2.4 yrs, J Group) while another group (n = 9) began CR at approximately 4.6 years of age (range 4-5.25, A group). Beginning about 6 years after initiation of the study, behavioral activity was measured via ultrasonic motion detectors and recorded on videotape. Diurnal and circadian activity was clearly discernible. Peaks in activity were associated with mealtime and colony husbandry. Compared to Group A, Group J monkeys exhibited higher overall activity as measured by sensors, and also significantly more circling. Compared to AC monkeys, group AE monkeys demonstrated higher rates of gross motor behavior, pacing, stereotypies and grooming. The increases in motor activity observed in one group of monkeys were consistent with results obtained from rodent studies of CR and aging. CR did not significantly inhibit or negatively influence the display of behavior of rhesus monkeys in the laboratory environment. We report here, for the first time, increases in activity due to CR in a model other than the rodent.

Animals↗
PubMed1997

Age changes in signal transduction and gene expression.

Altered regulation of physiological and behavioral processes is an important functional manifestation of aging. Our laboratory has been examining a number of model systems in order to elucidate the mechanisms by which these processes, controlled mainly by hormones and neurotransmitters, change during aging. Two, in which alternations in gene expressions are critical, are loss of striatal dopaminergic motor control and impaired stimulation of hepatocyte DNA synthesis. Loss of striatal D2 dopamine receptors contributes substantially to reduced motor control in the elderly. Such receptor loss is due both to the death of some receptor-containing neurons and decreased expression of the receptor gene in the surviving neurons. Current efforts are focussed on the mechanisms responsible for neuronal death, reduced gene expression and the relationship between the two. In addition, the D2 receptor gene has now been inserted into attenuated adenoviral vectors which elicit expression of functional receptors when injected into the brains of living rats and mice. Stimulation of DNA synthesis by various agents including catecholamines and growth factors is markedly reduced in primary cultures of hepatocytes obtained from aged rats when compared with younger counterparts. Such impairment is not the consequence of receptor loss. Moreover, since very different signal transduction pathways are employed by G protein linked receptors and those mediated by tyrosine kinases, the defect would appear to be at a very functional level. Results to date indicate that increased expression of sdi-1/p21, an inhibitor of cyclin-dependent kinases, is not responsible. However, decreased stimulation of the MAP Kinase pathway, possibly due to elevated levels of MAP Kinase Phosphatase, may also play a role. IN addition, cells of aged rats appear to shift to other growth factor responsive pathways. In summary, altered gene expression during aging may be responsible for some important impairments in signal transduction and corresponding physiological and behavior functions.

Aging↗
PubMed1997

Interaction of nuclear factors from young and old rat brain regions with regulatory sequences of the D2 dopamine receptor gene promoter.

Alterations in the number or functional state of D2 dopamine receptors have been implicated in the decreased motor abilities associated with normal aging, Parkinson's disease and other neurodegenerative diseases. Previous work has demonstrated a substantial decrease in D2 receptor-containing neurons, receptor proteins, steady-state mRNA levels, and the rate of mRNA synthesis with age in the rat striatum in particular and in mammalian brains in general. These observations suggest that one key area of regulatory control is at the level of transcriptional initiation and/or elongation. In the present study gel mobility shift experiments were used to assess the interaction of nuclear proteins from different rat brain regions with DNA containing putative DNA regulatory sites of the transcriptionally active rat D2 receptor gene promoter. Oligonucleotides containing either of the two SP1 binding sites immediately upstream of the primary transcriptional start site were bound by proteins found in nuclear extracts obtained from rat striatum, hippocampus, cortex, and cerebellum. Extracts from striatum and hippocampus formed predominantly low molecular weight complexes which do not contain SP1, as well as a small amount of high molecular weight complexes which may contain SP1 or an SP1-related protein. Cerebellar extracts formed two similar sets of complexes, but they were formed in roughly equal amounts. Extracts from cortex produced a more involved pattern of complexes, but still formed both high molecular weight complexes which contain SP1 and low molecular weight complexes which do not contain SP1. There were differences in the gel mobility as well as the relative amounts of complexes formed with the two SP1-specific oligonucleotides among different brain regions. With respect to possible age-related changes in transcription of the D2 dopamine receptor gene, there appeared to be no statistically significant difference in the DNA-protein complexes formed with striatal nuclear proteins from a population of young rats versus a population of old rats.

Age Factors↗
PubMed1997

Effect of age and caloric restriction on cutaneous wound closure in rats and monkeys.

Cutaneous wounds close more slowly in rats and monkeys as age increases. Caloric restriction of 40% in rats and 30% in monkeys did not significantly affect healing rates, although it did exert a trend toward faster closure. Similarly, voluntary exercise did not significantly alter healing rates in rats. Thus, impaired wound healing appears to be a generalized physiological manifestation of aging, but its possible amelioration by "anti-aging" interventions remains to be established.

Aging↗
PubMed1997

Caloric restriction increases HDL2 levels in rhesus monkeys (Macaca mulatta).

Caloric restriction (CR) prolongs the life of rodents and other small animals, but the benefits of CR for primates and people are as yet unknown, and mechanisms by which CR may slow aging remain unidentified. A study of rhesus monkeys, Macaca mulatta, is underway to determine if CR might prolong life span in primates and to evaluate potential mechanisms for life prolongation. Thirty rhesus monkeys in three age cohorts, restricted to 70% of ad libitum calorie intake for 6-7 yr, were compared with 30 controls. Plasma lipid, lipoprotein, and high-density lipoprotein (HDL) apolipoproteins and subfractions were measured and compared with weight, percent fat, glucose, and insulin level. CR caused decreased triglyceride levels in adult monkeys and increased levels of HDL2b, the HDL subfraction associated with protection from atherosclerosis. Multivariate statistical analyses showed that differences in lipid and lipoprotein levels occurring with CR could be accounted for, at least in part, by decreased body mass and improved glucose regulation. These studies have used a novel dietary modification paradigm in nonhuman primates focused on calorie reduction. Results suggest that CR, as mediated by its beneficial effect on body composition and glucose metabolism, could prolong human life by decreasing the incidence of atherosclerosis.

Aging↗
PubMed1997

Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction.

The adrenal steroids, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), have attracted attention for their possible antiaging effects. DHEAS levels in humans decline markedly with age, suggesting the potential importance of this parameter as a biomarker of aging. Here we report that, as seen in humans, male and female rhesus monkeys exhibit a steady, age-related decline in serum DHEAS. This decline meets several criteria for a biomarker of aging, including cross-sectional and longitudinal linear decreases with age and significant stability of individual differences over time. In addition, the proportional age-related loss of DHEAS in rhesus monkeys is over twice the rate of decline observed in humans. Most important is the finding that, in rhesus monkeys, calorie restriction, which extends life span and retards aging in laboratory rodents, slows the postmaturational decline in serum DHEAS levels. This represents the first evidence that this nutritional intervention has the potential to alter aspects of postmaturational aging in a long-lived species.

Aging↗
PubMed1996

Physiological levels of beta-amyloid peptide promote PC12 cell proliferation.

Alzheimer's beta-amyloid peptide (A beta) is normally present at a subnanomolar (225-625 pM) concentration in body fluids and in the medium of cultured cells. The potential actions of physiologic levels of A beta are being investigated. We have recently shown that nanomolar doses of A beta can stimulate tyrosine phosphorylation and activate phosphatidylinositol-3-kinase in neuronal cells. Here we show evidence that A beta at nanomolar levels promotes cell growth determined by [3H]thymidine incorporation, protein content and cell counts. Physiological levels of A beta peptides, including 1-40, 1-42, 25-35, all promote growth of PC12 cells in low serum medium with doubling times of 71 h to around 30 h. Although the promotion of cell proliferation can be detected at nanomolar levels of A beta, it's potency is less than that of serum. This suggests that A beta may normally play a neurotrophic/mitogenic role in neuronal biology.

Amyloid beta-Peptides↗
PubMed1996

Effect of aging on regulation of sdi-1 in rat hepatocytes.

We examined basal and EGF stimulated DNA synthesis as well as sdi-1 mRNA and protein in primary hepatocyte cultures, and basal levels of sdi-1 mRNA and protein in whole liver homogenates from 6 and 24 month old rats. Since EGF stimulated DNA synthesis decreases with age, it was hypothesized that basal and EGF stimulated levels of sdi-1 mRNA and protein, an inhibitor of DNA synthesis, might increase. Surprisingly, however both sdi-1 mRNA and protein actually decreased both in cells and homogenates of old rats. These results indicate that the age-related impairment in EGF stimulated DNA synthesis in hepatocytes appears to occur prior to or parallel with sdi-1 expression and cannot be explained on the basis of increased inhibition due to elevated levels of this protein.

Aging↗
PubMed1996

Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.

Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD.

Amyloid beta-Peptides↗
PubMed1996

Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents.

Many studies of caloric restriction (CR) in rodents and lower animals indicate that this nutritional manipulation retards aging processes, as evidenced by increased longevity, reduced pathology, and maintenance of physiological function in a more youthful state. The anti-aging effects of CR are believed to relate, at least in part, to changes in energy metabolism. We are attempting to determine whether similar effects occur in response to CR in nonhuman primates. Core (rectal) body temperature decreased progressively with age from 2 to 30 years in rhesus monkeys fed ad lib (controls) and is reduced by approximately 0.5 degrees C in age-matched monkeys subjected to 6 years of a 30% reduction in caloric intake. A short-term (1 month) 30% restriction of 2.5-year-old monkeys lowered subcutaneous body temperature by 1.0 degrees C. Indirect calorimetry showed that 24-hr energy expenditure was reduced by approximately 24% during short-term CR. The temporal association between reduced body temperature and energy expenditure suggests that reductions in body temperature relate to the induction of an energy conservation mechanism during CR. These reductions in body temperature and energy expenditure are consistent with findings in rodent studies in which aging rate was retarded by CR, now strengthening the possibility that CR may exert beneficial effects in primates analogous to those observed in rodents.

Aging↗
PubMed1996

Age-related decline in mitogen-activated protein kinase activity in epidermal growth factor-stimulated rat hepatocytes.

A number of studies have demonstrated that the proliferative capacity of cells declines with aging. In particular, epidermal growth factor (EGF)-stimulated DNA synthesis is reduced in hepatocytes from aged rats relative to young rats. Growth factor stimulation activates a genetic program in large part regulated by a family of mitogen-activated protein kinases (MAPK) that phosphorylate and thereby activate transcription factors involved in controlling the expression of proliferation-associated genes. In the present study, we compared the activation of the extracellular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1) MAPK in EGF-stimulated hepatocytes derived from young (6-month) and aged (24-month) rats. JNK activity was not appreciably altered by EGF treatment of cells from either age group. In contrast, ERK2 was highly activated by EGF treatment, but the magnitude of activation was significantly lower in hepatocytes of aged animals compared to those of young animals (7-fold versus 20-fold, respectively). The reduced ERK2 activity in response to EGF was associated with decreased c-fos and c-jun mRNA expression and lower levels of AP-1 transcription factor DNA binding activity in the aged hepatocytes. Finally, the basal expression of MAPK phosphatase 1, a MAPK-regulated gene involved in regulating MAPK activity, was higher in aged hepatocytes. Taken together, these findings suggest that an alteration in the balance between MAP kinase-phosphatase activities could contribute to the age-related decline in proliferative capacity.

Aging↗
PubMed1996

Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence.

A fundamental question in the basic biology of aging is whether there is a universal aging process. If indeed such a process exists, one would expect that it develops at a higher rate in short- versus long-lived species. We have quantitated pentosidine, a marker of glycoxidative stress in skin collagen from eight mammalian species as a function of age. A curvilinear increase was modeled for all species, and the rate of increase correlated inversely with maximum life-span. Dietary restriction, a potent intervention associated with increased life-span, markedly inhibited glycoxidation rate in the rodent. On the assumption that collagen turnover rate is primarily influenced by the crosslinking due to glycoxidation, these results suggest that there is a progressive age-related deterioration of the process that controls the collagen glycoxidation rate. Thus, the ability to withstand damage due to glycoxidation and the Maillard reaction may be under genetic control.

Aging↗