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Rel 3.4 - 9th May 1998

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Caloric restriction retards the aging associated changes in gamma-aminobutyric acidA receptor gene expression in rat cerebellum.

Mhatre MC, Ticku MK

Department of Pharmacology, The University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78284-7764, USA

Brain Res Mol Brain Res 1998 Mar 1;54(2):270-275

It is widely accepted that calorie restriction is an effective way of delaying the aging process. Also, there is an indication that the beneficial effects exerted by dietary manipulation may be due to a direct effect at the molecular level like gene expression. The studies were conducted to determine whether calorie restriction prevents any age-related changes in the structural and molecular aspects of the GABAA-BZ receptor. In aged (24-month old diet ad libitum) rats, the binding of [35S]t-butyl-bicyclophosphorothionate (TBPS) was significantly reduced in the cerebellum. In contrast, [35S]TBPS binding remained unchanged in the cerebellum of calorie restricted old rats. In order to evaluate the molecular basis of these changes, the alpha sub-unit mRNA levels were measured. The GABAA receptor alpha1 sub-unit mRNA level remained unchanged in both the old groups of rats. The alpha2 subunit mRNA level was significantly decreased in the cerebellum of aged rats (24-month old ad libitum), whereas it remained unchanged in the cerebellum of calorie restricted old animals. These findings indicate a selective age and diet related modulation in the stoichiometry of the GABAA receptor in aging. Copyright 1998 Elsevier Science B.V.

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Differential induction of nerve growth factor and basic fibroblast growth factor mRNA in neonatal and aged rat brain.

Colangelo AM, Follesa P, Mocchetti I

Department of Cell Biology, Division of Neurobiology, Georgetown University, School of Medicine, Washington, DC 20007, USA.

Brain Res Mol Brain Res 1998 Jan;53(1-2):218-225

Stimulation of glucocorticoid or beta-adrenergic receptors (BAR) has been shown to increase nerve growth factor (NGF) biosynthesis in adult rat brain. Little is known about the role of these receptors in the regulation of NGF expression in neonatal and aged brain. We have examined the effect of the synthetic glucocorticoid dexamethasone (DEX) and the BAR agonist clenbuterol (CLE) on the levels of NGF mRNA in neonatal (8 day old), adult (3 month old) and aged (24 month old) rats. By 3 h, DEX (0.5 mg/kg, s.c.) evoked a comparable increase in NGF mRNA in the cerebral cortex and hippocampus in both 8-day and 3-month-old rats. In contrast, CLE (10 mg/kg, i.p.) failed to change NGF mRNA levels in neonatal rats, while increasing (2-3-fold) NGF mRNA levels in the cerebral cortex of adult rats. In 24-month-old rats, both DEX and CLE elicited only a modest increase in NGF mRNA. This increase was, however, anatomically and temporally similar to that observed in adult animals. The weak effect of DEX or CLE was not related to a down-regulation of receptor function because both DEX and CLE were able to elicit a comparable increase in the mRNA levels for basic fibroblast growth factor (FGF2) in neonatal, adult and aged rat brain. Our data demonstrate that induction of NGF expression by neurotransmitter/hormone receptor activation varies throughout life and suggest that pharmacological agents might be useful tools to enhance trophic support in aging.

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Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span.

Vaziri H, Benchimol S

Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada. vaziri@oci.utoronto.ca

Curr Biol 1998 Feb 26;8(5):279-282

Normal somatic cells have a finite life span [1] and lose telomeric DNA, present at the ends of chromosomes, each time they divide as a function of age in vivo or in culture [2-4]. In contrast, many cancer cells and cell lines established from tumours maintain their telomere length by activation of an RNA-protein complex called telomerase, an enzyme originally discovered in Tetrahymena [5], that synthesizes telomeric repeats [6-8]. These findings have led to the formation of the 'telomere hypothesis', which proposes that critical shortening of telomeric DNA due to the end-replication problem [9] is the signal for the initiation of cellular senescence [10,11]. In yeast, the EST2 gene product, the catalytic subunit of telomerase, is essential for telomere maintenance in vivo [12-14]. The recent cloning of the cDNA encoding the catalytic subunit of human telomerase (hTERT) [15,16] makes it possible to test the telomere hypothesis. In this study, we expressed hTERT in normal human diploid fibroblasts, which lack telomerase activity, to determine whether telomerase activity could be reconstituted leading to extension of replicative life span. Our results show that retroviral-mediated expression of hTERT resulted in functional telomerase activity in normal aging human cells. Moreover, reconstitution of telomerase activity in vivo led to an increase in the length of telomeric DNA and to extension of cellular life span. These findings provide direct evidence in support of the telomere hypothesis, indicating that telomere length is one factor that can determine the replicative life span of human cells.


Dermal connective tissue metabolism in photoageing.

Miyachi Y, Ishikawa O

Department of Dermatology, Gunma University School of Medicine, Japan. ymiyachi@sb.gunma-u.ac.jp

Australas J Dermatol 1998 Feb;39(1):19-23

The term photoageing describes the clinical and histological cutaneous changes that are the consequence of repeated chronic sun exposures and are qualitatively different from those observed in chronological ageing. The connective tissue of the skin is composed mainly of collagen, glycosaminoglycans and elastin and, thus, alterations of these components in photoageing are briefly reviewed in the present article. Collagen changes in photoageing are partly explained by cross-links as well as the unbalanced regulation of collagen production and breakdown. Some visible skin changes can be induced by the consequence of dermal glycosaminoglycans, because the total amount, as well as the composition of the main disaccharide units, is significantly altered in the exposed sites of both aged people and photoaged mice. As for the mechanism of solar elastosis, increased elastin mRNA levels resulting from transcriptional up-regulation of the gene have been reported. Taken together, all components of the dermal connective tissue are affected by chronic actinic damage; however, further in vitro investigation is required to unmask the exact events in photoageing. With regard to this, our novel three-dimensional culture system should be of great help because it mimics the in vivo condition by self producing the extracellular matrices.

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