Recent Papers

2.5 - 14th November 1997

Editor: Steven A. Garan .


J Clin Endocrinol Metab 1997 Jul;82(7):2093-2096

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

Lane MA, Ingram DK, Ball SS, Roth GS

Gerontology Research Center, Nathan W. Shock Laboratories, National Institutes of Health, Johns Hopkins University Bayview Campus, Baltimore, Maryland 21224, USA.

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.

Proc Soc Exp Biol Med 1997 Jul;215(3):237-242

Increased longevity, reduced fecundity, and delayed development in fruitfly (Zaprionus paravittiger) fed on butylated hydroxy anisole.

Bains JS, Kakkar R, Sharma SP

Department of Pathology, University of Calgary, Alberta, Canada.

Oxygen free radicals are generated as a by-product during normal metabolism, and they cause damage to proteins, lipids, and DNA in organisms. The defense system of the body counteracts these highly reactive chemical moieties and neutralizes them. However, a small fraction of free radicals escapes, which causes lipid peroxidation and hence aging of the organism. It has been hypothesized that, if the free radicals are arrested/reduced, then aging can be delayed or life span could be enhanced. To test the above hypothesis, we fed butylated hydroxy anisole (BHA) to a drosophilid insect, Zaprionus paravittiger, and observed its effect on life span, fecundity, and developmental period. The insects were reared and maintained on standard corn meal agar (CMA) medium at 26 degrees +/- 2 degrees C. Various concentrations (1, 5, 10, 25, 50, and 100 mM) of BHA were mixed with CMA medium, and the cultures were reared and maintained on these mixtures to study the life span of insects. Survivor curves showed that lower concentrations (5, 10, 25 mM) of BHA increased the life span, while higher concentrations (50, 100 mM), which were rather toxic, decreased life span. The most suitable concentration was 10 mM, which increased median (LT50) (27% and 15% in male and female) and maximum (LT100) (18% and 27% in male and female) life spans of insects maximally. Females exhibited longer life spans compared with males. The cultures were fed on the optimal concentration (10 mM) of BHA to study its effect on developmental period and egg-laying rate. The total developmental period was delayed by 7.2%, and egg-laying rate was reduced by 19.7% on BHA feeding. The extension in developmental period and reduction in egg-laying capacity could be the contributory factors to the favorable effect of BHA on life span.

J Am Coll Cardiol 1997 Jul;30(1):113-118

Chinese adults are less susceptible than whites to age-related endothelial dysfunction.

Woo KS, McCrohon JA, Chook P, Adams MR, Robinson JT, McCredie RJ, Lam CW, Feng JZ, Celermajer DS

Department of Medicine, Chinese University of Hong Kong, Hong Kong.

OBJECTIVES: We sought to assess the effects of aging on the endothelial physiology of a group of Chinese adults. BACKGROUND: Several studies have documented an association between aging and progressive arterial endothelial dysfunction in white subjects. We hypothesized that age-related endothelial dysfunction, an important event in atherosclerosis, might be less marked in southern Chinese subjects, in whom the prevalence of coronary heart disease is only approximately 20% of that in industrialized countries. METHODS: We studied endothelial function in 76 healthy adults aged 16 to 70 years: 38 Chinese from a village of 3,000 people in southern China and 38 white subjects from Sydney, Australia. In each ethnic group, there were 19 younger persons (16 to 40 years) and 19 older adults (55 to 70 years). None had evidence of diabetes, hypertension or clinical vascular disease or had ever been regular cigarette smokers. With the use of high resolution external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). RESULTS: Endothelium-dependent dilation was similar in young Chinese (mean +/- SD 8.3 +/- 2.5%), young whites (7.9 +/- 2.0%) and older Chinese (6.8 +/- 2.9%), but it was significantly impaired in older whites (1.8 +/- 2.5%, p < 0.001 by analysis of variance). On multivariate analysis, older age was associated with impaired endothelium-dependent dilation (p < 0.001) (independent of the effects of serum cholesterol, gender and vessel size) in the white but not in the Chinese subjects (p = 0.83). Nitroglycerin-induced dilation was not significantly different with aging in either ethnic group. CONCLUSIONS: Endothelium-dependent dilation is similar in the arteries of healthy young Chinese and white adults. With older age, however, Chinese subjects are less susceptible to impaired endothelial function.

Brain Dev 1997 Jun;19(4):290-294

Developmental and aging changes in the expression of amyloid precursor protein in Down syndrome brains.

Arai Y, Suzuki A, Mizuguchi M, Takashima S

Department of Mental Retardation and Birth Defect Research, National Center for Neurology and Psychiatry, Tokyo, Japan.

We studied immunohistochemically the expression of beta-amyloid precursor protein (APP) in the frontal lobes of 18 Down syndrome (DS) patients (20 gestation weeks (GW) to 50 years) and 15 controls (17 GW to 50 years) using six purified antibodies against the secretory forms (N-terminal, N-Amy and Amy540), the Kunitz-type protease inhibitor (KPI) domain, residues 1-28 of beta protein (Affi28), and the carboxyl-terminal fragment (Ac) of APP. In the cortex of fetuses, neonates and infants, immunoreactivity for N-Amy and Ac was observed in both neurons and glial cells, and that for Affi28 in glial cells in the subpial layer in both DS patients and controls suggesting the functioning role of APP was a growth factor. This immunoreactivity disappeared in childhood and reappeared in adulthood in only DS patients. The earlier reappearance of those in DS patients from a young adult age than in normal controls may result from a gene dosage effect, since APP is encoded on chromosome 21. The N-Amy, Amy540, Affi28 and Ac immunoreactivity in glial cells in the developing white matter in the both DS patients and controls may be associated with myelination glia. Immunoreactivity for KPI was noted on the tunica media of the arteries from the neonatal period to adulthood in only DS patients. In senile plaques in DS patients, N-terminal and Affi28 immunoreactivity became detectable at the age of 32 years. N-terminal immunoreactivity in the senile plaques was noted along the periphery of the senile plaques, while that for Affi28 was around the amyloid core. Thus, each fragment of APP exhibited a different localization and time course of immunohistochemical expression. The results indicated that APP plays a role in neuronal development and that its earlier reappearance in adult DS patients is associated with the regeneration process related to aging.

Proc Natl Acad Sci U S A 1997 Jun 10;94(12):6303-6306

Drosophila drop-dead mutations accelerate the time course of age-related markers.

Rogina B, Benzer S, Helfand SL

Department of BioStructure and Function, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.

Mutations of the drop-dead gene in Drosophila melanogaster lead to striking early death of the adult animal. At different times, after emergence from the pupa, individual flies begin to stagger and, shortly thereafter, die. Anatomical examination reveals gross neuropathological lesions in the brain. The life span of flies mutant for the drop-dead gene is four to five times shorter than for normal adults. That raises the question whether loss of the normal gene product might set into motion a series of events typical of the normal aging process. We used molecular markers, the expression patterns of which, in normal flies, change with age in a manner that correlates with life span. In the drop-dead mutant, there is an acceleration in the temporal pattern of expression of these age-related markers.

Cancer Res 1997 Jul 15;57(14):2956-2960

Mismatch repair in extracts of Werner syndrome cell lines.

Bennett SE, Umar A, Oshima J, Monnat RJ Jr, Kunkel TA

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Werner syndrome (WS) is an autosomal recessive disease, the phenotype of which is a caricature of premature aging. WS cells and cell lines display several types of genetic instability, and WS patients have an increased risk of developing cancer. The WS locus (WRN) encodes a protein that shows significant sequence homology to the RecQ family of DNA helicases. Because a DNA helicase may function in DNA mismatch repair, we examined extracts of WS cell lines for mismatch repair activity. Extracts from four different WS lymphoblastoid cell lines containing different WRN mutations and from three within-pedigree control cell lines were all proficient in mismatch repair. In marked contrast, extracts from three independent WS fibroblastoid cell lines were deficient in repair of base-base and insertion/deletion mismatches. Extracts of one of these lines restored activity to extracts of mismatch repair-deficient tumor cells with defined mutations in hMSH2, hMSH3, hMSH6, hMLH1, or hPMS2. This suggests that the WRN mutation in this fibroblast line is not a dominant negative inhibitor of mismatch repair activity and that the repair defect does not reside in these five known mismatch repair genes. Defective mismatch repair in fibroblastoid but not lymphoblastoid cells is consistent with the possibility that WRN protein could have a cell type- and/or tissue-specific role in mismatch repair. Alternatively, a mutation in WRN could predispose cells to mutations in other genes required for mismatch repair activity, at least one of which could be an unknown gene.

Mech Ageing Dev 1997 Apr;95(1-2):31-42

Effect of age on the vasodilatory action of elastin peptides.

Faury G, Chabaud A, Ristori MT, Robert L, Verdetti J

Laboratoire de Bioenergetique Fondamentale et Appliquee, Universite Joseph Fourier, Grenoble, France.

We have recently shown, on young adult rat aorta rings, that elastin peptides induce a dose and endothelium-dependent vasodilation mediated by the 67 kDa subunit of the high affinity elastin-laminin receptor and, at least in part, by EDRF (NO). Here we have studied the effects of elastin peptides at circulating concentrations and below, on noradrenaline-contracted rat aortic rings, as a function of age. First, we have observed that, unlike 2-month-old (2M), 4-6-month-old (4M) and 12-month-old (12M) rat aorta rings, 30-month-old (30M) rat aorta rings were unable to maintain their contraction in long lasting experiments. Secondly, elastin peptides at physiological circulating concentrations (10(-6)-10(-3) mg/ml) induce a dose-dependent vasodilation on 4M rings. By contrast, only higher elastin peptide concentrations (10(-3) mg/ml) were effective on 12M rings, whereas rings from both younger (2M) and older animals (30M) did not respond to elastin peptides. Finally, using lactose and laminin as inhibitors, we have demonstrated that elastin peptide-induced vasodilation on 4M and 12M rings is mediated by the 67 kDa subunit of the elastin-laminin receptor. These experiments suggest that the functional availability of the 67 kDa subunit of the elastin-laminin receptor changes with age. It could be hypothesized that in young animals (0-2M) the reusable shuttle role recently demonstrated for the 67 kDa receptor subunit during elastic fiber formation leads to a major decrease in its availability for signal transduction. On the contrary, in adult animals. (4-12M), when developmental elastogenesis is completed, this subunit is essential for extracellular signal transduction. Inefficiency of this receptor in old animals (30M) can be attributed to its uncoupling from its transduction pathway, as previously shown on human cells. Finally, the age-dependent variations of circulating elastin peptide concentration and elastin-laminin receptor responsiveness to elastin peptides are two independent parameters which could influence the vascular tension regulation.



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