Journal of the American Aging Association

Sometime ago we obtained biomarker data suggesting that the earliest determining event in the expression of the extended longevity phenotype in our selected strains of Drosophila took place early in adult life at about 5-7 days of age. In a later series of experiments we documented that our La and Lb long lived strains underwent a specific up-regulation of the antioxidant defense system (ADS) genes and enzymes. This led to a reduction in oxidative damage and an extended longevity. In the current work, we assayed the activity of 17 metabolically important enzymes in 5-7 day old flies of 13 strains variously selected for different longevities...

Aging is associated with an accumulation of oxidative damage to proteins, lipids and DNA. Cellular mechanisms designed to prevent oxidative damage decline with aging and in diseases associated with aging. A long-lived mouse, the Ames dwarf, exhibits growth hormone deficiency and heightened antioxidative defenses. In contrast, animals that over express GH have suppressed antioxidative capacity and live half as long as wild type mice. In this study, we examined the generation of H2O2 from liver mitochondria of Ames dwarf and wild type mice and determined the level of oxidative damage to proteins, lipids and DNA in various tissues of these animals...

The ultrastructural features of perikaryal mitochondria positive to the copper ferrocyanide cytochemical reaction due to SDH activity were investigated in Purkinje cells of adult rats fed a vitamin E (α-tocopherol) deficient diet (AVED) for 11 months. The mitochondrial volume fraction (volume density: Vv), the number of organelles/μm(3) of tissue (numeric density: Nv) and their average volume (V) were estimated by computer-assisted morphometry. The data obtained were compared with our previous results on 3, 12 and 24 month-old normally fed rats...

During the last years, the hypothesis that aging and diseases are two distinct phenomena, and that successful aging is possible for most humans, has been put forward. We studied the TCR Vβ repertoire of T lymphocytes of healthy longevals and centenarians as crossing point of genetic predisposition and environmental effects to longevity, using the Spectra-typing method. TCR Vβ1, Vβ8, and Vβ20 were found to be expanded in the longeval population, compared with the younger control population. This repertoire can have been shaped by the selective action of particular HLA alleles, or by the clonal expansion of specific T cell clones, able to modulate the immune response to endogenous and exogenous antigens...

Background. Elevated serum total cholesterol (TC) and triglycerides (TG) are risk factors for atherosclerosis and ischemic heart disease. Adult growth hormone deficiency (AGHD) is associated with elevated TC and TG. Many treatment protocols for AGHD use relatively high doses of growth hormone (GH) given at low frequency, which is associated with increased incidences of edema, joint pains, and carpal tunnel syndrome. We have treated > 2200 patients using a low-dose high frequency (LDHF) dosing regimen of GH which results in similar beneficial subjective responses, and fewer of the side-effects associated with the higher-dosage treatment at a substantial cost savings...

The aim of the present study was to determine whether oxidative stress contributes to aging of the liver in a mouse model. Liver was obtained from young (3-5 months old) and aged (18-24 months old) mice. No age-induced gross changes in liver morphology were detected by light microscopy. Apoptosis was measured using the fragment end labeling of DNA for the immunohistochemical identification of the apoptotic nuclei. The total apoptotic cells represented 1% of the total cells in livers of young mice and 8% in those of aged mice...

The oxygen radical-induced DNA lesion 8-oxo,7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the most commonly measured marker of oxidative DNA damage, which is currently considered a main cause of aging. However, a detailed study of the age-related variations of this marker in both mitochondrial (mtDNA) and nuclear (nDNA) DNA of post-mitotic organs throughout the life span has not been previously performed. In this investigation 8-oxodG steady-state levels were simultaneously measured in mtDNA and nDNA in the heart and brain of Sprague-Dawley rats at up to five different ages covering most of the adult life span, 4, 8, 12, 17 and 24 months of age, using exactly the same digestion of DNA to deoxynucleosides and chromatographic procedures for mtDNA and nDNA...

Brain infarction is one of the most important age-associated diseases. We have developed aged animal models for brain ischemia, and found the age-related neuronal vulnerability to brain ischemia. Investigation of that mechanism would lead to the effective treatment of brain infarction in the elder population. Recent advancement of gene transfer technique has provided strong tools for the neuronal and vascular biology. We described our recent approaches of gene transfer to blood vessels, including cerebral circulation, using adenoviral vectors...

In this series of experiments, we found that Sanguisorbae Radix extract possesses strong free radical-scavenging activity in vitro and in vivo. This crude drug protected against renal disease, which is closely associated with excessive generation of reactive oxygen species. We also showed that Sanguisorbae Radix extract can suppress lipid peroxidation and stimulate an antioxidant defense ability in SAM, suggesting that this crude drug may be an effective agent for ameliorating the pathological conditions related to excessive generation of free radicals and oxidant damage, particularly in the aging process...

Peroxynitrite produced from nitric oxide and superoxide has been proposed to cause neuronal dysfunction and cell death in aging and age-related degenerative diseases. 3-Nitrotyosine, an oxidation product of tyrosine by peroxynitrite, was reported to increase in degenerating brains. In this paper, involvement of peroxynitrite in neuronal cell death was studied by analyses of human brains and in vitro experiments on cell death induced by a peroxynitrite-generating agent, SIN-1. 3-Nitrotyrosine-containing proteins were detected in lipofuscin, a typical aging-related pigment in human brains...

The importance of apolipoprotein E (apoE) in the central nervous system (CNS) became increasingly clear since the descovery that apoE ε4 allele is a major risk factor for Alzheimer's disease. ApoE is one of the major apolipoproteins that acts as a ligand for the cellular uptake of lipoproteins via apoE receptors, members of low-density lipoprotein receptor (LDLR) family, in the CNS. Recently, LDLR family has been shown to have new functions that modulate intracellular signalling and affect neuronal and glial functions, survival and regeneration...

Most biogerontologists agree that oxygen (and nitrogen) free radicals play a major role in the process of aging. The evidence strongly suggests that the electron transport chain, located in the inner mitochondrial membrane, is the major source of reactive oxygen species in animal cells. It has been reported that there exists an inverse correlation between the rate of superoxide/hydrogen peroxide production by mitochondria and the maximum longevity of mammalian species. However, no correlation or most frequently an inverse correlation exists between the amount of antioxidant enzymes and maximum longevity...

The potential usefulness of growth hormone (GH) as an anti-aging therapy is of considerable current interest. Secretion of GH normally declines during aging and administration of GH can reverse age-related changes in body composition. However, mutant dwarf mice with congenital GH deficiency and GH resistant GH-R-KO mice live much longer than their normal siblings, while a pathological elevation of GH levels reduces life expectancy in both mice and men. We propose that the actions of GH on growth, development, and adult body size may serve as important determinants of aging and life span, while the age-related decline in GH levels contributes to some of the symptoms of aging...

Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan. It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence...

Alzheimer's disease (AD) is the major cause of dementia. It is a systemic disorder whose major manifestations are in the brain. AD cases can be categorized into two groups on the basis of the age of onset-before or after about age 60. The majority of cases, 90-95 percent, are in the late onset category. Early onset cases are largely, if not all, familial (FAD). These are caused by mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). In contrast late onset cases are mainly sporadic...

The effects of 40% diet restriction on skeletal muscle fiber area, capillary density (CD) and capillary to fiber ratio (C/F) were compared in 12, 24 and 30-month-old female B6C3F1 female hybrid mice. We hypothesized that diet restriction (DR) would retard the aging effects observed in skeletal muscle, in particular DR would pose opposite effects on skeletal muscle capillarity and fiber area. Samples were prepared for light microscopic examination by standard methods and for morphometric analysis using NIH-image software...

Recently, we have shown that insulin receptors (InsRs) in the brain undergo impairments with aging. Interestingly, age-related alterations of brain InsRs, are not irreparable as thymus grafts are able to recover them. With the present study we verified the possibility that an aqueous extract from calf thymus (TME) can mimic the restoring action of age-related impairments induced by thymus graft. InsR characteristics were assayed in a group of 25 months old BALB/c-nu mice treated with TME: 2μg/g body weight every third day, for total five subcutaneous injections...

Principles, properties and use of a program for evaluation of survival curves are described. Parameters of Gompertzian mortality curves are computed from survival data of two populations by help of nonlinear regression. The differences in parameters of both curves are evaluated statistically. This method evaluates effectively even survival data of very small populations. The results are presented in numeric, verbal and graphic forms. Finally, reading of the results is offered to distinguish changes corresponding to altered aging rate from changes caused by influences not affecting the basic mechanism of aging...

Xanthine oxidase (XOD), one of the major intracellular sources of superoxide production, is well characterized as a causative factor in ischemia/reperfusion related damage. In the present study, we investigated age-effect on the status of XOD, an enzyme interconvertible with xanthine dehydrogenase (XDH) under oxidative stress. We also examined the modulation of the enzyme using the anti-oxidative action of dietary restriction (DR). We obtained evidence showing XOD activity to be significantly increased by DR, peaking at 24 months, although no progressive, age-related changes were noticed...

Numerous alterations in hormonal secretion occur with aging. In general, these tend towards a disintegration of the normal cyclic secretory patterns resulting in lower total circulating levels. In addition, declines in receptors and postreceptor function further decreases the ability of the hormonal orchestra to maintain coordinated function throughout the organism. Clues to some of these age-related changes in humans may come from the study of simpler organisms where regulatory systems are known to modulate the aging process...