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Biomedical subjects

R Weindruch

Publications and source records attributed to R Weindruch.

At least 55 records · Page 3Linked to original sources
PubMed1997

Influence of fat intake and caloric restriction on bone in aging male rats.

Caloric and fat intake may have important skeletal consequences. To evaluate this possibility, skeletal effects of adult-onset caloric restriction (CR) at differing fat intakes were assessed in male Lobund-Wistar rats. At age 17 months, two groups of animals received an anti-obesity diet, restricted approximately 35% from individual ad libitum baseline calorie consumption, and two groups received a diet approximately 50% restricted. Dietary fat concentrations were 5, 15, 15, and 25% by weight, respectively. At ages 20, 24, 28, 30, and 32 months, ex vivo femoral bone densitometry and serum biochemical analyses were performed. Body weight (BW) decreased with time on CR in each group (p < .005), declining faster at the more severe restriction (p = .001). Femoral bone mineral contents (BMC) were also reduced. After adjusting for bone area and BW differences among groups, the only significant difference was a reduction in distal femur BMC in the 25% fat group subjected to more severe CR (p = .02). No differences were observed in serum parathyroid hormone, calcium, phosphorus, or creatinine. Femoral bone loss occurred with CR. This was entirely accounted for by reduction in BW. Higher dietary fat content did not affect BW in CR animals, but did result in lower distal femur BMC.

Aging↗
PubMed1997

Adult-onset energy restriction of rhesus monkeys attenuates oxidative stress-induced cytokine expression by peripheral blood mononuclear cells.

We previously reported that energy restriction (ER) of mice attenuated age-associated increases in serum levels of interleukin-6 (IL-6). Here, we studied peripheral blood mononuclear cells (PBMC) from male rhesus monkeys to investigate the following: 1) the production of IL-6 and other cytokines become dysregulated with aging; 2) ER influences cytokine production and mRNA expression; and, 3) oxidative stress, as induced in vitro by xanthine and xanthine oxidase (X/XOD), influences cytokine mRNA and protein levels. Two types of comparisons were made as follows: 1) between normally fed young (6-9 y) and old monkeys (22-33 y); and 2) between middle-aged monkeys (15-21 y) fed either a normal energy intake or subjected to ER (for 5.5 y at 30% less than base-line intake). IL-6 protein levels and X/XOD-induced IL-6 mRNA levels in PBMC from old monkeys were significantly greater than those in PBMC from young animals. In contrast, interleukin-1beta (IL-1beta) and interleukin-8 mRNA levels were not strongly influenced by advancing age. X/XOD, which increased levels of protein carbonyls (indicative of oxidative damage) in PBMC, induced the expression of all three cytokines. ER reduced IL-6 protein and mRNA levels induced by X/XOD and the unstimulated mRNA levels of IL-1beta. These results indicate that, in a nonhuman primate model, oxidative stress may contribute to age-associated increases in the levels of certain cytokines and that adult-onset ER partially ameliorates this alteration.

Aging↗
PubMed1997

Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle.

The influence of caloric restriction (CR) initiated at 17 months of age was investigated on selected age-associated measures in skeletal muscle. Tissue from young (3-4 months) ad libitum-fed, old (30-32 months) restricted (35% and 50% CR, designated CR35 and CR50, respectively), and old ad libitum-fed rats (29 months) was studied. CR preserved fiber number and fiber type composition in the vastus lateralis muscle of the CR50 rats. In the old rats from all groups, individual fibers were found with either no detectable cytochrome c oxidase activity (COX-), hyperreactivity for succinate dehydrogenase activity (SDH++; also known as ragged red fibers [RRF]), or both COX- and SDH++. Muscle from the CR50 rats contained significantly fewer COX- and SDH++ fibers than did the muscle from CR35 rats. CR50 rats also had significantly lower numbers of mtDNA deletion products in two (adductor longus and soleus) of the four muscles examined compared to CR35 rats. These data indicate that CR begun in late middle age can retard age-associated fiber loss and fiber type changes, as well as increases in the number of skeletal muscle fibers showing mitochondrial enzyme abnormalities. CR also decreased the accumulation of mtDNA deletions.

Aging↗
PubMed1997

Energy expenditure of adult male rhesus monkeys during the first 30 mo of dietary restriction.

Energy expenditure, activity, and body composition were measured in 30 adult male rhesus monkeys used in a study having the long-term goal of determining the effects of moderate dietary restriction (DR) on aging. All animals were fed a defined diet, with the restricted animals maintained at approximately 70% of the caloric intakes of the controls. After 12 mo of DR, body fat mass of restricted monkeys was 33% less than that of controls (P = 0.004), whereas lean body mass differences were not present until after 24 mo. At the 24- and 30-mo assessments, nighttime energy expenditure was significantly reduced (P < 0.01) in the restricted compared with control monkeys after adjustment for lean body mass differences, whereas morning, afternoon, and total energy expenditure were not significantly different (P > 0.05). No significant differences (P > 0.05) in activity were noticed between treatment groups at any time point. DR resulted in a prolonged decrease in resting energy expenditure, which could contribute to the possible life-extending action of this treatment.

Animals↗
PubMed1996

Influences of age and dietary restriction on gastrocnemius electron transport system activities in mice.

Alterations in the mitochondrial electron transport system (ETS) may contribute to aging. Dietary restriction (DR) provides a model to investigate retarded aging. ETS activities were measured in gastrocnemius from 10- and 20-month-old B6C3F1 female mice fed either ad libitum (AL) or DR diets (40% < AL). Older (26 month old) AL mice were studied for complex IV. Activities of complexes I, III, and IV decreased 54-74% from 10 to 20 months of age in AL mice. At 10 months, activities of complexes I, III, and IV were 33-64% lower in DR compared to AL mice. The Km for ubiquinol-2 of complex III increased 29% by 20 months of age in AL mice while no change occurred in DR mice. The Vmax of complex IV declined by 90% from 10 to 26 months of age in AL mice and this change was opposed by DR. Complex IV contains high- and low-affinity binding sites. The Km for high-affinity sites was not influenced by age or diet through 20 months; however, the Km was approximately twofold higher at 26 months in AL mice. The percentage of total binding sites which were of high affinity fell from 68% at 10 months in AL mice to 46% at 20 months and was even lower (33%) at 26 months. This value was 80% for DR mice at 10 and 20 months. These alterations with aging in mitochondrial ETS capacities may contribute to decreases in skeletal muscle function.

Aging↗
PubMed1996

Oxidative stress, caloric restriction, and aging.

Under normal physiological conditions, the use of oxygen by cells of aerobic organisms generates potentially deleterious reactive oxygen metabolites. A chronic state of oxidative stress exists in cells because of an imbalance between prooxidants and antioxidants. The amount of oxidative damage increases as an organism ages and is postulated to be a major causal factor of senescence. Support for this hypothesis includes the following observations: (i) Overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster. (ii) Variations in longevity among different species inversely correlate with the rates of mitochondrial generation of the superoxide anion radical (O2) and hydrogen peroxide. (iii) Restriction of caloric intake lowers steady-state levels of oxidative stress and damage, retards age-associated changes, and extends the maximum life-span in mammals.

Aging↗
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-associated mitochondrial DNA deletions in mouse skeletal muscle: comparison of different regions of the mitochondrial genome.

The abundance of mitochondrial DNA (mtDNA) deletions has been shown to increase with age in a number of species and may contribute to the aging process. Estimating the total mtDNA deletion load of an individual is essential in evaluating the potential physiological impact. In this study, we compared three 5-kb regions of the mitochondrial genome: one in the major arc, one in the minor arc, and a third containing the light strand origin of replication. Through PCR analysis of mouse skeletal muscle, we have determined that not all regions produce equal numbers of age-associated deletions. There are, on average, twofold more detectable deletions in the major arc region than in the minor arc region. Deletions that result in the loss of the light strand origin of replication are rarely detected. Furthermore, the mechanism of deletion formation seems to be similar in both the major and minor arcs, with direct repeats playing an important, although not essential, role.

Aging↗
PubMed1996

Neuropeptide Y- and peptide YY-containing colonic cells increase with ageing in male rats.

Colonic mucosal cells are known to contain several neuropeptides. The distribution of various peptide-containing cells in the colon and their possible modulation by aging and diet are unknown. We quantitated various peptide-containing cells from male Lobund-Wistar rat colon at 2, 22, 28, 30 and 33 months of age using indirect immunohistochemical techniques for several peptides including: neuropeptide Y, peptide YY, somatostatin, and chromogranin A. Four diets, varying in total calories and fat content, were examined. Serum gastrin was quantified by RIA at 2 and 33 months. Only NPY-, PYY- and SOM-positive cells were found in the colon. The number per crypt of neuropeptide Y-positive (0.55 +/- 0.04 at 2 months vs 0.80 +/- 0.22 at 33 months, P = 0.015) and peptide YY-positive cells increased with age. Staining for somatostatin and chromogranin, a marker for all enterochromaffin (EC) cells, revealed no change with aging. Diet did not influence the numbers of any peptide-containing cell. Serum gastrin was not different between the groups. A specific increase in NPY- and PYY-positive cells occurs in the aged rat colon. The extent to which this change may be related to age-related colonic dysmotility seen in elderly humans is worthy of exploration.

Aging↗
PubMed1996

Reduced immune responses in rhesus monkeys subjected to dietary restriction.

Dietary restriction (DR) has emerged as a major paradigm in experimental gerontology. The effects of DR on rodents are numerous and include reduced rates of immunologic aging, delayed morbidity, and increases in longevity. The effects of DR on primate species remain largely unknown. We began a randomized trial of long-term, adult-onset DR in rhesus monkeys (Macaca mulatta) in 1989. This report describes some early differences in immunologic function after two to four years of DR. Peripheral blood mononuclear cells were studied for mitogen-induced proliferation, natural killer (NK) cell lysis, and expression of cell surface antigens. Antibody response to influenza vaccine and the number of peripheral blood lymphocytes were also measured. Unexpectedly, concanavalin A and pokeweed mitogen response measures were reduced in restricted monkeys compared to controls (p < or = .01). NK activity and antibody responses were also reduced (p < .05). Neither cell surface antigens nor peripheral blood lymphocyte counts appear affected by DR thus far.

Aging↗
PubMed1995

High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys.

Mitochondrial DNA (mtDNA) deletions increase in abundance with age in many tissues, however, their calculated low levels (usually < 0.1%) in samples from tissue homogenates containing thousands of cells argue against physiologic significance. Through the analysis of defined numbers of cells (skeletal muscle fibers) from rhesus monkeys, we report that the calculated abundance of specific mtDNA deletions is dependent upon the number of fibers analyzed: as the number of fibers decreases, the calculated deletion abundance increases. Also, most mtDNA deletions appear to occur in a mosaic pattern, varying from cell to cell in size, number and abundance. These data support the hypothesis that mtDNA deletions can focally accumulate to high levels contributing to declines in mass and function of aging skeletal muscle.

Aging↗
PubMed1995

The expression of heat shock protein 70 decreases with age in lymphocytes from rats and rhesus monkeys.

The ability of cells to express heat shock proteins in response to a stress such as heat is universal to all organisms and is believed to play a critical protective role. Therefore, it was of interest to determine the influence of aging on the ability of lymphocytes to express the heat shock protein hsp70 in response to a heat shock (42.5 degrees C for 1 h). Splenic lymphocytes isolated from old (24-26 months) rats showed a marked decrease in the induction of hsp70 protein levels or hsp70 synthesis when compared to lymphocytes isolated from young (4-5 months) rats. An age-related decrease in the induction of hsp70 levels by heat also was observed in peripheral lymphocytes isolated from rhesus monkeys. The decline with age in the induction of hsp70 by lymphocytes from rats was paralleled by a decrease in the induction of hsp70 mRNA and the nuclear transcription of hsp70. In addition, it was found that the ability of extracts from heat-shocked lymphocytes to bind the heat shock element (HSE) decreased approximately 50% with age. Therefore, it appears that the reduced ability of lymphocytes from old rats to express hsp70 in response to a heat shock occurs at the level of transcription because of an alteration in the ability of the heat shock transcription factor to bind the HSE on the promoter of the hsp70 gene. The age-related decrease in the induction of hsp70 appears to be physiologically important because the viability of spleen lymphocytes exposed to high temperatures decreases significantly with age.

Aging↗
PubMed1995

Interventions based on the possibility that oxidative stress contributes to sarcopenia.

Skeletal muscle is a tissue which accounts for a large part of the body's total oxygen consumption at rest, due to its large mass and the majority of oxygen consumption during vigorous physical activity. Also, skeletal muscle and nervous tissues do not possess the very high repair capacities that occur in more mitotically active tissues. Accordingly, oxidative stress may accumulate with age in these tissues and contribute to the development of sarcopenia; however, this possibility has not been thoroughly investigated. Although long-term intervention studies which test the hypothesis that oxidative stress contributes to sarcopenia have not been conducted, recent findings using the caloric restriction (CR) paradigm for studying retarded aging processes indirectly support this concept. Several research directions appear important to pursue, including the measurement of free radical production in skeletal muscle at diverse ages, antioxidant supplementation as an intervention for retarding the development of sarcopenia, the use of genetically manipulated animal models, and determining the influence of CR on oxidative stress in specific skeletal muscles and individual fibers and neurons therein.

Aging↗
PubMed1995

The effect of caloric restriction on lipofuscin accumulation in mouse brain with age.

Caloric restriction (CR), has been shown to extend average and maximum lifespan in rodents and other animals as well as to delay a wide variety of manifestations of aging. The purpose of this study was to further elucidate the relationship between lipofuscin (LF) accumulation and the aging process by examining the effect of lifelong CR on LF accumulation in brain cells. Specifically, 1) we include age groups of CR (CR1 approximately equal to 90 kcal/wk and CR2 approximately equal to 58 kcal/wk) and ad libidum fed (AL; approximately 120 kcal/wk) mice including groups at maximum lifespan; 2) CR was the major dietary manipulation; 3) LF was identified using EM; 4) LF was quantified by areal measurement; and 5) the results were analyzed by inferential statistics. We have found that 1) LF increased with age and 2) that animals in the CR2 group had significantly less overall LF in the perikarya of the granule cells of the dentate gyrus when compared to CR1 or AL animals at equivalent ages. In addition, CR2 mice at maximum lifespan (45 mo.) had slightly less LF than did CR1 or AL mice at their maximum lifespans (36 mo.). Our results clearly demonstrate that CR (at 52%, but not 25% of AL diet) retards the overall accumulation of LF with time and, further, suggest that LF accumulation is not simply a linear function of age.

Aging↗
PubMed1994

Prostatic localization of spontaneous early invasive carcinoma in Lobund-Wistar rats.

Animal models of human prostate cancer are very limited in number but are of obvious importance to develop. Dr. Morris Pollard (M. Pollard, J. Natl. Cancer Inst., 51: 1235-1241, 1973) has reported that Lobund-Wistar rats develop spontaneous metastatic prostatic cancer when they become old (approximately 25% incidence after 25 months). A chemically induced form of the disease has also been described in Lobund-Wistar rats. However, recent reports suggest that most of the chemically induced adenocarcinomas are not prostatic in origin, with most arising in the seminal vesicle, and thereby raise questions about the origin of the spontaneous cancers. We herein report cancer spontaneously arising in the lateral lobes of the prostates in Lobund-Wistar rats. One of 8 rats killed at 16 months of age showed prostatic carcinoma in situ. Two of 39 rats killed at 20 months displayed early invasive adenocarcinomas with no signs of metastases. Because sectioning of the prostates in this study was limited to face sections from a single block for each rat, it is highly probable that the true incidence of dysplasias and carcinomas is underestimated by these data. Dysplastic or neoplastic changes were not seen in either the seminal vesicles or other portions of the prostatic complex. The nuclei of adenocarcinoma cells showed less labeling with antibody to the androgen hormone receptor than did normal cells. These data strongly support the validity of the Pollard model of spontaneous prostate cancer in Lobund-Wistar rats.

Age Factors↗