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Biomedical subjects

Richard Weindruch

Publications and source records attributed to Richard Weindruch.

At least 19 recordsLinked to original sources
PubMed2007

Metabolic reprogramming in dietary restriction.

It is widely accepted that energy intake restriction without essential nutrient deficiency delays the onset of aging and extends life span. The mechanism underlying this phenomenon is still unknown though a number of different, nonmutually exclusive explanations have been proposed. In each of these, different facets of physiology play the more significant role in the mechanism of aging retardation. Some examples include the altered lipid composition model, the immune response model and models describing changes in endocrine function. In this paper we propose the hypothesis that metabolic reprogramming is the key event in the mechanism of dietary restriction, and the physiological effects at the cellular, tissue and organismal level may be understood in terms of this initial event.

Adipose Tissue↗
PubMed2006

SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.

Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic beta cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.

Adenosine Diphosphate Ribose↗
PubMed2006

Influences of calorie restriction and age on energy expenditure in the rhesus monkey.

Caloric restriction (CR) is known to retard the aging process, and a marker of aging is decreased energy expenditure (EE). To assess longitudinal effects of CR on EE in rhesus monkeys (Macaca mulatta), data from 41 males (M) and 26 females (F) subjected to 9 or 15 yr of CR were studied. EE and body composition of monkeys 11-28 yr of age were measured using indirect calorimetry and dual X-ray absorptiometry. Total EE (24-h EE) was divided into daytime (day EE), nighttime (night EE), and daytime minus nighttime (D - N EE). M calorie-restricted monkeys showed a lower 24-h EE (means +/- SD = 568 +/- 96 kcal/day, P < 0.0001) than controls (C; 630 +/- 129 kcal/day). Calorie-restricted M had a lower night EE (difference = 36 kcal P < 0.0001) compared with C M, but after adjusting for FFM and FM, night EE was not different between calorie-restricted and C males (P = 0.72). The 24-h EE decreased with age (13 kcal decrease/yr, P < 0.0001), but there was no difference between CR and C. Adjusted for FFM and FM, D - N EE decreased with age (9 kcal/yr, P < 0.0001), with no interaction with age (P = 0.72). The F were compared with age-matched M selected from the male cohort. F had a lower 24-h EE (496 +/- 84 kcal/day) than M (636 +/- 139 kcal/day) (P < 0.0001). Adjusting for FFM and FM, night EE was lower in F compared with M (difference = 18 kcal, P = 0.077). Night EE did not differ between calorie-restricted and C younger monkeys after adjusting for FFM and FM. In conclusion, CR did not alter the age-related decrease in EE with CR.

Age Factors↗
PubMed2006

Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis.

Presbycusis is characterized by an age-related progressive decline of auditory function, and arises mainly from the degeneration of hair cells or spiral ganglion (SG) cells in the cochlea. Here we show that caloric restriction suppresses apoptotic cell death in the mouse cochlea and prevents late onset of presbycusis. Calorie restricted (CR) mice, which maintained body weight at the same level as that of young control (YC) mice, retained normal hearing and showed no cochlear degeneration. CR mice also showed a significant reduction in the number of TUNEL-positive cells and cleaved caspase-3-positive cells relative to middle-age control (MC) mice. Microarray analysis revealed that CR down-regulated the expression of 24 apoptotic genes, including Bak and Bim. Taken together, our findings suggest that loss of critical cells through apoptosis is an important mechanism of presbycusis in mammals, and that CR can retard this process by suppressing apoptosis in the inner ear tissue.

Aging↗
PubMed2006

Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss.

Mitochondrial DNA (mtDNA) mutations/deletions are considered to be associated with the development of age-related hearing loss (AHL). We assessed the role of accumulation of mtDNA mutations in the development of AHL using Polg(D257A) knock-in mouse, which exhibited increased spontaneous mtDNA mutation rates during aging and showed accelerated aging primarily due to increased apoptosis. They exhibited moderate hearing loss and degeneration of the hair cells, spiral ganglion cells and stria vascularis by 9 month of age, while wild-type animals did not. We next examined if mitochondrial damage induced by systemic application of germanium dioxide caused progressive hearing loss and cochlear damage. Guinea pigs and mice given germanium dioxide exhibited degeneration of the muscles and kidney and developed hearing loss due to degeneration of cochlear tissues, including the stria vascularis. Calorie restriction, which causes a metabolic shift toward increased energy metabolism in some organs, has been shown to attenuate AHL and age-related cochlear degeneration and to lower quantity of mtDNA deletions in the cochlea of mammals. Together these findings indicate that decreased energy metabolism due to accumulation of mtDNA mutations/deletions and decline of respiratory chain function play an important role in the manifestation of AHL.

Animals↗
PubMed2006

Will dietary restriction work in primates?

This issue of Biogerontology addresses whether dietary restriction (DR) "...can increase longevity in all species, particularly in human beings". The possibility that DR can increase longevity in all species seems a trivial issue compared to that of DR's potential efficacy in people. The striking phylogenetic breadth of DR's longevity increasing effect supports the notion of human translatability. The available evidence in primates (human and nonhuman) suggests that it is highly probable that DR will increase the span of good health (and the average lifespan) but the magnitude of this predicted increase is unknown. Robust survival data for monkeys subjected to highly controlled DR will be available in approximately 25 years; similar data for large numbers of human practitioners of DR appear to be many decades away.

Aging↗
PubMed2006

Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue.

Using high-density oligonucleotide microarrays, we examined the actions of energy restriction (ER) on the expression of >11,000 genes in epididymal white adipose tissue (WAT) of 10- to 11-mo-old male C57Bl6 mice. Four groups were studied: controls not subjected to food restriction (CO), food-restricted 18 h before being killed (FR), short-term ER for 23 d (SER), and long-term ER for 9 mo (LER). As we reported previously, compared with CO mice, FR and SER minimally influenced the gene expression profiles; however, 345 transcripts of 6,266 genes determined to be expressed in WAT were significantly altered by LER. We focus here on the 109 (31%) of these genes that were involved in either inflammation (56 genes), cytoskeleton (16 genes), extracellular matrix (23 genes), or angiogenesis (14 genes). Among these 109 genes, 104 transcripts (95%) were down regulated by LER. Western blotting for heat shock protein 47 and osteonectin, and immunohistochemical staining for hypoxia inducible factor (HIF)-1alpha), supported the microarray data that LER down regulated the expressions of these genes. Additionally, a 75% reduction in adipocyte size with LER reflected the change in the expression of genes involved in cell morphology. Our findings provide evidence that LER suppresses the expression of genes encoding inflammatory molecules in WAT while promoting structural remodeling of the cytoskeleton, extracellular matrix, and vasculature. These alterations may play an important role in the protection against WAT-derived inflammation and in lifespan extension by LER.

Adipose Tissue↗
PubMed2005

A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging.

Aging is the single most important risk factor for AD (Alzheimer's disease). However, the molecular events that connect normal aging to AD are mostly unknown. The abnormal accumulation of Abeta (amyloid beta-peptide) in the form of senile plaques is one of the main characteristics of AD. In the present study, we show that two members of the neurotrophin receptor superfamily, TrkA (tyrosine kinase receptor A) and p75NTR (p75 neurotrophin receptor), differentially regulate the processing of APP (amyloid precursor protein): TrkA reduces, whereas p75NTR activates, beta-cleavage of APP. The p75NTR-dependent effect requires NGF (nerve growth factor) binding and activation of the second messenger ceramide. We also show that normal aging activates Abeta generation in the brain by 'switching' from the TrkA to the p75NTR receptor system. Such an effect is abolished in p75NTR 'knockout' animals, and can be blocked by both caloric restriction and inhibitors of nSMase (neutral sphingomyelinase). In contrast with caloric restriction, which prevents the age-associated up-regulation of p75NTR expression, nSMase inhibitors block the activation of ceramide. When taken together, these results indicate that the p75NTR-ceramide signalling pathway activates the rate of Abeta generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD.

Aging↗
PubMed2005

Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria.

Calorie restriction (CR) without malnutrition increases life span and delays the onset of a variety of diseases in a wide range of animal species. However, the mechanisms responsible for the retardation of aging with CR are poorly understood. We proposed that CR may act, in part, by inducing a hypometabolic state characterized by decreased reactive oxygen species (ROS) production and mitochondrial proton leak. Here, we examine the effects of long-term CR on whole animal energetics as well as muscle mitochondrial energetics, ROS production, and ROS damage. CR was initiated in male FBNF1 rats at 6 mo of age and continued for 12 or 18 mo. Mean whole body VO2 was 34.6 (P < 0.01) and 35.6% (P < 0.001) lower in CR rats than in controls after 12 and 18 mo of CR, respectively. Body mass-adjusted VO2 was 11.1 and 29.5% lower (both P < 0.05) in CR rats than in controls after 12 and 18 mo of CR. Muscle mitochondrial leak-dependent (State 4) respiration was decreased after 12 mo compared with controls; however, after 18 mo of CR, there were slight but not statistically significant differences. Proton leak kinetics were affected by 12 mo of CR such that leak-dependent respiration was lower in CR mitochondria only at protonmotive force values exceeding 170 mV. Mitochondrial H2O2 production and oxidative damage were decreased by CR at both time points and increased with age. Muscle UCP3 protein content increased with long-term CR, consistent with a role in protection from ROS but inconsistent with the observed decrease or no change in proton leak.

Aging↗
PubMed2005

The effects of intentional weight loss as a latent variable problem.

Although obesity is associated with increased mortality rate and short-term weight loss improves risk factors for mortality, it has not been convincingly shown that weight loss among obese people results in reduced mortality rate. When considering the human literature, it has been pointed out that weight loss is often a sign of illness and that investigators therefore need to separate intentional from unintentional weight loss. It has generally been assumed that among people who state that they do not intend to lose weight, weight change subsequently observed is unintentional. Among such people, weight loss has been consistently associated with increased mortality rate. Complementarily, it has generally been assumed that among people who state that they do intend to lose weight, weight change subsequently observed is intentional. In these people who are intending to lose weight, some studies show apparent benefits of weight loss, some are neutral, and some show deleterious effects. The overall conclusion that some reviewers have drawn from this literature is that intentional weight loss (IWL) is at best not beneficial and may even be harmful with respect to mortality rate. We believe that this conclusion is drawn by inappropriately conflating weight loss (or more generally weight change) among people intending to lose weight with IWL (or change). Herein, under certain assumptions, we: (1) show that the association between mortality rate and weight loss among people intending to lose weight and between mortality rate and IWL are two different things; (2) show that the association between IWL and mortality rate is an inherently unobservable entity; (3) derive a method for estimating the plausible range of true effect of IWL on mortality rate if one is willing to make a number of restrictive, but perhaps reasonable assumptions; and (4) illustrate the method by application to a data set involving middle-age onset calorie restriction in mice.

Animals↗
PubMed2005

Serine utilization in mouse liver: influence of caloric restriction and aging.

The influence of caloric restriction (CR) on the activities of hepatic serine metabolizing enzymes in young (3 months) and old (30 months) mice was studied. Serine dehydratase (SDH) activity increased markedly with age in both diet groups and in old mice was higher in the CR group. No effects of CR were observed in the young. Serine:pyruvate transaminase (SPT) and glycerate kinase activities were unaffected by age and diet. However, glycerate dehydrogenase activity was decreased in old CR mice but not in young CR. The results of this study show that long-term CR influenced serine utilization only in the pathway catalyzed by SDH. This suggests that in mouse liver this pathway is critical for serine utilization in gluconeogenesis, while the SPT pathway plays a minor role. The increase in SDH activity with long-term CR is consistent with sustained increase in gluconeogenesis.

Aging↗
PubMed2005

Muscle mass loss in Rhesus monkeys: age of onset.

Sarcopenia, the decline in skeletal muscle mass and function with age, contributes to increased frailty and decreased functional performance in the aging human population. The negative health consequences of muscle mass loss emphasize the need for development of a nonhuman primate model for the prevention or attenuation of sarcopenia. The age of onset for muscle mass loss in Rhesus macaques was determined using three datasets; (i) dual-energy X-ray absorptiometry (DXA) data from a cross-sectional study of 90 adult Rhesus monkeys; (ii) lean tissue mass and estimated skeletal muscle mass (ESM) from 727 DXA scans taken in 38 monkeys in a long-term, longitudinal aging study; and, (iii) quadriceps weights taken at necropsy from 13 male and 28 female Rhesus monkeys. These data indicate that both male and female Rhesus monkeys develop sarcopenia with age. The onset of sarcopenia is 14.1 +/- 2.8 years in females and 15.8 +/- 2.5 years in males. Muscle loss reaches 20% in males by 23.2 years of age and in females by 24.5 years of age. Furthermore, our data indicate percentage declines in ESM similar to those seen in humans with advancing age. These data support the suitability of the Rhesus monkey as a primate sarcopenia model.

Absorptiometry, Photon↗
PubMed2005

Intentional weight loss reduces mortality rate in a rodent model of dietary obesity.

OBJECTIVE: We used a rodent model of dietary obesity to evaluate effects of caloric restriction-induced weight loss on mortality rate. Research Measures and Procedures: In a randomized parallel-groups design, 312 outbred Sprague-Dawley rats (one-half males) were assigned at age 10 weeks to one of three diets: low fat (LF; 18.7% calories as fat) with caloric intake adjusted to maintain body weight 10% below that for ad libitum (AL)-fed rat food, high fat (HF; 45% calories as fat) fed at the same level, or HF fed AL. At age 46 weeks, the lightest one-third of the AL group was discarded to ensure a more obese group; the remaining animals were randomly assigned to one of three diets: HF-AL, HF with energy restricted to produce body weights of animals restricted on the HF diet throughout life, or LF with energy restricted to produce the body weights of animals restricted on the LF diet throughout life. Life span, body weight, and leptin levels were measured. RESULTS: Animals restricted throughout life lived the longest (p < 0.001). Life span was not different among animals that had been obese and then lost weight and animals that had been nonobese throughout life (p = 0.18). Animals that were obese and lost weight lived substantially longer than animals that remained obese throughout life (p = 0.002). Diet composition had no effect on life span (p = 0.52). DISCUSSION: Weight loss after the onset of obesity during adulthood leads to a substantial increase in longevity in rats.

Aging↗
PubMed2005

Reference body composition in adult rhesus monkeys: glucoregulatory and anthropometric indices.

Rhesus monkeys have been used as models to study obesity and disease. The aim of this study was to define body mass indices for underweight and obesity in rhesus monkeys. Longitudinal data collected over 8-14 years from 40 male and 26 female rhesus monkeys were analyzed. Body weight, insulin sensitivity index, and disposition index were regressed against percent body fat (%BF). A minimal %BF beyond which further loss of body weight resulted in loss of lean mass was determined to be 11.5% in older males, 8% in adult females, and 9% in younger adult males. Insulin sensitivity index and disposition index reached minimum values at 23% fat in older males, 18% in adult females, and 21% in younger adult males, indicating obesity. The estimated reference range for %BF was 9%-23% in male and 8%-18% in female monkeys, corresponding to body mass indices of 32-44 kg/m(2) for male and 27-35 kg/m(2) for female monkeys.

Animals↗
PubMed2005

Assessment of nutritional status in rhesus monkeys: comparison of dual-energy X-ray absorptiometry and stable isotope dilution.

Body composition estimates from dual-energy X-ray absorptiometry and stable isotope dilution ((2)H and (18)O) were compared in 61 rhesus monkeys (Macaca mulatta) from the ongoing long-term energy restriction study at the University of Wisconsin. Their average age was 18.9 +/- 2.5 y/o. Of the animals, 51% were in the energy restricted group and 38% were females. Although the correlation between methods was highly significant for fat mass (R(2) = 0.97, SEE = 0.25 kg or 7.5%, P < 0.0001) and fat-free mass (R(2) = 0.98, SEE = 0.29 kg or 3.6%, P < 0.0001), we observed that dual-energy X-ray absorptiometry underestimated fat mass by 0.67 +/- 0.26 kg (7.5%, P < 0.0001) and overestimated fat-free mass by 0.57 +/- 0.29 kg (20%, P < 0.0001) when compared with isotope dilution. Taken together with data from the literature, the present results emphasize the usefulness of dual-energy X-ray absorptiometry to derive body composition and thus nutritional status in monkeys, but demonstrate the importance of validation experiments for a given DXA model and software.

Absorptiometry, Photon↗
PubMed2004

Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria.

Calorie restriction (CR) without malnutrition increases maximal life span in diverse species. It has been proposed that reduction in energy expenditure and reactive oxygen species (ROS) production could be a mechanism for life span extension with CR. As a step toward testing this theory, mitochondrial proton leak, H2O2 production, and markers of oxidative stress were measured in liver from FBNF1 rats fed control or 40% CR diets for 12 or 18 mo. CR was initiated at 6 mo of age. Proton leak kinetics curves, generated from simultaneous measures of oxygen consumption and membrane potential, indicated a decrease in proton leak after 18 mo of CR, while only a trend toward a proton leak decrease was observed after 12 mo. Significant shifts in phosphorylation and substrate oxidation curves also occurred with CR; however, these changes occurred in concert with the proton leak changes. Metabolic control analysis indicated no difference in the overall pattern of control of the oxidative phosphorylation system between control and CR animals. At 12 mo, no significant differences were observed between groups for H2O2 production or markers of oxidative stress. However, at 18 mo, protein carbonyl content was lower in CR animals, as was H2O2 production when mitochondria were respiring on either succinate alone or pyruvate plus malate in the presence of rotenone. These results indicate that long-term CR lowers mitochondrial proton leak and H2O2 production, and this is consistent with the idea that CR may act by decreasing energy expenditure and ROS production.

Animals↗
PubMed2004

Fructose metabolizing enzymes from mouse liver: influence of age and caloric restriction.

The influence of caloric restriction (CR) on the activities of liver fructose metabolizing enzymes and metabolite levels were studied in young (3 months) and old (30 months) mice. Fructokinase activity was increased (P<0.05) in both young and old CR mice when compared to controls while triokinase activity was increased (P<0.05) only in old CR versus control mice. Aldolase was not altered by CR in either old or young mice. No age-related differences in activities were observed in controls although a trend towards an increase was observed for triokinase, while significant age-related increases were observed for fructokinase and triokinase, but not aldolase, in CR mice. Both young and old mice on CR showed significant decreases in fructose and fructose-1-phosphate, however, no age-related changes in metabolite levels were observed for either control or CR mice. A fructose-1-phosphate kinase activity was also measured and found to be unchanged in both young and old mice on CR, but the activity was significantly lower in the old mice compared with young. We show here that the enzymes involved in fructose metabolism are influenced by CR and that this could contribute to alterations in gluconeogenesis and glycolysis observed with CR.

Adaptor Proteins, Signal Transducing↗