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Biomedical subjects

R Weindruch

Publications and source records attributed to R Weindruch.

At least 73 records · Page 4Linked to original sources
PubMed1994

Dietary restriction from middle age attenuates age-associated lymphoma development and interleukin 6 dysregulation in C57BL/6 mice.

Dietary restriction (DR) started in middle age profoundly reduces the occurrence of lymphoma in C57BL/6 mice. Here, we report immunocellular and molecular changes associated with this mode of cancer prevention. Twelve-month-old male C57BL/6 mice were either fed a control diet or subjected to moderate DR (approximately 25% < control intake). DR significantly reduced lymphoma development (incidence at 25 months, 19% of 72 control mice versus 5% of 60 DR mice). Flow cytometry of splenocytes showed that DR increased the percentage of CD4+ and CD8+ cells. Lymphomatous spleens displayed varied labeling patterns and high percentages of cells in S phase. Splenocyte c-myc expression tended to increase with age in controls and was reduced by DR. Lymphopenia and markedly reduced nucleated cell yields from peripheral lymphoid tissues were induced by DR. Serum interleukin 6 levels increased with age and were quite high (> 2500 pg/ml) in several mice with lymphoma and other histopathological findings. DR attenuated this age-associated increase. Immunohistochemical studies of lymphomatous spleens showed the presence of interleukin 6 in monocytic appearing cells but not in lymphoma cells. These observations support the possibility that an age-associated interleukin 6 dysregulation is important in lymphomagenesis.

Age Factors↗
PubMed1994

Multiple age-associated mitochondrial DNA deletions in skeletal muscle of mice.

Multiple mitochondrial DNA (mtDNA) deletions have been associated with aging in humans and monkeys. Since the inbred mouse strain, C57BL/6, has been extensively studied gerontologically, we sought to investigate its utility as a model for examining the importance of mtDNA deletions in aging. Using the polymerase chain reaction (PCR), we analyzed hind limb skeletal muscle from mice of three age groups (5, 16 and 25 months) for the presence of age-associated mtDNA deletions. We observed multiple mtDNA deletions in all three age groups. Further, the number of deletions detected per mouse increased greatly with advancing age.

Aging↗
PubMed1994

Direct repeat sequences are not required at the breakpoints of age-associated mitochondrial DNA deletions in rhesus monkeys.

The large majority of mitochondrial DNA (mtDNA) deletions analyzed from mitochondrial myopathies and aging humans have been found to be flanked by direct repeats, a finding which has led to the slip-replication hypothesis of deletion formation. In this study, we have characterized 13 mtDNA deletion breakpoints from skeletal muscle harvested from 9- to 27-year-old rhesus monkeys. Seven of the deletions, five of which were unique to a particular animal, did not have direct repeats at the deletion breakpoints. In contrast, two of the three deletions common to several animals had direct repeats flanking the breakpoints. It appears, therefore, that at least two different mechanisms exist by which mtDNA deletions are formed during aging, one requiring and one independent of flanking direct repeats. Furthermore, the species in which mtDNA deletions are detected may determine which mechanism predominates.

Animals↗
PubMed1994

Dietary restriction attenuates age-related increases in rat skeletal muscle antioxidant enzyme activities.

Dietary restriction (DR) retards aging in rodents, but its mechanism of action remains unclear. Free radicals have been hypothesized to be involved in aging and in DR's actions. We investigated the influences of age and DR on the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD) in skeletal muscle from 11-, 26- and 34-mo-old (BN x Fischer 344) F1 rats fed either ad libitum (AL) or subjected to a 30% DR from 14 weeks of age. The mass of the upper hindlimb muscles recoverable in 34-mo-old AL rats was only 52% that of 11-mo-old AL rats, whereas rats on DR showed a stable, intermediate value at both ages. CAT and GPX activities increased progressively and markedly in muscle of AL animals with aging. The increase in CAT activity was partially attenuated by DR, while that of GPX was entirely prevented. These effects of aging and DR were more profound in 12,000 x g pellets than in cytosolic fractions. SOD activities were more variable and not clearly influenced by age or DR. These data agree with prior reports of an age-related increase in skeletal muscle antioxidant enzyme activities. Further, DR attenuates this alteration and does so most profoundly in the 12,000 x g pellet, the fraction which is enriched in mitochondria.

Aging↗
PubMed1994

Dietary restriction increases insulin sensitivity and lowers blood glucose in rhesus monkeys.

Insulin sensitivity and glucose tolerance typically decline during later life. In a multidimensional randomized trial of the effects of dietary restriction started in adulthood on the processes of aging, we are studying insulin sensitivity and glucoregulation longitudinally in control (C, n = 15, fed a defined diet ad libitum for 6-8 h/day) and restricted (R, n = 15, fed 30% less than C) monkeys using the Modified Minimal Model method. Linear rates of change were calculated for individual animals through 30 mo of diet treatment and compared between treatment groups. Basal glucose, basal insulin, and insulin responses to glucose and tolbutamide increased for C and decreased for R animals (P < or = 0.002), whereas insulin sensitivity decreased for C and increased for R (P = 0.008). Glycosylated hemoglobin at 30 mo was marginally lower in R (P = 0.06) and was positively correlated with fasting plasma glucose (r = 0.508, P < 0.001). Insulin changes were significantly correlated with changes in adiposity (weight and abdominal circumference). Identification of the mechanisms through which these effects are achieved may aid in ameliorating glucose intolerance, insulin resistance, and associated illnesses in older persons.

Animals↗
PubMed1993

Caloric restriction, aging, and antioxidant enzymes.

The basic mechanisms of aging and its retardation by caloric restriction (CR) remain unclear. One suggested means by which CR could retard aging is based on production of mitochondrial free radicals, and efficiency of their subsequent metabolism. Currently, there is little information concerning the influences of age and CR on the rates of in vivo mitochondrial free radical production. However, evidence for CR-induced modulation of free radical detoxification capacities is mounting. The direction of the influence of CR on free radical detoxification is tissue-specific. These effects are broad and appear to provide positive advantage.

Aging↗
PubMed1993

Dietary restriction of adult male rhesus monkeys: design, methodology, and preliminary findings from the first year of study.

Dietary restriction (DR) retards aging processes and extends maximum life span in rodents and in simpler animals. We initiated a study in 30 adults (8-14 years old) male rhesus monkeys to determine whether or not aging processes are retarded by adult-onset DR in a primate species and herein report results from the experiment's first year. Following a 3-6 month period when baseline data were obtained, 15 animals were assigned to a control group and given free access to a semipurified diet for 6-8 hours per day. The other 15 monkeys were fed the same diet but at 70% of their baseline intake levels predetermined individually. The animals are being evaluated semi-annually for body size and composition, physical activity, metabolic rate, glucose tolerance and insulin sensitivity, hematologic indices, immunologic function, and fingernail growth. Ocular function is assessed annually. The preliminary observations after one year are: (a) all monkeys appear to be in excellent health; (b) average body weights for controls increased by 9% while monkeys on DR did not gain weight; (c) monkeys on DR have less body fat than do control monkeys, whereas the amount of lean body mass has not been significantly influenced by DR; (d) there was a small but statistically significant reduction in physical activity for monkeys on DR relative to controls; and (e) DR has not overtly influenced the other measures. Control monkeys gradually reduced their voluntary levels of food intake during the first year of study, and food allotments to DR monkeys are being adjusted accordingly in order to reinstate the intended 30% difference between groups. These early data indicate that DR can be safely instituted in adult monkeys, but that longer term and/or more severe DR is required to determine if it is capable of influencing age-sensitive indices in long-lived primates.

Accommodation, Ocular↗
PubMed1993

Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesus monkeys.

We have examined skeletal muscle for the presence of age-associated mitochondrial DNA (mtDNA) deletions from 16 rhesus monkeys (age range 6-27 years). All animals over 13 years of age contained potential mtDNA deletions, whereas the presence of deletions was greatly reduced or absent in younger animals. The specific deletion patterns varied from individual to individual. Numerous mtDNA deletions accumulate with age in skeletal muscle from a nonhuman primate, indicating that the rhesus monkey may provide an excellent animal model to study mtDNA deletions. Further, the existence of multiple mtDNA deletions supports the possibility that they may contribute to geriatric muscular deficits, which are nearly universal in occurrence yet poorly understood.

Aging↗
PubMed1993

Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction.

Interleukin-6 (IL-6) is a multifunctional cytokine that is proving to be a major contributor to the acute phase inflammatory response. IL-6 expression is normally low and serum levels are usually nondetectable in the absence of inflammation. With advancing age, however, serum levels become detectable and it is proposed that this reflects an age-associated loss in the normal regulation of gene expression for this molecule. There is also speculation that IL-6 may contribute to the pathogenesis of several diseases that are common in late-life including lymphoma, osteoporosis, and Alzheimer's disease. In this report we demonstrate that plasma levels of IL-6 rise with advancing age in well-selected healthy elderly people and comparably in old rhesus monkeys. That this change reflects a primary aging process is suggested by our findings in C57BL/6 mice in which the age-associated increase in the in vitro synthesis of IL-6 is largely prevented by life span-extending dietary restriction.

Adult↗
PubMed1992

Mitotic activity in mice is suppressed by energy restriction-induced torpor.

We monitored core body temperature by telemetry in energy-restricted (201 kJ/wk) and control (397 kJ/wk) C57BL/6 and SHN/C3H F1 mice to determine whether torpor may be involved in the suppression of mitotic activities resulting from energy restriction. The energy restriction regimen employed inhibited the development of cancer and greatly extended longevity in both these mouse strains. Male and female C57BL/6 mice subjected to energy restriction from 4 wk of age and tested at 3 mo of age became torporific (body temperature less than 31 degrees C) at ambient air temperatures of 20-22 degrees C, whereas control animals stayed euthermic (greater than 35 degrees C). Energy restriction also induced torpor in 3- and 13-mo-old SHN/C3H F1 female mice, whereas 3-, 13- and 24-mo-old control mice were euthermic. Energy restriction decreased mitotic activities to approximately 30% of control values in both jejunum and epidermis in 3-mo-old female C57BL/6 mice maintained at 20-22 degrees C. However, this suppression of mitotic activities was antagonized by housing the energy-restricted mice at 30 degrees C for 2 wk, indicating that torpor plays a substantial role in suppressing mitotic activities in energy-restricted mice.

Animals↗
PubMed1991

Influences of dietary restriction on immunity to influenza in aged mice.

Our previous studies of the immune response of aged mice inoculated with influenza A virus revealed age-related decreases in antigen-specific cytotoxic T-lymphocyte function (CTL), T-cell proliferation, IL-2 production, antigen presentation, and antibody production. Because dietary restriction (DR) of rodents has been shown to extend maximum life span, delay the onset of tumors, and improve many immunologic parameters in aged animals, we tested the effect of such a regimen on the immune response to the influenza virus. We report that DR significantly inhibited the age-related decline in antigen presentation and T-cell proliferation. It also reduced the decline in antibody production to the virus. This is the first demonstration of improved immunity to an actual infectious agent resulting from DR. The improvement appears to be on a number of levels and to reflect more than one operative mechanism.

Aging↗
PubMed1991

The role of calories and caloric restriction in carcinogenesis.

Studies in mice and rats show that caloric restriction (CR) without malnutrition lowers the incidence of most spontaneous and induced tumors and delays their onsets. The maximum life spans of rodents and other experimental animals (e.g., fish, spiders, water fleas) are extended by CR. The molecular events that underlie these outcomes remain unelucidated. Although epidemiologic studies have not usually examined the relationship between caloric intake and cancer incidence, recent findings suggest a positive association for certain cancers such as colorectal, breast, and stomach. It is apparent that future studies of diet and cancer in humans must seriously assess the role of calories and energy balance as well as their interaction with the effects of specific nutrients.

Animals↗
PubMed1990

Dietary restriction alone and in combination with oral ethoxyquin/2-mercaptoethylamine in mice.

To investigate effects of dietary caloric restriction (DR) combined with antioxidant feeding, long-lived hybrid mice were divided into four dietary groups at weaning, and followed until natural death. Groups "C" and "R" received control (97 kcal/wk) and restricted (56 kcal/wk) diets respectively. Groups "C+ alpha ox" and "R+ alpha ox" received C or R diets supplemented with an antioxidant mixture (2-mercaptoethylamine plus ethoxyquin). R mice (mean life span 41 months) significantly outlived the other three groups (mean life span 30-34 months). Hepatic degeneration and increased hepatoma in the R+ alpha ox group suggested unusual hepatotoxicity of this regimen. Antioxidants had little effect on splenic cell mitogen response in similarly fed mice sacrificed at 12-15 months. Gompertz analysis suggests that the beneficial effect of DR may be due to reductions in initial vulnerability or rate-of-aging parameters, or both, and that the relative influence of each factor may vary with animal strain and DR protocol used.

Animals↗
PubMed1990

Dietary restriction and aging: the initiation of a primate study.

Juvenile (1 yr) and adult (3-5 yr) male rhesus monkeys (Macaca mulatta) and juvenile (1-4 yr) and adult (5-10 yr) male squirrel monkeys (Saimiri sciureus) were fed a diet at or near ad libitum levels based on recommended caloric intake for age and body weight or fed 30% less of the same diet with this restriction gradually introduced over a 3-mo period. Analysis of body weights among these respective control and experimental groups from the first year of the study indicated that the monkeys undergoing dietary restriction were gaining weight at a markedly slower rate compared to control values. Actual food intake among diet-restricted groups had been reduced 22-24% below control levels. Periodic analysis of hematology and blood chemistry measurements over the first year of the study detected few significant differences between control and experimental groups to indicate that diet restriction was not detrimental to general health. When values obtained from hematology and blood chemistry measurements of juvenile and adult groups (control and experimental groups combined) were compared to ad libitum fed old monkeys from each species (greater than 18 yr for rhesus; greater than 10 yr for squirrel monkeys), many significant age differences were noted. Among the largest and most consistent findings in both species were age-related decreases in concentrations of lymphocytes, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, and phosphates as well as the albumin/globulin ratio and the blood urea nitrogen/creatinine ratio. Age-related increases in serum globulin and creatinine concentrations were also found. These parameters as well as many others being implemented in the study will be monitored further to determine if diet restriction affects the rate of development as well as aging as observed in numerous rodent studies applying such nutritional manipulations.

Aging↗
PubMed1990

Effects of energy restriction on mouse mammary tumor virus mRNA levels in mammary glands and uterus and on uterine endometrial hyperplasia and pituitary histology in C3H/SHN F1 mice.

We investigated the effects of energy restriction on the pituitary-ovarian axis and on a hormone responsive gene, the mouse mammary tumor virus (MMTV). Female C3H/SHN F1-hybrid mice, known to display a high incidence of mammary tumors, ate an energy-restricted diet (48 kcal/wk) or a control diet (95 kcal/wk) beginning at the time of weaning. By 67 wk of age, 12 of 32 mice in the control group, but none of the 33 mice in the energy-restricted group, had developed mammary tumors. Six tumor-free mice from each group were studied in detail at 67 wk of age. All six tumor-free control mice, but none of the six energy-restricted mice, showed uterine endometrial hyperplasia at autopsy. Mice subjected to energy restriction did not display an estrous cycle. The average levels of MMTV mRNA in mammary glands and uteri were strongly reduced by energy restriction. MMTV mRNA levels in mammary glands from control mice were two orders of magnitude lower than those in mammary tumors. Energy restriction lowered the percentage of pituitary mammatropes and suppressed proliferation of mammatropes with advancing age. Energy restriction thus appeared to inhibit endometrial hyperplasia and to decrease MMTV production at the mRNA level in the mammary glands and in the uterus. These effects may be a consequence of hormonal changes originating at the pituitary-ovarian axis.

Animals↗
PubMed1989

Dietary restriction, tumors, and aging in rodents.

A chronic 30-50% restriction of dietary energy intake (but without malnutrition) typically and strongly lowers the incidence of most spontaneous and induced tumors, delays their onsets, and extends maximum life span in rodents. When compared to normally fed controls, animals fed these dietary restriction (DR) regimens show decreased rates of change for most (but not all) age-sensitive biologic indexes studied to date. DR's impact on chemically induced tumors appears to depend more on energy than on fat restriction, and result from less promotion (and not less initiation). The molecular and cellular events underlying these various outcomes of DR are unclear. Viable explanations include less cellular oxidative damage, a retardation in the age-related changes in the immune system, hormonal changes, less exposure to dietary carcinogens and promoters, less energy for tumor growth, less carcinogen activation, and better DNA repair. New findings are consistent with the notion that DR reduces cellular damage mediated by active oxygen. A lower production or higher detoxification rate of active oxygen species, which damages molecules and promotes tumor growth, could explain DR's effects on aging and tumors.

Aging↗
PubMed1989

The prevalence of dysequilibrium and related disorders in older persons.

Dysequilibrium disorders such as dizziness, balance and gait changes, and falls are among the most common yet poorly understood medical problems for older persons. A recent analysis of data about people aged 65 and older indicates that dysequilibrium is one of most common diagnoses in short-stay hospitalizations, and it accounts for an average of 4.3 days of medical care. Older people without overt disease of any type tend to perform more poorly on balance tests than do younger people. Gait deficits in many older people are associated with considerable functional impairments. Deficits in postural control are associated with an increased risk of falling. Geriatric dysequilibrium disorders can be caused by one or more factors--vestibular, vascular, visual, neuromuscular, pharmacologic--each of which must be considered to understand and appropriately treat the dysequilibrium. The accurate identification of the cause of dysequilibrium must involve the testing of multiple, interacting systems. The literature suggests that often no clear cause for an older person's dysequilibrium can be found, and indicates the possible existence of presently unappreciated etiologic factors. Progress in understanding these problems probably has been stymied by the fact that only a small, select subgroup of older patients is referred to specialists in otolaryngology. Quite probably, considerable progress on the understanding of the cause, diagnosis, and treatment of geriatric dysequilibria would result from more extensive research collaboration between otorhinolaryngologists, geriatricians, epidemiologists, and other specialists.

Accidental Falls↗