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R G Cutler

Publications and source records attributed to R G Cutler.

At least 37 records · Page 2Linked to original sources
PubMed1995

Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points.

Male rhesus monkeys (Macaca mulatta) of different age groups representing the species life span were fed ad libitum or a 30% reduced calorie diet over a 7-yr period. During the first 2-3 yr of this longitudinal study, glucose and insulin levels were not altered by diet restriction (DR). However, reductions in fasting blood glucose became apparent in DR animals after 3-4 yr. At the end of the 6th yr of study, glycated hemoglobin was measured, and intravenous glucose tolerance tests (IVGTTs) were conducted. Maximum glucose levels reached during IVGTTs increased with age but were lower in DR animals compared with controls. Several measures of the insulin response (baseline, maximum, and integrated areas under curve) increased with age and were lower in DR monkeys. With the exception of glycated hemoglobin, which was not different in monkeys subjected to DR, these findings confirm previous studies in rodents demonstrating that DR alters glucose metabolism and may be related to the antiaging action of this intervention.

Aging↗
PubMed1993

The effect of caloric restriction on the lateral diffusion constant of hepatocyte membrane proteins in C57BL/6 male mice of different ages: FRAP studies on liver smears.

The lateral mobility of proteins in hepatocyte plasma membranes was compared in calorically restricted and ad libitum (AL)-fed C57BL/6 male mice in age groups from 7 to 28 months. Caloric restriction was achieved by means of the every-other-day (EOD) feeding regimen, maintained for various periods from 1 to 15 months. Protein lateral diffusion constant (D) in hepatocyte membranes was measured by means of fluorescence recovery after photobleaching (FRAP) in liver smears. The peroxide-induced autofluorescence (PIAF) was utilized as a fluorescent label. A mild (1 mM for 10 min) H2O2 treatment of liver smears produces oxidation of riboflavin that is bound to all proteins of the cell membrane. Using this technique, the average lateral diffusion constant (D) and the fractional recovery (FR) of these proteins can be measured. EOD feeding resulted in a significant decrease in body weights and also a significant increase in the values of D in all age groups after 1 month of EOD feeding. After 3.5 months of EOD feeding a further increase of D was observed (up to about 15%). Nevertheless no further change in D occurred if the EOD feeding was maintained for 6.5 or even 15 months. The negative linear age correlation of D observed in the AL-fed animals was present also under the EOD feeding; however, the whole regression equation shifted towards higher values. These experiments indicate that caloric restriction influences the lateral diffusion constant of membrane proteins in hepatocytes. The results are interpreted as a result of an increased protein turnover caused by the caloric restriction.

Aging↗
PubMed1993

Nitric oxide formation during light-induced decomposition of phenyl N-tert-butylnitrone.

Phenyl N-tert-butylnitrone (PBN) is a spin trap commonly employed in free radical research. PBN has been shown to have adverse and beneficial effects on various biological systems. We report here evidence that photolysis (or even ambient light) decomposes PBN to nitric oxide in aqueous solutions. Non-heme and heme proteins have been employed to form nitrosyl complexes, which were detected using EPR spectroscopy. Concomitantly, nitrite formation was detected after light-induced decomposition of PBN. In addition, we found that tert-nitrosobutane and decomposed PBN caused an activation of guanylate cyclase. We propose a mechanism where PBN is decomposed by light to tert-nitrosobutane. The latter compound is, in turn, decomposed to nitric oxide. This study suggests the possibility that PBN or PBN radical adducts may be sources of nitric oxide in biological environments. When using PBN as a spin trap in biological samples, not only is the trapping of reactive free radicals operative, but nitric oxide produced from PBN decomposition may play an important role in altering biological functions.

Animals↗
PubMed1993

Oxygen-radical absorbance capacity assay for antioxidants.

A relatively simple but sensitive and reliable method of quantitating the oxygen-radical absorbing capacity (ORAC) of antioxidants in serum using a few microliter is described. In this assay system, beta-phycoerythrin (beta-PE) is used as an indicator protein, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) as a peroxyl radical generator, and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox, a water-soluble vitamin E analogue) as a control standard. Results are expressed as ORAC units, where 1 ORAC unit equals the net protection produced by 1 microM Trolox. The uniqueness of this assay is that total antioxidant capacity of a sample is estimated by taking the oxidation reaction to completion. At this point all of the nonprotein antioxidants (which include alpha-tocopherol, vitamin C, beta-carotene, uric acid, and bilirubin) and most of the albumin in the sample are oxidized by the peroxyl radical. Results are quantified by measuring the protection produced by antioxidants. This solves many problems associated with kinetics or lag-time measurements. A linear correlation of ORAC value with concentration of serum. Trolox, vitamin C, uric acid, and bovine albumin is demonstrated. The coefficient of variation within a run is found to be about 2% and from run to run about 5%. Trolox, alpha-tocopherol, vitamin C, beta-carotene, uric acid, and bilirubin completely protect beta-PE from oxidation, while bovine albumin protects beta-PE only partially. On a molar basis, the relative peroxyl radical absorbance capacity of Trolox, alpha-tocopherol acid succinate, uric acid, bilirubin, and vitamin C is 1:1:0.92:0.84:0.52. Bovine albumin per unit weight has a lower peroxyl absorbing capacity than these antioxidants.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Comparison of the lateral diffusion constant of hepatocyte membrane proteins in two wild mouse strains of considerably different longevity: FRAP studies on liver smears.

The liver cells of male and female wild mice (Peromyscus leucopus and Mus musculus) have been studied in young, adult, and old age groups. Because P. leucopus displays a life expectancy of 7-8 years, the age groups of this strain were from 5.5 to 68 months. M. musculus survives only to about 2.5 years; therefore, the age groups of this strain ranged from 6 to 27 months. Protein lateral diffusion in hepatocyte membranes was measured by means of fluorescence recovery after photobleaching (FRAP) in liver smears. The peroxide-induced autofluorescence was utilized as a fluorescent label, which in H2O2 treated liver smears is caused by the oxidation of riboflavin bound uniformly to all proteins of the cell membrane. This way the average lateral diffusion constant (D) and the fractional recovery of those proteins can be measured. In both males and females of both strains D displayed a negative linear age correlation. Intraspecies sex differences were small and statistically insignificant. However, interspecies comparisons of males or females resulted in a strongly significant difference: although the intercept points of the regression lines describing D were identical in both strains (3.1 x 10(-10) cm2/sec), the decay of D with aging was about 2.5 times faster in the short-living M. musculus than in the long-living P. leucopus. By the end of life expectancy, both strains reached practically identical values (about 1.9 x 10(-10) cm2/sec). The results lend further support to the membrane hypothesis of aging.

Aging↗
PubMed1992

Dietary restriction in nonhuman primates: progress report on the NIA study.

Rhesus and squirrel monkeys have been fed a semisynthetic diet at approximately ad libitum or 30% reduced levels for 3.5 (rhesus group 2) to 4.5 (rhesus group 1 and squirrel) years. Animals have maintained excellent health status as determined by physical examinations, hematology, and blood chemistry. While relative rates of body weight gain in restricted group 1 rhesus and squirrel monkeys have been markedly reduced, DR effects on crown-rump length (body height) have been variable. In addition, numerous physiological and biochemical parameters have been measured, and several exhibit significant cross-sectional age effects. Interestingly, several of these also exhibit possible species and genotype (group 1 and 2 rhesus) differences. A number of physiological parameters are emerging that might be altered by DR; however, further explanation of these effects awaits more extensive and detailed analyses.

Aging↗
PubMed1992

Genetic stability and oxidative stress: common mechanisms in aging and cancer.

Much evidence indicates that age-related diseases as well as the aging process itself may be a result of genetic instability, resulting in cells changing their proper state of differentiation. Such genetic changes could be of an epigenetic or genetic nature (or both) and suggest that mechanisms acting to stabilize the differentiated state of cells could be major determinants of animal species' general health and longevity. There is also much data indicating that a causative factor in cancer is genetic instability, suggesting the importance of genetic stabilized factors governing the frequency of this disease. Possibly related to these two observations is the good positive correlation between rate of cancer and the rate of aging of different mammalian species. In addition, cells from longer-lived species appear to have a higher intrinsic ability to maintain their proper differentiated state and animals whose life span has been extended by food restriction also have a postponed onset of cancer. These data suggest the possibility that genetic instability may represent a common causative mechanism for both aging and cancer. This suggestion is supported by evidence indicating that oxidative stress can increase cancer frequency and that longer-lived species appear to have a lower oxidative stress state. However, there appears to be a serious lack of evidence indicating that physical and chemical mutagenic agents accelerate aging as they do cancer. For these and other considerations, it is proposed that aging is not a result of genetic instability as are many different age-related diseases. Thus, physiological aging and some age-related diseases could have separate and distinct mechanisms of causation and control.

Aging↗
PubMed1992

Plasma concentrations of glucose, insulin, and percent glycosylated hemoglobin are unaltered by food restriction in rhesus and squirrel monkeys.

Plasma concentrations of glucose and percentage of glycosylated hemoglobin have been reported to be reduced in food-restricted rats when compared with ad libitum-fed controls (Masoro et al., 1989). A similar experiment in primates, in which we also measured plasma insulin, is reported in this article. Rhesus and squirrel monkeys were fed either ad libitum or 30% less than weight-matched controls for up to 36 months. No significant age or diet effects on plasma concentration of glucose, insulin, or percentage glycosylated hemoglobin were observed, except that glucose concentration decreased with age in ad libitum-fed rhesus monkeys. Moreover, no correlations between glucose levels and the percentage of glycosylated hemoglobin could be established within any group of animals. These results suggest possible differences in glucose-related metabolism in ad libitum and food-restricted primates as compared to observations made in rats.

Aging↗
PubMed1991

Gene expression of an endogenous retrovirus-like element during murine development and aging.

We have measured intracisternal A-particle (IAP) RNA levels during development and aging in C57BL/6J mouse tissues to determine possible age-dependent changes in gene expression of these retrovirus-like sequences. Total RNA was isolated from tissues of embryonic and new born mice and mice ranging in age from 2 months to 32 months of age. RNA samples were either slot-blotted directly or fractionated on denaturing agarose gels and transferred to nylon membranes. Hybridization with cloned, 32P-labeled IAP sequences showed that both the mass amounts and the relative proportions of IAP transcripts varied between tissues and as a function of age. IAP gene products were higher in brain and kidney tissues than in liver and heart tissues. The relative proportion of transcripts increased in embryonic tissues until birth and following birth, was highest in neonatal or 2-month-old tissues. The adult levels of IAP-related RNAs did not change significantly from 6 to 24 months of age. However, 32-month-old tissues exhibited the lowest content of IAP transcripts, with the exception of heart tissue which did not change with age. A 5.4-kb RNA was the predominant IAP transcript in most samples, but each tissue had a characteristic size distribution of IAP-related transcripts. These results demonstrate that transcription of IAP genes continues throughout the life span of this mouse strain with tissue-specific and age-dependent regulation of expression.

Aging↗
PubMed1991

Antioxidants and aging.

Aging in mammalian species appears to be the result of normal developmental and metabolic processes. In spite of the vast complexity of aging processes, relatively less complex processes such as longevity determinant genes (LDGs) may exist governing aging rate. Much experimental data exists indicating a causative role of oxyradicals in aging processes. In testing the hypothesis that antioxidants may represent LDGs, a positive correlation in the tissue concentration of specific antioxidants with life span of mammals was found. These antioxidants include superoxide dismutase, carotenoids, alpha-tocopherol, and uric acid. We also found that the resistance of tissues to spontaneous autoxidation and the amount of oxidative damage to DNA correlates inversely with life span of mammals. These results suggest a role of oxyradicals in causing aging and that the antioxidant status of an individual could be important in determining frequency of age-dependent diseases and duration of general health maintenance.

Aging↗
PubMed1991

Human longevity and aging: possible role of reactive oxygen species.

A brief overview has been given of the biological nature of human aging processes, where it has been emphasized that, in addition to the diseases of aging, there is also great economic loss as a result of human aging processes that began many years before medical costs related to aging begin to escalate. Because of the ubiquitous nature of aging, reducing the function of essentially all physiological processes, it appears that the only long-term solution to human aging problems is to decrease uniformly the aging rate of the entire body. Although the uniform decrease of aging rate has usually been considered impossible, where emphasis has consequently been placed on diseases of aging by the medically-orientated investigator, there is now at least one theoretical argument, accompanied by some experimental data, that suggests that progress can be made in achieving this goal. This progress has been based on the longevity determinant gene hypothesis predicting the existence of a relatively few key regulatory factors governing aging rate of the entire organism. If this hypothesis is not true, then indeed the prospect for significant intervention into human aging would appear impossible in the near future. Experiments have been briefly reviewed testing the longevity determinant gene hypothesis, the possibility that aging may be a result of dysdifferentiation and if aging rate is determined by mechanisms acting to stabilize the differentiated state of cells. In testing the dysdifferentiation hypothesis of aging, there is not yet much data one way or the other. It is evident, however, that changes in gene expression do occur with age, sometimes involving endogenous retroviruses or oncogenes. Other morphological evidence shows an increase with age in unusual cell type such as metaplasia cells. However, there is considerably more evidence indicating that aging may be a result of genetic instability (as it is in cancer) and that longer-lived species appear to have a more stable genetic apparatus and superior protective mechanisms against reactive oxygen species. There is a striking similarity in this model of aging and models of cancer, and much might be gained in bringing together these two fields of research. Taking all of these data together, as summarized in Table 14, it appears we may be on the right track and that mechanisms acting to protect DNA against oxidative damage may be one class of longevity determinant mechanisms. There is of course much work remaining to be done, some of which is listed in Table 15 in terms of our knowledge and our gaps of knowledge in this field.

Age Factors↗
PubMed1990

Mouse satellite DNA is transcribed in senescent cardiac muscle.

Mouse satellite DNA consists of highly repetitive tandem sequences located in the centromeric heterochromatin. It is generally assumed that these simple sequences are not transcribed. We have analyzed total cellular RNA preparations from mouse liver, kidney, brain, and heart tissues at different ages for satellite transcripts. Using recombinant probes containing the major mouse satellite sequence, satellite transcripts were detected only in the heart RNA samples. These transcripts were not detected in the heart muscle of young adult animals (2 and 6 months), but then appeared at the age of 12 months and continued to increase over 2-fold up to the age of 32 months. The transcripts were resistant to DNase I and sensitive to RNases and alkaline treatment. Northern hybridization experiments showed a large and heterogeneous size range of satellite transcripts. Control studies using short-interspersed (B1 and B2) and long-interspersed (L1 and IAP) repetitive DNA sequence probes did not show a similar age-related pattern of transcription. These results indicate that satellite transcription does occur in mice but is highly tissue- and age-specific. The unique occurrence of satellite transcription only in adult and senescent heart tissue indicates age to be an important determinant of gene activity. An understanding of the regulatory mechanisms involved could lead to new insights in the biological role of satellite DNA, gene derepression of reiterated DNA sequences, and the aging processes of cardiac muscle.

Aging↗
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↗
PubMed1989

Development, cancer and aging: possible common mechanisms of action and regulation.

The incidence of most types of cancer intensifies throughout an animal's life span. This correlation of cancer incidence with age raises the question of a possible causative link. Over the past few years there has been a rapid increase in our knowledge of genetic mechanisms of cancer initiation and propagation. In view of these advances, a reevaluation of the links between aging and cancer appears appropriate. This article attempts such a reevaluation and concludes that there is indeed much evidence indicating common causes of cancer and aging. This conclusion is primarily based on the positive correlation between aging rate of different species with their cancer rate and that both cancer and aging may be initiated and propagated by impairments of gene regulation driven by destabilizing processes affecting regulatory elements. Reduction of cancer incidence and aging rate would then be based on enhancing common mechanism acting to maintain proper gene regulation of differentiated cells.

Aging↗
PubMed1989

Tissue and age specific expression of the myc proto-oncogene family throughout the life span of the C57BL/6J mouse strain.

The expression of the proto-oncogene myc family (c, L and N) in terms of steady-state mRNA levels was determined in seven different normal non-cancerous tissues throughout the life span (seven different ages) of the C57BL/6J male mouse strain. C-myc oncogene expression was highest in prenatal and newborn ages and then decreased to its lowest levels at about 6 months of age. With further increase of age, a progressive pattern of increase in expression of c-myc was found in brain, liver, skin, and small intestine. However, for kidney, spleen and heart, little or no significant change was evident. Significant differential expression of c-myc was found in most tissues in animals of the same age, with highest expression consistently being found in spleen and liver at all ages. For the N-myc and L-myc oncogenes, expression was also highest in prenatal and newborn tissue as compared to the 6-month young adult, but little or no further change was found at older ages. However, substantial tissue-dependent differences in expression were also found, and no expression at all was detected at any age for N-myc in liver and for L-myc in heart, small intestine and liver. Taken together, these results indicate that the expression of the proto-oncogenes c-, L- and N-myc is dependent not only on tissue and embryonic development, as previously shown by other workers, but also on age past the young adult stage of life span. The age-dependent increase in expression of c-myc oncogene found in normal-appearing non-cancerous tissues is of particular interest as possibly reflecting tissue alterations related to both the aging process and the age-dependent increase in cancer incidence.

Age Factors↗
PubMed1988

Dysdifferentiation hypothesis of aging and cancer: a comparison with the membrane hypothesis of aging.

Our laboratories have been testing the basic concept that the age-dependent deterioration of the molecular components of living systems may be due in part to the biochemical effects of active oxygen species. The dysdifferentiation hypothesis of aging and cancer (DHAC) as well as the membrane hypothesis of aging (MHA) are discussed and compared to each other. These two hypotheses consider cellular mechanisms through which free radical-induced alterations may lead to the aging process. DHAC emphasizes the importance of the instability of the differentiated state of cells and how active oxygen species may interact with the genetic apparatus of cells, leading to improper gene regulation. The evidence supporting this hypothesis includes an age-dependent increase in the expression of specific genes that normally are expected to be repressed. Such evidence now includes the c-myc oncogene as well as an age-dependent decrease in the average methylation level of the entire genome in liver tissue of mice. The central concept of DHAC is that aging is a result of gene regulatory instability and that lifespan is governed by mechanisms acting to stabilize proper gene regulation. MHA is based on the concept that all cellular components are exposed to free-radical attacks, and that the damaging efficiency of the radicals is density-dependent. Compact structures like membranes are consequently more susceptible to damage than cytosolic components. In addition, the cell plasma membrane is exposed to another damaging effect called residual heat damage, which is due to the depolarization-induced discharge of the membrane during the action potential. MHA predicts that a key process of normal differentiation as well as aging is a continuous, age-dependent loss of the passive permeability of the cell membrane for potassium and probably also for water. This is due to a constant difference between the rates of damage and replacement of the membrane components and results in a gradual dehydration of the intracellular mass from the embryonic state to the aging state. The increasing intracellular density will eventually become rate-limiting for many different cellular functions, resulting in the cessation of growth and the beginning of aging. MHA also predicts an overall decrease of gene expression and protein turnover rate during aging. Pharmacological interventions on the cell membrane have supported the validity of MHA and have indicated specific mechanisms of how aging and dysdifferentiation may occur.

Aging↗