Biomedical subjects

R D Lipman

Publications and source records attributed to R D Lipman.

At least 19 recordsLinked to original sources

PubMed1999

Lesion biomarkers of aging in B6C3F1 hybrid mice.

This study of B6C3F1 hybrid mice was designed to determine the effects of caloric restriction (CR) on age-related pathologic changes. These changes accompany and may, in part, account for the apparent effect of CR in slowing the rate of aging. The study also explored whether lesions observed in groups of animals killed at 6 month intervals can serve as biomarkers of aging. Approximately 30 mice of each sex and each of two diet groups--CR and ad libitum fed (AL)--and each of six age groups--6, 12, 18, 24, 30, and 36 months of age--from the Biomarkers of Aging Program of the National Institute on Aging were killed and all tissues from each were examined for the histological presence or absence of lesions. A total of 209 distinct lesions were observed, of which 51 occurred in at least 10% of the AL or CR mice. The average number of lesions per mouse increased linearly with age in all diet-sex groups except in male CR mice. This increase was significantly smaller in CR than in AL mice of both sexes. The number of distinct lesions also increased with age in both diet groups but much less rapidly in CR mice. Nearly all lesions, including neoplastic, and nonneoplastic proliferative and degenerative ones, occurred significantly less often in CR than in AL mice at all ages. Foci of leukocytes in the liver, however, occurred more frequently in CR mice. Lung adenomas in old female mice occurred with equal frequency in both diet groups. A parsimonious classification tree analysis showed that diet groups could have been distinguished at each age by an evaluation of relatively few lesions and tissues. Altogether, this study suggests strongly that the prevalence of many individual lesions, the total lesion burden, and the total types of lesions are good biomarkers of aging because they increase with age and reflect the effect of CR in slowing the aging process. The study also shows that lesions occur stochastically, randomly, and independently in genetically homogeneous mice raised in a nonvariable environment.

Aging↗

PubMed1999

Effects of genotype and diet on age-related lesions in ad libitum fed and calorie-restricted F344, BN, and BNF3F1 rats.

The effects of calorie restriction (CR) on age-related lesions in Brown Norway, Fischer 344, and BNF3F1 hybrid rats are presented. A logistic regression analysis of data from histologic samples from rats of each genotype, sex, and diet at 12, 18, 24, 30, and 36 months of age demonstrated the effects of age, diet, and sex on lesion prevalence in all three genotypes. CR reduced the prevalence of neoplastic, nonneoplastic proliferative, and degenerative lesions. All genotype-sex-age cohorts demonstrated a reduced average lesion burden with CR. Importantly, some lesions common to Brown Norway rats seldom occurred in Fischer 344 rats and vice versa. Some lesions that occurred in only one parental strain also occurred in BNF3F1 rats. Many traits occurred in all three genotypes but at significantly different prevalence rates. We suggest that the diseases and lesions that rats develop as they age are controlled by genes and environmental factors such as CR.

Adrenal Glands↗

PubMed1999

Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program.

The collaborative Interagency Agreement between the National Center for Toxicological Research (NCTR) and the National Institute on Aging (NIA) was aimed at identifying and validating a panel of biomarkers of aging in rodents in order to rapidly test the efficacy and safety of interventions designed to slow aging. Another aim was to provide a basis for developing biomarkers of aging in humans, using the assumption that biomarkers that were useful across different genotypes and species were sensitive to fundamental processes that would extrapolate to humans. Caloric restriction (CR), the only intervention that consistently extends both mean and maximal life span in a variety of species, was used to provide a model with extended life span. C57BI/6NNia, DBA/2JNia, B6D2F1, and B6C3F1 mice and Brown Norway (BN/RijNia), Fischer (F344/NNia) and Fischer x Brown Norway hybrid (F344 x BN F1) rats were bred and maintained on study. NCTR generated data from over 60,000 individually housed animals of the seven different genotypes and both sexes, approximately half ad libitum (AL) fed, the remainder CR. Approximately half the animals were shipped to offsite NIA investigators internationally, with the majority of the remainder maintained at NCTR until they died. The collaboration supplied a choice of healthy, long-lived rodent models to investigators, while allowing for the development of some of the most definitive information on life span, food consumption, and growth characteristics in these genotypes under diverse feeding paradigms.

Aging↗

PubMed1999

Childhood energy intake and cancer mortality in adulthood.

A retrospective mortality follow-up of a British survey of family diet and health (1937-1939) identified significant associations between childhood energy intake and mortality from cancer, particularly those cancers not thought to be associated with smoking. This is the first large-scale epidemiologic study to suggest that the observed reduction in tumor incidence in energy-restricted rodents has relevance for humans.

Adolescent↗

PubMed1998

The effect of long-term dietary supplementation with antioxidants.

The impact of diet and specific food groups on aging and age-associated degenerative diseases has been widely recognized in recent years. The modern concept of the free radical theory of aging takes as its basis a shift in the antioxidant/prooxidant balance that leads to increased oxidative stress, dysregulation of cellular function, and aging. In the context of this theory, antioxidants can influence the primary "intrinsic" aging process as well as several secondary age-associated pathological processes. For the latter, several epidemiological and clinical studies have revealed potential roles for dietary antioxidants in the age-associated decline of immune function and the reduction of risk of morbidity and mortality from cancer and heart disease. We reported that long-term supplementation with vitamin E enhances immune function in aged animals and elderly subjects. We have also found that the beneficial effect of vitamin E in the reduction of risk of atherosclerosis is, in part, associated with molecular modulation of the interaction of immune and endothelial cells. Even though the effects of dietary antioxidants on aging have been mostly observed in relation to age-associated diseases, the effects cannot be totally separated from those related to the intrinsic aging process. For modulation of the aging process by antioxidants, earlier reports have indicated that antioxidant feeding increased the median life span of mice to some extent. To further delineate the effect of dietary antioxidants on aging and longevity, middle-aged (18 mo) C57BL/6NIA male mice were fed ad libitum semisynthetic AIN-76 diets supplemented with different antioxidants (vitamin E, glutathione, melatonin, and strawberry extract). We found that dietary antioxidants had no effect on the pathological outcome or on mean and maximum life span of the mice, which was observed despite the reduced level of lipid peroxidation products, 4-hydroxynonenol, in the liver of animals supplemented with vitamin E and strawberry extract (1.34 +/- 0.4 and 1.6 +/- 0.5 nmol/g, respectively) compared to animals fed the control diet (2.35 +/- 1.4 nmol/g). However, vitamin E-supplemented mice had significantly lower lung viral levels following influenza infection, a viral challenge associated with oxidative stress. These and other observations indicate that, at present, the effects of dietary antioxidants are mainly demonstrated in connection with age-associated diseases in which oxidative stress appears to be intimately involved. Further studies are needed to determine the effect of antioxidant supplementation on longevity in the context of moderate caloric restriction.

Aging↗

PubMed1998

Disease incidence and longevity are unaltered by dietary antioxidant supplementation initiated during middle age in C57BL/6 mice.

The ability of augmented antioxidant consumption to alter disease incidence, lesion burden and/or longevity was studied in adult male C57BL/6 mice. Mice were fed modified AIN76 diet or modified AIN76 supplemented with vitamin E, glutathione (GSH), vitamin E and GSH, melatonin or strawberry extract starting at 18 months of age. All the mice in this study were heavier than reference populations of male C57BL/6 mice fed NIH-07 or NIH-31, which were maintained without a mid-life change in diet. Fatty liver, focal kidney atrophy and proteinacious casts in the renal tubules were observed more frequently in this study population than in the reference populations. Lesion burden and incidence of specific lesions observed amongst the various groups in this study did not differ. There were no differences observed for longevity of any of the study groups. The longevity observed in this study was similar to that previously reported for male C57BL/6 mice. Thus, diet supplementation with antioxidants initiated during middle age did not appear to affect age-associated lesions patterns, lesion burden or longevity for ad libitum fed male C57BL/6 mice.

Aging↗

PubMed1998

Effects of caloric restriction or augmentation in adult rats: longevity and lesion biomarkers of aging.

Caloric restriction (CR) initiated in young rodents has been thoroughly documented to enhance longevity, but its efficacy when introduced at older ages has not been well investigated. Cohorts of 18- and 26-month-old male F344 x BN F1 hybrid rats were fed either: 1) NIH-31 meal (C); 2) vitamin and mineral fortified NIH-31 meal (R); or 3) vitamin and mineral fortified NIH-31 meal supplemented with corn oil and sweetened condensed milk (S). The C control rats were fed ad libitum, R rats were restricted to 32% of the caloric intake of the controls, and S rats were allowed to consume not more than 8% more calories than C rats. After 6 weeks, the average weights were significantly different between all diet and age groups. Although calorie manipulation altered body weight, no significant effect of the dietary intervention on longevity was found. The average lesion burden, including tumor burden and prevalence of nearly all commonly occurring lesions, were comparable between the groups. Thus, the manipulation of weight at ages beyond middle age has a much less profound impact than similar interventions during growth and maturation in rats.

Adrenal Gland Neoplasms↗

PubMed1996

Evidence that lysosomal storage of proteolipids is a cell autonomous process in the motor neuron degeneration (mnd) mouse, a model of neuronal ceroid lipofuscinosis.

The motor neuron degeneration (mnd) mouse has been documented to accumulate proteolipid and thus is a model of neuronal ceroid lipofuscinosis [Dunn, W.A., Raizada, M.K., Vogt, E.S. and Brown, E.A., Int. J. Dev. Neurosci., 12 (1994) 185-196; Faust, J.R., Rodman, J.S., Daniel, P.F., Dice, J.F. and Bronson, R.T., J. Biol. Chem., 269 (1994) 10150-10155]. While accumulation of proteolipid in the hippocampus of chimeric mice composed of mnd and +/+ cells was found to be proportional to the contribution of mnd in the brain, accumulation within individual cells was the same for cells from chimeric and age-matched mnd mice. Bone marrow transplantation was used to altering the milieu of circulating factors to determine whether this might modify the disease phenotype in mnd mice. Transplantation of bone marrow in neonatal or young mice did not reduce the age-associated accumulation of proteolipid within hippocampal neurons. The results of these experiments indicate that mnd results in a cell autonomous defect.

Aging↗

PubMed1996

Pathologic characterization of brown Norway, brown Norway x Fischer 344, and Fischer 344 x brown Norway rats with relation to age.

The rat is a common laboratory animal utilized in a variety of investigations including experimental gerontology. Gerontologic investigations can be compromised when the differences observed when comparing young and old animals are actually differences between normal and disease states. It is of critical interest to know the pathology of the animals being studied and to understand the impact of these disease processes on the parameters being measured. The incidence and average age of occurrence for lesions have been characterized and are reported here for one inbred (Brown Norway) and two hybrid strains (Brown Norway x Fischer 344 and Fischer 344 x Brown Norway) of rat. Total lesion incidence functions as a biomaker of aging for all of the strains examined (p < or = .00001). These three genotypes have significantly lower incidence of several major pathologic processes (including glomerulonephritis, retinal atrophy, and leukemia) than do the Fischer 344 and the Wistar rats, two commonly utilized strains. Additionally, the BN and F344 x BN F1 hybrid attain 50% mortality at 130 and 146 weeks of age, respectively, which is significantly greater than the 103 weeks for the F344 rat. It is hoped that access to basic information on these three rat genotypes will increase their utilization by the community of gerontologic scientists.

Aging↗

PubMed1996

Weight gain by middle-aged mice: dietary modification does not result in loss.

Dietary induced obesity susceptibility and persistence was examined in middle aged female retired C57BL/6J breeder mice. One year old mice were fed control chow (C), chow with added corn oil (O), or chow with added sweetened condensed milk (SCM) for 18 weeks, during which time food consumption and weight change were monitored. Mice in both the O and SCM groups gained significantly more weight than the C group. Weight increase correlated with caloric intake for the O and SCM groups. All mice were then fed standard laboratory chow for 22 weeks. The increased weight of both supplemented groups was maintained during this time suggesting that caloric intake is not the sole variable controlling weight maintenance in adult female mice. We encourage the use of older mice as a model to explore means of manipulating adult weight in humans.

Adipose Tissue↗

PubMed1995

Dietary calorie restriction in the Emory mouse: effects on lifespan, eye lens cataract prevalence and progression, levels of ascorbate, glutathione, glucose, and glycohemoglobin, tail collagen breaktime, DNA and RNA oxidation, skin integrity, fecundity, and cancer.

The Emory mouse is the best model for age-related cataract. In this work we compare the effects of feeding a control diet (C) with a diet restricted (R) by 40% relative to C animals. In the R animals, median lifespan was extended by 40%. The proportion of R mice with advanced cataract was lower than C mice as early as 5 months of age. The mean grade of cataract was lower in R animals, beginning at 11 months and continuing until the end of the study. Ascorbate levels in R plasma and liver were 41-56% of C animals. There was no difference between diet groups with respect to lens ascorbate. Aging was associated with a decrease in ascorbate in lenses and kidneys in C and R mice. By 22 months, R animals had 48% higher liver glutathione levels than C mice. Liver glutathione levels were maximal at 12 months. Plasma glucose levels were > 27% lower in R animals at 6.5 and 22 months, and there was a 14% increase in glucose levels upon aging for both diet groups. In R mice, glycohemoglobin levels were 51% lower and tail collagen breaktime was decreased by 40%, even in younger animals. Collagen breaktime increased > 360% upon aging for both diet groups. Rates of production of urinary oxo8dG and oxo8G were higher in R animals compared with C animals, and increased upon aging. C animals exhibited more cancer and dermatological lesions, but less tail tip necrosis and inflamed genitals than R mice. These data allow evaluation of several theories of aging.

Animals↗

PubMed1995

Is late-life caloric restriction beneficial?

Caloric restriction initiated in young mice and rats results in increases in mean and median life span. When caloric restriction is implemented in older animals, an increase in life span is still observed; however, the magnitude of the increase is not as great as that observed in animals calorie restricted since they were young. Here we report the results of a pilot study in which caloric restriction was initiated in mature, older rats. Survival rates and terminal pathology were characterized and compared between a cohort of 17 continually ad libitum fed Long Evans rats and a cohort of 18 Long Evans rats, which were gradually introduced to 33% restriction in diet consumption at 18 months of age. No difference in the median life span was observed between the two groups. The data suggest there may be a level of maturity, or a stage in the aging process, after which caloric restriction no longer increases longevity.

Aging↗

PubMed1995

Dietary restriction delays cataract and reduces ascorbate levels in Emory mice.

Dietary restriction can effectively extend lifespan and retard many age-related debilities. One hypothesis to explain the beneficial effects of dietary restriction is that it prolongs maintenance of cellular homeostasis by limiting endogenous oxidative stress and preserves oxidative defense mechanisms during aging. Ascorbate, a primary antioxidant, may play a major role in preventing oxidative damage. Ascorbate levels were determined in dietary restricted (R) and control (C) Emory mice, a strain which develops age-related cataract due in part to oxidative damage to lens proteins. Mice which consumed a diet restricted by 40% in calories had lower ascorbate concentrations in plasma, liver and kidney. Nevertheless, R animals showed significantly delayed progression of cataract which extended over the entire second half of life. The R diet did not result in different ascorbate levels in this lens. Aging was associated with a decrease in ascorbate in all the examined tissues except lens of both the R and C groups. It is not clear from these data that ascorbate is a prominent factor in the delay of cataract formation or other debilities in R Emory mice. However, it also appears unlikely that lens ascorbate is cataractogenic.

Aging↗

PubMed1993

Age-related gliosis in the white matter of mice.

A histopathologic study of the brains from 96 mice, ranging in age from 3 to 57 months in age, documents an age-associated increase in hypertrophic astrocytes in white matter. This report of gliosis is distinct from previously reported proliferation of glial cells in the grey matter. Four genotypes, CBA/HT6J, C57BL/6J, B6CBAT6F1J, and B6C3F1 were positive for this age-related lesion. Most very old mice utilized in this study were calorically restricted, a dietary manipulation long known to result in increased longevity in rodents. Caloric restriction appears to delay the age associated increase of this lesion. Immunoperoxidase staining for the astrocyte-specific glial fibrillary acidic protein (GFAP) confirmed the progressive increase in the density of stainable astrocytes with increase in age. GFAP staining of white matter increased in both diet groups with age. These findings present an interesting model for the study of aberrant cellular activity and perhaps neurodegeneration, modulated by caloric restriction.

Aging↗

PubMed1993

FRAR course on laboratory approaches to aging. The role of pathology in rodent experimental gerontology.

The distinction between aging and age-related disease is a blurred one at best. Pathologic lesions and diseases, while having obvious importance for the well-being of an individual, are not more indicative of aging than are silent or benign aging changes. All lesions are useful as biomarkers of aging. They are definable, and can be characterized in terms of their prevalence and severity in different species, genotypes, genders, and age groups. Some data from previous studies are presented as examples. Many lesions of aging are quite restricted, in terms of prevalence or severity, to specific genotypes, species or genders. Recognition of the very great diversity of lesion biomarkers between genotypes, genders and species should prevent investigators from extrapolating findings in one genotype-gender to any other.

Aging↗

PubMed1993

Husbandry factors and the prevalence of age-related amyloidosis in mice.

A retrospective study of the prevalence of amyloidosis in mice from several facilities was done. Amyloid deposition is an age-related lesion. The influence of common laboratory factors on the occurrence of this lesion was analyzed. This study documented genotypic difference in susceptibility to amyloidosis and showed that caging and pathogen status both impact on the number of cases of amyloidosis seen in a population. The lowest percentage of affected mice was seen when the animals were individually caged in a specific pathogen-free facility where conditions of stress were minimized.

Age Factors↗

PubMed1992

Mammary gland mass and breast cancer risk.

Evidence indicates that early life events and conditions, possibly extending to the intrauterine stages of life, and including energy restriction in early life, affect the risk of breast cancer. The mechanism of this effect is likely to be through a reduction in mammary gland mass and, inferentially, the total number of ductal stem cells. The evidence derives from epidemiologic and animal studies. It can explain certain epidemiologic findings that cannot be accounted for by more established breast cancer risk factors, including the more frequent occurrence of breast cancer in the left breast and the higher incidence of this disease among caucasian women than among Asian women in Asia.

Breast↗

PubMed1991

Calpain in cultured bovine lens epithelial cells.

Calcium dependent proteolysis was examined in supernatant prepared from cultured bovine lens epithelial (BLE) cells. The presence of the calcium activated protease, calpain, was indicated by immunorecognition of 80 kDa and 30 kDa subunits of calpain in BLE cell supernatant. Degradation of 125I-alpha-crystallin and FITC labeled casein by BLE cell supernatant were shown to be calcium dependent. Inhibition of activity was achieved with EGTA, calpastatin or CbzValPheH. The data presented are the first measurement of calpain activity in cultured lens cells.

Animals↗