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Biomedical subjects

David Berrigan

Publications and source records attributed to David Berrigan.

At least 19 recordsLinked to original sources
PubMed2007

Intra-abdominal fat burden discriminated in vivo using proton magnetic resonance spectroscopy.

OBJECTIVE: To assess proton magnetic resonance spectroscopy (1H-MRS) as a means to distinguish among mice with disparate intra-abdominal body fat compositions, and to measure changes in intra-abdominal fat burden during weight loss and regain. RESEARCH METHODS AND PROCEDURES: Intra-abdominal fat burden was analyzed as a ratio of integrated areas under the curves of fat to water (1)H-MRS signals collected from a region of interest standardized across B6.V-Lep(ob), C57BL/6, and A-ZIP/F mice that exhibited various genotypically related body fat compositions, ranging from obese (B6.V-Lep(ob)) to minimal body fat (A-ZIP/F). 1H-MRS analysis of fat burden was compared with intra-abdominal fat volume and with a single cross-sectional intra-abdominal fat area calculated from segmented magnetic resonance images. Similar measurements were made from obese B6.V-Lep(ob) mice before, during, and after they were induced to lose weight by leptin administration. RESULTS: Relative amounts of intra-abdominal fat analyzed by 1H-MRS differed significantly according to body composition and genotype of the three strains of mice (p < 0.05). Intra-abdominal fat assessed by 1H-MRS correlated with both intra-abdominal fat volume (r = 0.88, p < 0.001) and body weight (r = 0.82, p < 0.001) among, but not within, all three genotypes. During weight loss and regain, there was a significant overall pattern of changes in intra-abdominal fat quantity that occurred, which was reflected by 1H-MRS (p = 0.006). DISCUSSION: Results support the use of localized 1H-MRS for assessing differences in intra-abdominal fat. Refinements in 1H-MRS voxel region of interest size and location as well as instrument precision may result in improved correlations within certain body compositions.

Animals↗
PubMed2006

Thermodynamics constrains the evolution of insect population growth rates: "warmer is better".

Diverse biochemical and physiological adaptations enable different species of ectotherms to survive and reproduce in very different temperature regimes, but whether these adaptations fully compensate for the thermodynamically depressing effects of low temperature on rates of biological processes is debated. If such adaptations are fully compensatory, then temperature-dependent processes (e.g., digestion rate, population growth rate) of cold-adapted species will match those of warm-adapted species when each is measured at its own optimal temperature. Here we show that cold-adapted insect species have much lower maximum rates of population growth than do warm-adapted species, even when we control for phylogenetic relatedness. This pattern also holds when we use a structural-equation model to analyze alternative hypotheses that might otherwise explain this correlation. Thus, although physiological adaptations enable some insects to survive and reproduce at low temperatures, these adaptations do not overcome the "tyranny" of thermodynamics, at least for rates of population increase. Indeed, the sensitivity of population growth rates of insects to temperature is even greater than predicted by a recent thermodynamic model. Our findings suggest that adaptation to temperature inevitably alters the population dynamics of insects. This result has broad evolutionary and ecological consequences.

Adaptation, Physiological↗
PubMed2006

Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation.

Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-I, growth hormone, vascular endothelial growth factor, and proinflammatory Th2 cytokines, such as interleukin (IL)-1beta, IL-4, and IL-6, were elevated in A-ZIP/F-1 mice. Additionally, we examined multiple phosphorylated proteins (i.e., protein kinase B/Akt and ErbB2/HER-2 kinase) associated with cancer development. Results show that many of these phosphorylated proteins were activated specifically in the A-ZIP/F-1 skin but not in the wild-type skin. These findings suggest that adipokines are not required for the promotion of tumor development and thus contradict the epidemiologic data linking obesity to carcinogenesis. We postulate that insulin resistance and inflammation are responsible for the positive correlation with cancer observed in A-ZIP/F-1 mice.

Adiponectin↗
PubMed2006

Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice.

Treadmill running of approximately 0.9 km/day has had inconsistent effects on spontaneous intestinal polyp development in C57BL/6J-Apc(Min)/J (Min) mice; the amount of energy expenditure and/or a lack of hormonal changes could account for this variability. The purpose of this study was to examine the effects of a negative energy balance induced by voluntary wheel running on polyps, insulin-like growth factor-1 (IGF-1) and corticosterone in Min mice. Seven-week-old male Min mice were randomly assigned to control (CON, n = 23) or wheel running (EX, n = 24) conditions for a 10-week study period. All mice had water and AIN-76A diet ad libitum for the first approximately 3 weeks on study, after which the EX group was pair-fed to the CON group to maintain a negative energy balance due to the exercise. EX mice voluntarily ran 3.8 km/day (2.7-6.0 km/day) (median, interquartile range) and weighed less than CON mice throughout the study. More CON mice died before the end of the study versus EX mice (26 versus 0%, P < 0.01). CON mice had significantly more polyps versus EX mice (21.6 +/- 1.5 versus 16.9 +/- 2.0, P < 0.01; mean +/- SE), and daily running distance in EX was inversely correlated with total polyp number (r = -0.70, P < 0.01). Urinary corticosterone output (P < 0.01) and serum IGF-1 were significantly higher in EX than CON (P < 0.001); however, total polyp number was unrelated to corticosterone (r = 0.05, P = 0.84) and IGF-1 (r = -0.01, P = 0.93). In this study, a negative energy balance produced by wheel running exercise and restricted feeding decreased polyp burden in male Min mice and appeared to have a dose-response effect on polyp number. Although EX affected IGF-1 and corticosterone, neither marker was related to total polyp number.

Animals↗
PubMed2006

Active transportation increases adherence to activity recommendations.

BACKGROUND: Levels of physical activity (PA) contribute to health status and outcomes directly and indirectly via the effects of PA on obesity and other risk factors. Much past surveillance has focused on leisure-time physical activity (LTPA), but this may bias estimates of prevalence. This study explores inclusion of non-leisure-time walking and bicycling (NLTWB) used for transportation on the prevalence of adherence to PA recommendations and the magnitude of apparent disparities in adherence for California adults. METHODS: Results of the 2001 California Health Interview Survey, a large (n = 55,151) telephone survey were analyzed in 2005 using tabulation and logistic regression. RESULTS: Higher levels of LTPA were associated with youth, males, education, income, Pacific Islanders, and non-Hispanic (NH) whites. Inclusion of NLTWB reduced these differences for all five variables. The largest decreases in disparities in adherence occurred for race/ethnicity, education, and income, with decreases in adherence differences from approximately 18% to 7% for NH white vs Latino, approximately 27% to 16% for more than high school versus less than high school, and approximately 25% to 11% for more than 300% versus less than 100% of poverty level. Logistic regression comparing adherence gives similar results. For example, in respondents with more than high school education versus less than high school education (referent), the odds ratio changed from 2.23 (95% confidence interval [CI] = 2.0-2.4) to 1.7 (1.6-1.9) after the inclusion of NLTWB. CONCLUSIONS: Assessment of PA in multiple domains is required to understand differences in total levels of PA for people with different incomes, education levels, and racial/ethnic backgrounds. Inclusion of NLTWB reduces but does not eliminate disparities in adherence to recommended levels of PA.

Adolescent↗
PubMed2006

Relationship between urban sprawl and weight of United States youth.

BACKGROUND: Among United States youth there is an obesity epidemic with potential life-long health implications. To date, relationships between the built environment and body mass index (BMI) have not been evaluated for youth, and have not been evaluated longitudinally. OBJECTIVES: To determine if urban sprawl is associated with BMI for U.S. youth. METHODS: Using data from the 1997 National Longitudinal Survey of Youth (NLSY97), both cross-sectional and longitudinal analyses were conducted. Hierarchical modeling was used to relate characteristics of individuals, households, and places to BMI. Individual and household data were extracted from the NLSY97. The independent variable of interest was the county sprawl index, which was derived with principal components analyses from census and other data. RESULTS: In a cross-sectional analysis, the likelihood of U.S. adolescents (aged 12-17 years) being overweight or at risk of overweight (> or =85th percentile relative to the Centers for Disease Control growth charts) was associated with county sprawl (p=0.022). In another cross-sectional analysis, after controlling for sociodemographic and behavioral covariates, the likelihood of young adults (aged 18-23 years) being obese was also associated with county sprawl (p=0.048). By contrast, in longitudinal analyses, BMI growth curves for individual youth over the 7 years of NLSY97, and BMI changes for individual youth who moved between counties, were not related to county sprawl (although coefficient signs were as expected). CONCLUSIONS: Cross-sectional analyses suggest that urban form is associated with being overweight among U.S. youth. The strength of these relationships proved comparable to those previously reported for adults. Longitudinal analyses show no such relationship. It is unclear why these approaches give different results, but sample sizes, latent effects, and confounders may contribute.

Adolescent↗
PubMed2006

Physical activity and acculturation among adult Hispanics in the United States.

Understanding the prevalence and demographic correlates of physical activity is important for public health and epidemiological research. This analysis examines the association between acculturation and physical activity in a large (approximately 5,000) sample of Hispanic adults from the 2000 National Health Interview Survey. Scores for eight questions concerning language use were summed to produce an acculturation index. Factor analysis indicated that these questions assessed a single underlying construct. Self-reported adherence to recommendations concerning leisure time physical activity increased from 22. 6% in the least acculturated tertile to 47% in the most acculturated tertile. In contrast, prevalence of walking or bicycling for errands decreased from 25.2 to 18.2%, and prevalence of standing or walking during most of the day decreased from 82.8 to 65.6% as acculturation increased. Thus, patterns of physical activity associated with leisure versus nonleisure time differed among Hispanics with varying acculturation levels. Alternatively, cultural factors may have differential effects on responses to questions concerning leisure and nonleisure time physical activity. In either case, assessing both types of activity is important for monitoring and understanding Hispanic health behaviors and interpreting epidemiological studies that involve physical activity in Hispanics.

Acculturation↗
PubMed2005

Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer.

BACKGROUND: Reestablishment of metastasis suppressor gene expression may constitute a therapeutic strategy for high-risk breast cancer patients. We previously showed that medroxyprogesterone acetate (MPA), a progestin that has been tested as treatment for advanced breast cancer, elevates expression of the Nm23-H1 metastasis suppressor gene in hormone receptor-negative metastatic human breast carcinoma cell lines in vitro via a glucocorticoid receptor-based mechanism. Here, we tested whether MPA treatment inhibits metastatic colonization of a hormone receptor-negative breast cancer cell line in vivo. METHODS: We tested the soft-agar colony-forming efficiency of untransfected MDA-MB-231T human breast carcinoma cells and MDA-MB-231T cells transfected with antisense Nm23-H1 in the presence and absence of MPA. Pharmacokinetic studies were used to establish dose and injection schedules that led to MPA serum levels in mice similar to those achievable in humans. For in vivo studies, nude mice were injected intravenously with MDA-MB-231T cells. After 4 weeks, mice were randomized to control or MPA arms. Endpoints included incidence, number, and size of gross pulmonary metastases; Nm23-H1 protein expression in gross metastases; and side effects. All statistical tests were two-sided. RESULTS: MPA reduced colony formation of MDA-MB-231T cells by 40%-50% but had no effect on colony formation of Nm23-H1 antisense transfectants. Metastases developed in 100% (95% confidence interval [CI] = 78% to 100% and 77% to 100%, respectively) of control mice injected with MDA-MB-231T cells. In two independent experiments, only 73% (95% CI = 45% to 92%) and 64% (95% CI = 35% to 87%) of mice injected with 2 mg of MPA developed metastases. Mice injected with 2 mg of MPA showed reductions in the mean numbers, per mouse, of all metastases and of large (>3 mm) metastases (P = .04 and .013, respectively). Nm23-H1 was expressed at high levels in 43% of pulmonary metastases in MPA-treated mice but only 13% of metastases in untreated mice. Mice receiving at least 1-mg doses of MPA gained more weight than control-treated mice but exhibited no bone density alterations or abnormal mammary fat pad histology. CONCLUSION: Our preclinical results show that MPA appears to elevate Nm23-H1 metastasis suppressor gene expression, thereby reducing metastatic colonization. The data suggest a new use for an old agent in a molecularly defined subset of breast cancer patients.

Animals↗
PubMed2005

Dietary intake estimates in the National Health Interview Survey, 2000: methodology, results, and interpretation.

OBJECTIVES: To describe the implementation of the Multifactor Screener in the 2000 National Health Interview Survey (NHIS); to provide intake estimates for fruits and vegetables, fiber, and percentage of energy from fat by various demographic and behavioral characteristics; and to discuss the strengths and weaknesses of the method. DESIGN/SUBJECTS: The 2000 NHIS was conducted in 38,632 households in a clustered sample representative of the 48 contiguous states in the United States. The Cancer Control Module was administered to adults (18 years and older) and included 17 dietary intake questions. ANALYSES: After excluding individuals with missing data or unlikely values on the diet questions, we computed individual intake of servings of fruits and vegetables, percentage of energy from fat, and grams of fiber. We estimated median intakes and distributions of intakes using adjusted variance estimates. We present bivariate relationships between diet and demographics and diet and behavioral characteristics in almost 30,000 adults in the United States. RESULTS: In general, intakes of these dietary factors were closer to recommendations among well-educated individuals, those engaged in other healthful behaviors, and underweight and normal weight individuals. Latinos had higher intakes of fruits and vegetables (men: 6 servings; women: 4.8 servings) and fiber (men: 23 g; women: 17 g), and generally a lower percentage of energy intake from fat (men: 33.7%; women: 32.1%) than did non-Latino whites (men: 5.4 servings; women: 4.5 servings; men: 19 g; women: 14 g; men: 33.9%; women: 32.0%) and non-Latino blacks (men: 5.4 servings; women: 4.4 servings; men: 19 g; women: 13 g; men: 34.7%; women: 33.5%). The strengths and limitations of the short dietary assessment method are discussed. CONCLUSIONS: The Multifactor Screener in NHIS, when used in conjunction with external reference data, provides reasonable estimates for three dietary factors and suggests relationships between intakes and other characteristics that are consistent with other data. Thus, these NHIS estimates could provide useful national benchmarks for local surveys using the same instrument.

Adolescent↗
PubMed2004

Effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on serum hormones and bone characteristics in a preclinical tumor model for breast cancer.

PURPOSE: The purpose of this study was to evaluate and compare the effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on tumor growth, serum hormones, uterine weight, body composition, and bone characteristics in mice. EXPERIMENTAL DESIGN: Human estrogen-dependent breast cancer cells stably transfected with the aromatase gene (MCF-7CA cells) were inoculated in Matrigel subcutaneously into ovariectomized nude mice. This model represents postmenopausal breast cancer in many respects, including the fact that estrogen is no longer produced by the ovaries and is not under feedback regulation by gonadotropins. Mice that received subcutaneously implanted MCF-7CA cancer cells were then treated with tamoxifen or letrozole for 7 weeks. RESULTS: As reported previously, tumor growth was markedly inhibited by both tamoxifen (100 microg/day) and letrozole (10 microg/day). Tamoxifen treatment led to increased bone mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole had significantly smaller uteri than the controls and tamoxifen-treated mice. Letrozole did not affect BMD. There was no significant difference in systemic leptin and insulin-like growth factor I levels as a result of tamoxifen or letrozole treatment. CONCLUSIONS: Tamoxifen treatment inhibited breast cancer cell growth and increased BMD but caused uterine hypertrophy in this preclinical model of postmenopausal breast cancer. Letrozole inhibited tumor growth without inducing uterine hypertrophy. In addition, letrozole had no effect on BMD. These findings provide experimental evidence that letrozole is an effective and safe (in terms of risk of endometrial cancer risk and osteoporosis) alternative or complement to tamoxifen treatment for breast cancer.

Animals↗
PubMed2004

Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target.

Progress in cancer prevention research is being facilitated by the use of animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. Our lab, which focuses on nutrition (particularly energy balance/obesity) and molecular carcinogenesis, has shown in p53-/- mice that calorie restriction (CR) increases the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreases serum insulin-like growth factor (IGF)-1 and leptin levels, and induces apoptosis in immature (lymphoma-susceptible) thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and a one day/wk fast each significantly delay spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreases serum IGF-1 and leptin levels, even when begun late in life. We are presently comparing and combining CR and exercise (treadmill and running wheel) to further elucidate the relationships between energy balance, p53, and tumorigenesis in these models. Furthermore, we have capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a model for evaluating bladder cancer prevention approaches. Using this model, we have established that IGF-1 mediates many of the anti-cancer effects of CR. We are currently conducting oligonucleotide microarray studies to further characterize diet-gene interactions underlying the anti-cancer effects of CR and to determine which of the CR-responsive genes are IGF-1 dependent.

Animals↗
PubMed2003

Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms.

We evaluated the effects of diet on intestinal tumorigenesis in male Apc(Min) mice by comparing AIN-76A diet fed ad libitum (CON); calorie intake restricted by 40% of the CON (CR); diet high in olive oil and supplemented with freeze-dried fruit and vegetable extracts (OFV); and diet high in total fat (HF). Compared with CON, the frequency of intestinal polyps was reduced by 57% by CR (P < 0.001) and by 33% OFV diet (P = 0.04). Both effective interventions reduced total body weight, lean mass, and fat mass and increased daily urinary corticosterone output, but only CR reduced serum insulin-like growth factor I and leptin. We conclude that dietary interventions can partially offset genetic susceptibility to intestinal carcinogenesis.

Animals↗
PubMed2003

Patterns of health behavior in U.S. adults.

BACKGROUND: Associations between health-related behaviors are important for two reasons. First, disease prevention and health promotion depend on understanding both prevalence of health behaviors and associations among such behaviors. Second, behaviors may have synergistic effects on disease risk. METHODS: We document patterns of adherence to recommendations concerning five behaviors (physical activity, tobacco use, alcohol consumption, fruit and vegetable consumption, and dietary fat intake) in U.S. adults (n = 15,425) using data from the Third National Health and Nutrition Examination Survey. Division of individuals into categories associated with adherence or nonadherence to lifestyle recommendations results in 32 patterns of adherence/nonadherence. RESULTS: Proportions of U.S. adults with 21 of 32 behavior patterns characterized here deviated from proportions expected if health behaviors are independent of each other. The two extreme patterns, all adherence (5.9%) and all nonadherence (4.9%), were found in about double the proportion expected. Age, gender, race/ethnicity, education, and income were associated with a number of patterns, including the two extremes. CONCLUSIONS: This analysis of behavior patterns highlights population subgroups of public health importance, provides a benchmark for studies of multivariate associations between health behaviors, and supports a multidimensional model of health behavior.

Adult↗
PubMed2003

Exercise and intestinal polyp development in APCMin mice.

PURPOSE: Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise x sex interaction on polyp development and to begin to look at potential mechanisms. METHODS: Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m.min-1, 5% grade, 45 min.d-1, 5 d.wk-1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice. RESULTS: EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01). CONCLUSION: Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice.

Animals↗
PubMed2002

Respiratory cancer and exposure to man-made vitreous fibers: a systematic review.

BACKGROUND: Man-made vitreous fibers (MMVF's) have some structural features similar to those found in asbestos. This has lead to concern that exposure to MMVF's could increase the risk of respiratory cancer. METHODS: Bibliographic resources were used to identify 10 case-control and 10 cohort studies, which analyzed the relationship between exposure to MMVF's and cancer of the respiratory system. Standardized mortality ratio's (SMR's) were extracted from the cohort studies for a meta-analysis. RESULTS: A significant increase in SMR was observed for workers exposed to rock and glass wool, but not in workers exposed to glass filament. Meta-analysis of SMR's after stratification by fiber type resulted in aggregate estimates of risk of 1.23 (95% CI = 1.10-1.38), 1.08 (95% CI = 0.93-1.26), and 1.32 (95% CI = 1.15-1.52) for exposure to glass wool, glass filament, and rock wool, respectively. Some or all of the increased mortality could be attributed to tobacco use. CONCLUSIONS: The results highlight the difficulty of assessing small increases in risk of respiratory cancer potentially caused by occupational exposure in populations with high prevalence of tobacco use.

Air Pollutants, Occupational↗
PubMed2002

The association between urban form and physical activity in U.S. adults.

BACKGROUND: Physical inactivity is associated with multiple adverse health outcomes. Results from the transportation literature suggest that aspects of the urban environment may influence walking for transportation. In this paper we examine the association between a proxy measure of the urban environment and walking behavior. METHODS: We analyzed the association between home age and walking behavior in U.S. adults using data from the Third National Health and Nutrition Examination Survey. Logistic regression was used to estimate odds ratios and 95% confidence intervals and to control for the effects of gender, race/ethnicity, age, education level, household income, and activity limitations. RESULTS: Adults who lived in homes built before 1946 and from 1946 to 1973 were significantly more likely to walk 1+ miles > or =20 times per month than those who lived in homes built after 1973. This association was present among people living in urban and suburban counties, but absent among those living in rural counties. The association was also found in models that controlled for gender, race/ethnicity, age, education, income, and any health-related activity limitation. Other forms of leisure-time physical activity were not independently associated with home age. CONCLUSIONS: These results support the hypothesis that environmental variables influence walking frequency and suggest that home age may be a useful proxy for features of the urban environment that influence physical activity in the form of walking. Such proxy measures could facilitate testing ecologic models of health behavior using survey data.

Adult↗
PubMed2002

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice.

Heterozygous p53-deficient (p53(+/-)) mice, a potential model for human Li-Fraumeni Syndrome, have one functional allele of the p53 tumor suppressor gene. These mice are prone to spontaneous neoplasms, most commonly sarcoma and lymphoma; the median time to death of p53+/- mice is 18 months. We have shown previously that juvenile-onset calorie restriction (CR) to 60% of ad libitum (AL) intake delays tumor development in young p53-null (-/-) mice by a p53-independent and insulin-like growth factor 1 (IGF-1)-related mechanism. To determine whether CR is effective when started in adult p53-deficient mice, and to compare chronic CR with an intermittent fasting regimen, male p53+/- mice (7-10 months old, 31-32 mice/group) were randomly assigned to the following regimens: (i) AL (AIN-76A diet), (ii) CR to 60% of AL intake or (iii) 1 day/week fast. Food availability on non-fasting days was controlled to prevent compensatory over feeding. Relative to the AL group, CR significantly delayed (P = 0.001) the onset of tumors in adult mice, whereas the 1 day/week fast caused a moderate delay (P = 0.039). Substantial variation in longevity and maximum body weight within treatments was not correlated with variation in growth characteristics of individual mice. In a separate group of p53+/- mice treated for 4 weeks (n = five mice per treatment), plasma IGF-1 levels in CR versus AL mice were reduced by 20% (P < 0.01) and leptin levels were reduced by 71% (P < 0.01); fasted mice had intermediate levels of leptin and IGF-1. Our findings that CR or a 1 day/week fast suppressed carcinogenesis-even when started late in life in mice predestined to develop tumors due to decreased p53 gene dosage-support efforts to identify suitable interventions influencing energy balance in humans as a tool for cancer prevention.

Animals↗