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Life Extension Magazine July 2010

Calorie Restriction

Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality.

AIMS: We hypothesized that subjects with a normal body mass index (BMI), but high body fat (BF) content [normal weight obesity (NWO)], have a higher prevalence of cardiometabolic dysregulation and are at higher risk for cardiovascular (CV) mortality. METHODS AND RESULTS: We analysed 6,171 subjects >20 years of age from the Third National Health and Nutrition Examination Survey (NHANES III) and the NHANES III mortality study, whose BMI was within the normal range (18.5-24.9 kg/m(2)), and who underwent a complete evaluation that included body composition assessment, blood measurements, and assessment of CV risk factors. Survival information was available for >99% of the subjects after a median follow-up of 8.8 years. We divided our sample using sex-specific tertiles of BF%. The highest tertile of BF (>23.1% in men and >33.3% in women) was labelled as NWO. When compared with the low BF group, the prevalence of metabolic syndrome in subjects with NWO was four-fold higher (16.6 vs. 4.8%, P < 0.0001). Subjects with NWO also had higher prevalence of dyslipidaemia, hypertension (men), and CV disease (women). After adjustment, women with NWO showed a significant 2.2-fold increased risk for CV mortality (HR = 2.2; 95% CI, 1.03-4.67) in comparison to the low BF group. CONCLUSION: Normal weight obesity, defined as the combination of normal BMI and high BF content, is associated with a high prevalence of cardiometabolic dysregulation, metabolic syndrome, and CV risk factors. In women, NWO is independently associated with increased risk for CV mortality.

Eur Heart J. 2010 Mar;31(6):737-46

Obesity, high energy intake, lack of physical activity, and the risk of kidney cancer.

The authors conducted a population-based case-control study of 810 cases with histologically confirmed incident kidney cancer and 3,106 controls to assess the effect of obesity, energy intake, and recreational physical activity on renal cell and non-renal cell cancer risk in Canada from 1994 to 1997. Compared with normal body mass index (BMI; 18.5 to <25.0 kg/m2), obesity (BMI, >or=30.0 kg/m2) was associated with multivariable-adjusted odds ratios (OR) and 95% confidence intervals (95% CI) of 2.57 (2.02-3.28) for renal cell cancer and 2.79 (1.70-4.60) for non-renal cell cancer. The OR (95% CI) associated with the highest quartiles of calorie intake was 1.30 (1.02-1.66) for renal cell cancer and 1.53 (0.92-2.53) for non-renal cell cancer. Compared with the lowest quartile of total recreational physical activity, the highest quartile of total activity was associated with an OR (95% CI) of 1.00 (0.78-1.28) and 0.79 (0.46-1.36) for the two subtypes. There were no apparent differences between men and women about these associations. The influence of obesity and physical activity on the risk of renal cell and non-renal cell cancer did not change by age, whereas the effect of excess energy intake was stronger among older people. No significant effect modifications of physical activity on BMI among both genders and of energy intake on BMI among men were observed, with a synergic effect of obesity and high energy intake on renal cell cancer risk found among women. This study suggests that obesity and excess energy intake are important etiologic risk factors for renal cell and non-renal cell cancer. The role of physical activity needs further investigation.

Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2453-60

Being overweight in midlife is associated with lower cognitive ability and steeper cognitive decline in late life.

BACKGROUND: Although an increasing body of evidence links being overweight in midlife with an increased risk for dementia in late life, no studies have examined the association between being overweight in midlife and cognitive ability in late life. Our aim was to examine the association between being overweight in midlife as measured by body mass index (BMI) and cognitive ability assessed over time. METHODS: Participants in the Swedish Adoption/Twin Study Aging were derived from a population-based sample. The participants completed baseline surveys in 1963 or 1973 (mean age 41.6 years, range 25-63 years). The surveys included questions about height, weight, diseases, and lifestyle factors. Beginning in 1986, the same individuals were assessed on neuropsychological tests every 3 years (except in 1995) until 2002. During the study period, 781 individuals who were 50 years and older (60% women) had at least one complete neuropsychological assessment. A composite score of general cognitive ability was derived from the cognitive test battery for each measurement occasion. RESULTS: Latent growth curve models adjusted for twinness showed that persons with higher midlife BMI scores had significantly lower general cognitive ability and significantly steeper longitudinal decline than their thinner counterparts. The association did not change substantially when persons who developed dementia during the study period were excluded from the analysis. CONCLUSIONS: Higher midlife BMI scores precede lower general cognitive ability and steeper cognitive decline in both men and women. The association does not seem to be mediated by an increased risk for dementia.

J Gerontol A Biol Sci Med Sci. 2010 Jan;65(1):57-62

Caloric restriction delays disease onset and mortality in rhesus monkeys.

Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.

Science. 2009 Jul 10;325(5937):201-4

Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals.

Calorie restriction (CR) delays the development of age-associated disease and increases lifespan in rodents, but the effects in humans remain uncertain. PURPOSE: Determine the effect of 6 months of CR with or without exercise on cardiovascular disease (CVD) risk factors and estimated 10-year CVD risk in healthy non-obese men and women. METHODS: Thirty-six individuals were randomized to one of three groups for 6 months: Control, 100% of energy requirements; CR, 25% calorie restriction; CR+EX, 12.5% CR+12.5% increase in energy expenditure via aerobic exercise. CVD risk factors were assessed at baseline, 3 and 6 months. RESULTS: After 6 months, CR and CR+EX lost approximately 10% of body weight. CR significantly reduced triacylglycerol (-31+/-15mg/dL) and factor VIIc (-10.7+/-2.3%). Similarly CR+EX reduced triacylglycerol (-22+/-8mg/dL) and additionally reduced LDL-C (-16.0+/-5.1mg/dL) and DBP (-4.0+/-2.1mmHg). In contrast, both triacylglycerol (24+/-14mg/dL) and factor VIIc (7.9+/-2.3%) were increased in the Control group. HDL-cholesterol was increased in all groups while hsCRP was lower in the Controls versus CR+EX. Estimated 10-year CVD risk significantly declined from baseline by 29% in CR (P<0.001) and 38% in the CR+EX (P<0.001) while remaining unchanged in the Control group. CONCLUSIONS: Based on combined favorable changes in lipid and blood pressure, caloric restriction with or without exercise that induces weight loss favorably reduces risk for CVD even in already healthy non-obese individuals.

Atherosclerosis. 2009 Mar;203(1):206-13

Caloric restriction improves memory in elderly humans.

Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m(2)) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < -0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects. Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity. Our study may help to generate novel prevention strategies to maintain cognitive functions into old age.

Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1255-60

Pulmonary complications in diabetes mellitus: the role of glycemic control.

Insulin deficiency induces an increase in blood glucose levels that, in long run, becomes toxic for many organs and systems. Microangiopathy and derangements in the immune function are known consequences of hyperglycemia, but the way in which these systemic alterations may affect pulmonary function has been scarcely investigated. Although confirmation from large clinical trials is still to come, the diabetic disease seems to hit the pulmonary microcirculation as any other organ by increasing vessel wall thickness and impairing gas exchange, which leads to a measurable loss of function and respiratory efficiency. In addition, a diabetic lung is more susceptible to low respiratory tract infections by atypical microorganisms and more likely to host severe episodes of pneumonia than a normal, non-diabetic lung. This is a review of current knowledge on the impact of diabetes mellitus in lung health. We have paid special attention to the role of metabolic control in preventing damage to the lung by sustained hyperglycemia.

Curr Drug Targets Inflamm Allergy. 2004 Dec;3(4):455-8

Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction.

Acute inflammation is usually a self-limited life preserving response, triggered by pathogens and/or traumatic injuries. This transient response normally leads to removal of harmful agents and to healing of the damaged tissues. In contrast, unchecked or chronic inflammation can lead to persistent tissue and organ damage by activated leukocytes, cytokines, or collagen deposition. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction without malnutrition exerts a potent anti-inflammatory effect. As individuals accumulate fat and their adipocytes enlarge, adipose tissue undergoes molecular and cellular alterations, macrophages accumulate, and inflammation ensues. Overweight/obese subjects have significantly higher plasma concentrations of C-reactive protein and several cytokines, including IL-6, IL-8, IL-18, and TNF-alpha. Experimental animals on a chronic CR regimen, instead, have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range. Recent data demonstrate that CR exerts a powerful anti-inflammatory effect also in non-human primates and humans. Multiple metabolic and neuroendocrine mechanisms are responsible for the CR-mediated anti-inflammatory effects, including reduced adiposity and secretion of pro-inflammatory adipokines, enhanced glucocorticoid production, reduced plasma glucose and advanced glycation end-product concentrations, increased parasympathetic tone, and increased ghrelin production. Measuring tissue specific effects of CR using genomic, proteomic, and metabolomic techniques in humans will foster the understanding of the complex biological processes involved in the anti-inflammatory and anti-aging effects of CR.

Exp Gerontol. 2009 Jan-Feb;44(1-2):41-5

Life long calorie restriction increases heat shock proteins and proteasome activity in soleus muscles of Fisher 344 rats.

Heat shock proteins (HSP’s) closely interact with 20S proteasome and have been shown to maintain catalytic activity, responsible for the prevention of protein aggregation. A decrease in both proteasome activity and heat shock proteins (HSP’s) has been observed with age. We investigated whether life-long calorie restriction (CR), a natural intervention, which prolongs life span, could prevent the age-associated decline in HSP’s and restore the proteolytic activity of the 20S proteasome in skeletal muscle. Hence, we investigated HSP’s and proteasome activity in the soleus muscle from 12-mo-old (Adult) and 26-28 mo old ad libitum fed (Old), and 26-28 mo old CR (Old-CR; fed 40% of ad libitum for their lifespan) male Fisher 344 rats. Trypsin-like proteasome activity in Old rats was significantly less than both Adult and Old-CR rats. Furthermore, no significant changes where found in chymotrypsin-like proteasome activity due to age or diet. Levels of HSP 72 and 25 were significantly less in Old animals when compared to both Adult and Old-CR rats. In contrast, HSP 90 was elevated in Old rats by 220% compared to adult animals and life-long calorie restriction caused a significant induction (150%) compared to age-matched ad libitum fed animals. Protein carbonyls were significantly elevated in Old when compared to Adult rats, but showed no significant decline due to life long CR. This study shows that HSP’s may be largely responsible for the restoration of the trypsin-like activity of the 20S proteasome with age. The large increase in HSP 90 is intriguing and further studies are required to elucidate its role in maintaining 20S proteasome function.

Exp Gerontol. 2005 Jan-Feb;40(1-2):37-42

Lifelong calorie restriction alleviates age-related oxidative damage in peripheral nerves.

Aging is associated with protein damage and imbalance in redox status in a variety of cells and tissues, yet little is known about the extent of age-related oxidative stress in the peripheral nervous system. Previously, we showed a drastic decline in the expression of glial and neuronal proteins in myelinated peripheral nerves with age, which is significantly ameliorated by lifelong calorie restriction. The age-related decline in functional molecules is associated with alterations in cellular protein homeostatic mechanisms, which could lead to a buildup of damaged, aggregated proteins. To determine the extent of oxidative damage within myelinated peripheral nerves, we studied sciatic nerves from rats of four different ages (8, 18, 29, and 38 months) maintained on an ad libitum or a 40% calorie-restricted diet. We found a prominent accumulation of polyubiquitinated substrates with age, which are associated with the conglomeration of distended lysosomes and lipofuscin adducts. The occurrence of these structures is notably less frequent within nerves of age-matched rodents kept on a lifelong reduced calorie diet. Markers for lipid peroxidation, inflammation, and immune cell infiltration are all elevated in nerves of ad libitum-fed rats, whereas food restriction is able to attenuate such deleterious processes with age. Together these results show that dietary restriction is an efficient means of defying age-related oxidative damage and maintaining a younger state in peripheral nerves.

Rejuvenation Res. 2010 Feb;13(1):65-74

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