Calorie Restriction Extends Life Span— But Which Calories?

Heilbronn and Ravussin discuss the findings and implications of a study in PLoS Biology of caloric restriction in fruit flies. Are there implications for humans

Metabolic changes following a 1-year diet and exercise intervention in patients with type 2 diabetes

WSTĘP. Celem pracy było określenie związku między długotrwałą poprawą wskaźników obwodowej wrażliwości na insulinę [wskaźnik zużycia glukozy (GDR, glucose disposal rate)], stężenia glukozy na czczo i wolnych kwasów tłuszczowych (FFA, free fatty acids) a towarzyszącymi zmianami wagi, masy i dystrybucji tkanki tłuszczowej w wyniku wprowadzenia modyfikacji stylu życia u otyłych chorych na cukrzycę typu 2. MATERIAŁ I METODY. Zmierzono GDR, stężenie glukozy na czczo i FFA metodą klamry normoglikemicznej, a także masę i dystrybucję tkanki tłuszczowej, tłuszcz narządowy, rozmiar adipocytów za pomocą absorpcjometrii podwójnej energii promieniowania rentgenowskiego, tomografii komputerowej i biopsji tkanki tłuszczowej u 26 mężczyzn i 32 kobiet w próbie Look-AHEAD przed stosowaniem rocznej diety i ćwiczeń fizycznych, ukierunkowanych na utratę masy ciała, oraz po ich stosowaniu. WYNIKI. Masa ciała i stężenie glukozy na czczo znacznie się zmniejszyły (p < 0,0001), bardziej znamiennie u mężczyzn niż u kobiet (odpowiednio: -12% do -8% i -16% do -7%; p < 0,05), podczas gdy FFA zredukowano w czasie hiperinsulinemii, a GDR znamiennie wzrósł (p < 0,00001) u osób obojga płci (odpowiednio: -53% do -41% i 63% do 43%; p = NS). U mężczyzn stwierdzono korzystniejszą zmianę rozkładu tkanki tłuszczowej poprzez redukcję w większym stopniu górnych niż dolnych i głębszych niż płytszych magazynów tkanki tłuszczowej (p < 0,01). Spadki masy ciała i masy tkanki tłuszczowej poprzedzały poprawę GDR, ale nie stężenia glukozy na czczo lub FFA na czczo; jednak zmniejszenie FFA podczas hiperinsulinemii znacząco wpłynęło na polepszenie GDR. Tłuszcz wątrobowy był jedyną lokalizacją narządową, której zmiana wpływała niezależnie na zmianę wskaźników metabolicznych. WNIOSKI. U chorych na cukrzycę typu 2 poddanych rocznej zmianie stylu życia stwierdzono znaczącą poprawę GDR, stężenia glukozy na czczo, FFA i dystrybucji tkanki tłuszczowej. Natomiast najważniejszymi determinantami poprawy metabolizmu były ogólne zmiany masy ciała (masy tkanki tłuszczowej) i tłuszczu wątrobowego. (Diabet. Prakt. 2011; 11, 4: 142-152)OBJECTIVE. To characterize the relationships among long-term improvements in peripheral insulin sensitivity (glucose disposal rate, GDR), fasting glucose, and free fatty acids (FFA) and concomitant changes in weight and adipose tissue mass and distribution induced by lifestyle intervention in obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS. We measured GDR, fasting glucose, and FFAs during a euglycemic clamp and adipose tissue mass and distribution, organ fat, and adipocyte size by dual-energy X-ray absorptiometry, CT scan, and adipose tissue biopsy in 26 men and 32 women in the Look-AHEAD trial before and after 1 year of diet and exercise aimed at weight loss. RESULTS. Weight and fasting glucose decreased significantly (p < 0.0001) and significantly more in men than in women (-12 vs. -8% and -16 vs. -7%, respectively; p < 0.05), while FFAs during hyperinsulinemia decreased and GDR increased significantly (p < 0.00001) and similarly in both sexes (-53 vs. -41% and 63 vs. 43%; p = NS). Men achieved a more favorable fat distribution by losing more from upper compared with lower and from deeper compared with superficial adipose tissue depots (p < 0.01). Decreases in weight and adipose tissue mass predicted improvements in GDR but not in fasting glucose or fasting FFAs; however, decreases in FFAs during hyperinsulinemia significantly determined GDR improvements. Hepatic fat was the only regional fat measure whose change contributed independently to changes in metabolic variables. CONCLUSIONS. Patients with type 2 diabetes undergoing a 1-year lifestyle intervention had significant improvements in GDR, fasting glucose, FFAs and adipose tissue distribution. However, changes in overall weight (adipose tissue mass) and hepatic fat were the most important determinants of metabolic improvements. (Diabet. Prakt. 2011; 11, 4: 142-152

In Vitro Cellular Adaptations of Indicators of Longevity in Response to Treatment with Serum Collected from Humans on Calorie Restricted Diets

Calorie restriction (CR) produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF) and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL) animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals. Two pilot studies were undertaken to examine the effects of ADF and CR on indicators of health and longevity in humans. In this study, we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. Cells cultured in serum collected at the end of the dieting period were compared to cells cultured in serum collected at baseline (before the dieting period). Cells cultured in serum from ADF participants, showed a 20% increase in Sirt1 protein which correlated with reduced triglyceride levels. ADF serum also induced a 9% decrease in proliferation and a 25% increase in heat resistance. Cells cultured in serum from CR participants induced an increase in Sirt1 protein levels by 17% and a 30% increase in PGC-1α mRNA levels. This first in vitro study utilizing human serum to examine effects on markers of health and longevity in cultured cells resulted in increased stress resistance and an up-regulation of genes proposed to be indicators of increased longevity. The use of this in vitro technique may be helpful for predicting the potential of CR, ADF and other dietary manipulations to affect markers of longevity in humans

Overfeeding Reduces Insulin Sensitivity and Increases Oxidative Stress, without Altering Markers of Mitochondrial Content and Function in Humans

BACKGROUND: Mitochondrial dysfunction and increased oxidative stress are associated with obesity and type 2 diabetes. High fat feeding induces insulin resistance and increases skeletal muscle oxidative stress in rodents, but there is controversy as to whether skeletal muscle mitochondrial biogenesis and function is altered. METHODOLOGY AND PRINCIPAL FINDINGS: Forty (37±2 y) non-obese (25.6±0.6 kg/m2) sedentary men (n = 20) and women (n = 20) were overfed (+1040±100 kcal/day, 46±1% of energy from fat) for 28 days. Hyperinsulinemic-euglycemic clamps were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28 of overfeeding in a sub cohort of 26 individuals (13 men and 13 women) that consented to having all 3 biopsies performed. Weight increased on average in the whole cohort by 0.6±0.1 and 2.7±0.3 kg at days 3 and 28, respectively (P<0.0001, without a significant difference in the response between men and women (P = 0.4). Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5 mmol/min/kg FFM at day 28 of overfeeding (P = 0.03) without a significant difference between men and women (P = 0.4). Skeletal muscle protein carbonyls and urinary F2-isoprostanes increased with overfeeding (P,<.05). Protein levels of muscle peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1a) and subunits from complex I, II and V of the electron transport chain were increased at day 3 (all P<0.05) and returned to basal levels at day 28. No changes were detected in muscle citrate synthase activity or ex vivo CO2 production at either time point. CONCLUSIONS: Peripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was however increased, and may have contributed to the reduction in insulin sensitivity observed.Dorit Samocha-Bonet, Lesley V. Campbell, Trevor A. Mori, Kevin D. Croft, Jerry R. Greenfield, Nigel Turner and Leonie K. Heilbron

Metabolic and Behavioral Compensations in Response to Caloric Restriction: Implications for the Maintenance of Weight Loss

BackgroundMetabolic and behavioral adaptations to caloric restriction (CR) in free-living conditions have not yet been objectively measured.Methodology and principal findingsForty-eight (36.8+/-1.0 y), overweight (BMI 27.8+/-0.7 kg/m(2)) participants were randomized to four groups for 6-months;Controlenergy intake at 100% of energy requirements; CR: 25% calorie restriction; CR+EX: 12.5% CR plus 12.5% increase in energy expenditure by structured exercise; LCD: low calorie diet (890 kcal/d) until 15% weight reduction followed by weight maintenance. Body composition (DXA) and total daily energy expenditure (TDEE) over 14-days by doubly labeled water (DLW) and activity related energy activity (AREE) were measured after 3 (M3) and 6 (M6) months of intervention. Weight changes at M6 were -1.0+/-1.1% (CONTROL), -10.4+/-0.9% (CR), -10.0+/-0.8% (CR+EX) and -13.9+/-0.8% (LCD). At M3, absolute TDEE was significantly reduced in CR (-454+/-76 kcal/d) and LCD (-633+/-66 kcal/d) but not in CR+EX or controls. At M6 the reduction in TDEE remained lower than baseline in CR (-316+/-118 kcal/d) and LCD (-389+/-124 kcal/d) but reached significance only when CR and LCD were combined (-351+/-83 kcal/d). In response to caloric restriction (CR/LCD combined), TDEE adjusted for body composition, was significantly lower by -431+/-51 and -240+/-83 kcal/d at M3 and M6, respectively, indicating a metabolic adaptation. Likewise, physical activity (TDEE adjusted for sleeping metabolic rate) was significantly reduced from baseline at both time points. For control and CR+EX, adjusted TDEE (body composition or sleeping metabolic rate) was not changed at either M3 or M6.ConclusionsFor the first time we show that in free-living conditions, CR results in a metabolic adaptation and a behavioral adaptation with decreased physical activity levels. These data also suggest potential mechanisms by which CR causes large inter-individual variability in the rates of weight loss and how exercise may influence weight loss and weight loss maintenance.Trial registrationClinicalTrials.gov NCT00099151.Leanne M. Redman, Leonie K. Heilbronn, Corby K. Martin, Lilian de Jonge, Donald A. Williamson, James P. Delany, Eric Ravussin, for the Pennington CALERIE tea

Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans

BACKGROUND: Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. METHODS AND FINDINGS: The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, −135 ± 42 kcal/d, p = 0.002 and CREX, −117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (−0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (−0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. CONCLUSIONS: The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults

Metabolically protective cytokines adiponectin and fibroblast growth factor-21 are increased by acute overfeeding in healthy humans

Context: Circulating levels of metabolically protective and adverse cytokines are altered in obese humans and rodent models. However, it is not clear whether these cytokines are altered rapidly in response to over-nutrition, or as a later consequence of the obese state. Methods: Forty sedentary healthy individuals were examined prior to and at 3 and 28 days of high fat overfeeding (+1250 kCal/day, 45% fat). Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), adiposity, serum levels of adiponectin and fibroblast growth factor-21 (FGF21), fatty acid binding protein-4 (FABP4), lipocalin-2 and plasminogen activator factor-1 (PAI1) were assessed. Statistics were performed by repeated measures ANOVA. Results: Overfeeding increased weight, body fat and liver fat, fasting glucose, insulin and reduced insulin sensitivity by clamp (all P <0.05). Metabolically protective cytokines, adiponectin and FGF21 were increased at day 3 of overfeeding (P ≤0.001) and adiponectin was also elevated at day 28 (P=0.001). FABP4, lipocalin-2 and PAI-1 were not changed by overfeeding at either time point. Conclusion: Metabolically protective cytokines, adiponectin and FGF-21, were increased by over nutrition and weight gain in healthy humans, despite increases in insulin resistance. We speculate that this was in attempt to maintain glucose homeostasis in a state of nutritional excess. PAI-I, FABP4 and lipocalin 2 were not altered by overfeeding suggesting that changes in these cytokines may be a later consequence of the obese state.Leonie K. Heilbronn, Lesley V. Campbell, Aimin Xu, Dorit Samocha-Bone

A Time to Eat and A Time to Exercise

This Perspective for Progress provides a synopsis for the potential of time-restricted eating (TRE) to rescue some of the deleterious effects on circadian biology induced by our modern-day lifestyle. We provide novel insights into the comparative and potential complementary effects of TRE and exercise training on metabolic health