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. 2019 Jan 8;29(1):221-228.e3.
doi: 10.1016/j.cmet.2018.08.011. Epub 2018 Sep 6.

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories

Affiliations

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories

Sarah J Mitchell et al. Cell Metab. .

Abstract

The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens. Like CR animals, MF mice ate quickly, imposing periods of extended daily fasting on themselves that produced significant improvements in morbidity and mortality compared with AL. These health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications for human health and clinical applicability.

Keywords: aging; caloric restriction; diet composition; dietary restriction; fasting; lifespan extension; longevity; time-restricted feeding.

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Conflict of interest statement

DECLARATION of INTERESTS

The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Effects of diet composition, energy density, and feeding patterns on bodyweight and metabolism.
(A-B) Trajectories of daily food intake per mouse over a period of 54 weeks expressed as grams (A) and kCal (B). N=45 mice (NIA-AL), n=44 (WIS-AL), n=40 (NIA-MF), n=41 (WIS-MF), n=59 (NIA-CR), n=62 (WIS-CR). See also Table S1. (C) Bodyweight trajectories over a period of 96 weeks. See also Figure S1. (D) Upper two panels, Respiratory Exchange Ratio (RER) at 41–42 weeks of age, n= 5–6. Bottom panel, Representative schematic of the study showing the estimated fasting time for each of the two diets, and three feeding paradigms across the study with respect to the Zeitgeber time, which is defined as any external clue, such as the 12:12 light:dark cycle, that synchronizes common biological rhythms in an organism. This schematic was inferred using experimental evidence from panel E. AL mice had constant access to food and so were not subjected to a daily fasting time. Arrow, start of the feeding (15:00); CHO, carbohydrate; FA, fatty acids. See also Figure S2. (E) Scatter plot depicting the duration of eating in MF and CR mice at 113 weeks of age. The duration of eating (in hours) is expressed as the median and [5–95% percentile]: NIA-MF, 14.63 [5.5–20.5]; NIA-CR, 4.875 [1.61–9.27]; WIS-MF, 11.75 [1–24]; and WIS-CR, 1 [0.5–3.57]. Every data point represents the average of two independent determinations for each mouse. Because the NIA-CR and WIS-CR datasets did not pass the Shapiro-Wilk normality test, the non-parametric Kruskal-Wallis test combined with Dunn’s multiple comparisons test was performed to establish statistical significance between groups. Variables with different letters are considered significantly different at P < 0.01. (F) Three hour fasting blood glucose (FBG) levels in 41-week-old mice, n= 7–8 mice per cohort. (G-I) Blood was collected from 42 week-old mice after an overnight (16 h) fasting, n=6–8/group. (G) Serum insulin. (H) HOMA-IR index. (I) Serum β-hydroxybutyrate. Data are represented as whisker plots (F-I), and analyzed using two-way ANOVA as a function of diet type (NIA and WIS diet) and feeding regimen (AL, MF, CR) with Tukey’s post hoc analysis. Variables with different letters are considered significantly different at P < 0.05. See also Table S2.
Figure 2.
Figure 2.. Implications of diet composition and feeding patterns on survival, tumor and nontumor pathologies.
(A) Kaplan-Meier survival curves for mice fed either NIA diet (left panel) or WIS diet (middle panel) ad libitum (AL), meal-fed (MF), or maintained on 30% calorie restriction (CR). (B) Survival curves when the two diet groups were combined. (C) Kaplan-Meier survival curves for mice on NIA or WIS diet fed either AL (left panel), MF (middle panel), or 30% CR (right panel). (A-C) N = 44–45 mice each for AL, n=40–41 mice for MF, and n=59–62 mice for CR. Stacked bars depict the relative composition of the NIA and WIS diets, expressed as % kcal, P=protein; F=fat; CHO, carbohydrates other than sucrose (S). See also Tables S1 and S3-S5.
Figure 3.
Figure 3.. Heatmap of the average score of pathologies in various tissues and organs in each experimental group of mice.
The number of animals tallied and percent to total study mice were as followed: NIA-AL, 33(73.3%); NIA-MF, 31(77.5%); NIA-CR, 42(71.2%); WIS-AL, 28(63.6%); WIS-MF, 30(73.2%); WIS-CR, 41(66.1%). For a detailed breakdown of the histopathology data, see Table S6.

Comment in

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