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A nutritional memory effect counteracts benefits of dietary restriction in old mice.
Hahn O, Drews LF, Nguyen A, Tatsuta T, Gkioni L, Hendrich O, Zhang Q, Langer T, Pletcher S, Wakelam MJO, Beyer A, Grönke S, Partridge L.
Nat Metab. 2019 Nov;1(11):1059-1073. doi: 10.1038/s42255-019-0121-0. Epub 2019 Oct 21.
PMID: 31742247
Abstract
Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR switch experiment employing 800 mice, in which 24 months old female mice were switched from ad libitum (AL) to DR or vice versa. Strikingly, the switch from DR-to-AL acutely increases mortality, whereas the switch from AL-to-DR causes only a weak and gradual increase in survival, suggesting a memory of earlier nutrition. RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrate a largely refractory transcriptional and metabolic response to DR after AL feeding in fat tissue, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.

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Caloric restriction alters the hormonal profile and testicular metabolome resulting in alterations of sperm head morphology.
Martins AD, Jarak I, Morais T, Carvalho RA, Oliveira PF, Monteiro MP, Alves MG.
Am J Physiol Endocrinol Metab. 2019 Nov 26. doi: 10.1152/ajpendo.00355.2019. [Epub ahead of print]
PMID: 31770015
Abstract
Energy homeostasis is crucial for all physiological processes. Thus, when there is low energy intake, negative health effects may arise, including in reproductive function. We propose to study whether caloric restriction (CR) changes testicular metabolic profile and ultimately sperm quality.Male Wistar rats (n=12) were randomized into a CR group fed with 30% less calories than weight matched ad libitum fed animals (control group). Circulating hormonal profile, testicular glucagon like peptide-1 (GLP-1), ghrelin and leptin receptors expression and sperm parameters were analyzed. Testicular metabolites abundance and glycolysis-related enzymes were studied by NMR and Western blot, respectively. Oxidative stress markers were analyzed in testicular tissue and spermatozoa. Expression of mitochondrial complexes and mitochondrial biogenesis in testis were determined. CR induced changes in body weight along with altered GLP-1, ghrelin and leptin circulating levels. In testis, CR led to changes in receptors expression that followed those of the hormone levels; modified testicular metabolome particularly amino acids content; decreased oxidative stress-induced damage in testis and spermatozoa though increasing sperm head defects.In sum, CR induced changes in body weight, altering circulating hormonal profile, testicular metabolome and increasing sperm head defects. Ultimately, our data highlights that conditions of CR may compromise male fertility.
KEYWORDS:
Caloric Restriction; Hormonal Profile; Male Fertility; Testicular Bioenergetics; Testis

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On 11/20/2019 at 12:28 PM, AlPater said:

A nutritional memory effect counteracts benefits of dietary restriction in old mice.
Hahn O, Drews LF, Nguyen A, Tatsuta T, Gkioni L, Hendrich O, Zhang Q, Langer T, Pletcher S, Wakelam MJO, Beyer A, Grönke S, Partridge L.
Nat Metab. 2019 Nov;1(11):1059-1073. doi: 10.1038/s42255-019-0121-0. Epub 2019 Oct 21.
PMID: 31742247
Abstract
Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR switch experiment employing 800 mice, in which 24 months old female mice were switched from ad libitum (AL) to DR or vice versa. Strikingly, the switch from DR-to-AL acutely increases mortality, whereas the switch from AL-to-DR causes only a weak and gradual increase in survival, suggesting a memory of earlier nutrition. RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrate a largely refractory transcriptional and metabolic response to DR after AL feeding in fat tissue, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.

This will be of great concern to those of us who started CR relatively late in their lives. By all means keep us posted, Al!

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Calorie restriction slows age-related microbiota changes in an Alzheimer's disease model in female mice.
Cox LM, Schafer MJ, Sohn J, Vincentini J, Weiner HL, Ginsberg SD, Blaser MJ.
Sci Rep. 2019 Nov 29;9(1):17904. doi: 10.1038/s41598-019-54187-x.
PMID: 31784610
https://www.nature.com/articles/s41598-019-54187-x.pdf
Abstract
Alzheimer's disease (AD) affects an estimated 5.8 million Americans, and advanced age is the greatest risk factor. AD patients have altered intestinal microbiota. Accordingly, depleting intestinal microbiota in AD animal models reduces amyloid-beta (Aβ) plaque deposition. Age-related changes in the microbiota contribute to immunologic and physiologic decline. Translationally relevant dietary manipulations may be an effective approach to slow microbiota changes during aging. We previously showed that calorie restriction (CR) reduced brain Aβ deposition in the well-established Tg2576 mouse model of AD. Presently, we investigated whether CR alters the microbiome during aging. We found that female Tg2576 mice have more substantial age-related microbiome changes compared to wildtype (WT) mice, including an increase in Bacteroides, which were normalized by CR. Specific gut microbiota changes were linked to Aβ levels, with greater effects in females than in males. In the gut, Tg2576 female mice had an enhanced intestinal inflammatory transcriptional profile, which was reversed by CR. Furthermore, we demonstrate that Bacteroides colonization exacerbates Aβ deposition, which may be a mechanism whereby the gut impacts AD pathogenesis. These results suggest that long-term CR may alter the gut environment and prevent the expansion of microbes that contribute to age-related cognitive decline.

xx

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Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss.
Cintron-Colon R, Johnson CW, Montenegro-Burke JR, Guijas C, Faulhaber L, Sanchez-Alavez M, Aguirre CA, Shankar K, Singh M, Galmozzi A, Siuzdak G, Saez E, Conti B.
Curr Biol. 2019 Nov 5. pii: S0960-9822(19)31367-3. doi: 10.1016/j.cub.2019.10.027. [Epub ahead of print]
PMID: 31786059
Abstract
Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost that is sustainable if adequate calorie intake is maintained. When nutrients are scarce or experimentally reduced such as during calorie restriction (CR), endotherms can reduce energy expenditure by lowering Tb [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR is associated with increased hypothalamic levels of the endogenous opioid Leu-enkephalin, which is derived from the KOR agonist precursor dynorphin [11]. Pharmacological inhibition of KOR, but not of the delta or the mu opioid receptor subtypes, fully blocked CR-induced hypothermia and increased weight loss during CR independent of calorie intake. Similar results were seen with DIO mice subjected to CR. In contrast, inhibiting KOR did not change Tb in animals fed ad libitum (AL). Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, whereas chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nucleus lowered Tb. These data indicate that KOR signaling is a pivotal regulator of energy homeostasis and can affect body weight during dieting by modulating Tb and energy expenditure.
KEYWORDS:
body temperature; body weight; calorie restriction; dieting; dynorphin; energy expenditure; energy homeostasis; hypothermia; kappa opioid receptor

Negative genetic correlation between longevity and its hormetic extension by dietary restriction in Drosophila melanogaster.
Gomez FH, Stazione L, Sambucetti P, Norry FM.
Biogerontology. 2019 Nov 30. doi: 10.1007/s10522-019-09852-z. [Epub ahead of print]
PMID: 31786681
Abstract
Longevity is a highly malleable trait which is influenced by many genetic and environmental factors including nutrition. Mild stress of dietary restriction (DR) is often beneficial by extending longevity in many organisms. Here, DR-induced effects on longevity were tested for genetic variation in a set of recombinant inbred lines (RIL) in D. melanogaster. Genetic variability was significant in the longevity response following a DR-treatment across RIL, with detrimental effects in several RIL but beneficial effects in other RIL. One quantitative trait locus (QTL) was consistently significant in the middle of chromosome 2 for DR-induced changes in longevity, including hormesis (an increase in longevity by DR). Another QTL co-localized with a previously found QTL for starvation resistance in females. Several other QTL were also significant on most chromosomal arms. Longevity in controls was negatively correlated to DR effects across RIL for longevity in females, the sex showing higher DR-induced hormesis. This negative genetic correlation highlights the importance to further investigate the effects of genetic variation in the strength of DR-induced hormesis in longevity and its sex-specificity.
KEYWORDS:
Heat-induced hormesis; Hormesis; Quantitative trait loci; Sex-specificity; Starvation

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Protein Intake Greater than the RDA Differentially Influences Whole-Body Lean Mass Responses to Purposeful Catabolic and Anabolic Stressors: A Systematic Review and Meta-analysis.
Hudson JL, Wang Y, Bergia Iii RE, Campbell WW.
Adv Nutr. 2019 Dec 3. pii: nmz106. doi: 10.1093/advances/nmz106. [Epub ahead of print]
PMID: 31794597
Abstract
Under stressful conditions such as energy restriction (ER) and physical activity, the RDA for protein of 0.8 g · kg-1 · d-1 may no longer be an appropriate recommendation. Under catabolic or anabolic conditions, higher protein intakes are proposed to attenuate the loss or increase the gain of whole-body lean mass, respectively. No known published meta-analysis compares protein intakes greater than the RDA with intakes at the RDA. Therefore, we conducted a systematic review and meta-analysis to assess the effects of protein intakes greater than the RDA, compared with at the RDA, on changes in whole-body lean mass. Three researchers independently screened 1520 articles published through August 2018 using the PubMed, Scopus, CINAHL, and Cochrane databases, with additional articles identified in published systematic review articles. Randomized, controlled, parallel studies ≥6 wk long with apparently healthy adults (≥19 y) were eligible for inclusion. Data from 18 studies resulting in 22 comparisons of lean mass changes were included in the final overall analysis. Among all comparisons, protein intakes greater than the RDA benefitted changes in lean mass relative to consuming the RDA [weighted mean difference (95% CI): 0.32 (0.01, 0.64) kg, n = 22 comparisons]. In the subgroup analyses, protein intakes greater than the RDA attenuated lean mass loss after ER [0.36 (0.06, 0.67) kg, n = 14], increased lean mass after resistance training (RT) [0.77 (0.23, 1.31) kg, n = 3], but did not differentially affect changes in lean mass [0.08 (-0.59, 0.75) kg, n = 7] under nonstressed conditions (no ER + no RT). Protein intakes greater than the RDA beneficially influenced changes in lean mass when adults were purposefully stressed by the catabolic stressor of dietary ER with and without the anabolic stressor of RT. The RDA for protein is adequate to support lean mass in adults during nonstressed states.
KEYWORDS:
adults; body composition; exercise; fat-free mass; health; weight loss

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Timing of Calorie Restriction in Mice Impacts Host Metabolic Phenotype with Correlative Changes in Gut Microbiota.
Zhang L, Xue X, Zhai R, Yang X, Li H, Zhao L, Zhang C.
mSystems. 2019 Dec 3;4(6). pii: e00348-19. doi: 10.1128/mSystems.00348-19.
PMID: 31796564
https://msystems.asm.org/content/msys/4/6/e00348-19.full.pdf
Abstract
Calorie restriction (CR) is accompanied by self-imposed daily restriction of food intake and an extended fasting period between meals. The impact of restricting feeding to the dark or light phase on the effects of CR remains elusive. Here, light-fed CR mice showed physiological changes, such as muscle loss, concomitant with changes in the gut microbiota structure and composition. After switching to ad libitum access to food, light-fed mice had a period of food-craving behavior and short-lived physiological changes, while dark-fed mice displayed lasting changes in fat accumulation, glucose metabolism, intestinal barrier function, and systemic inflammatory markers. Moreover, the gut microbiota was modulated by when the food was consumed, and the most abundant Lactobacillus operational taxonomic unit (OTU) promoted by CR was enhanced in dark-fed mice. After switching to ad libitum feeding, the gut microbiota of dark-fed mice returned to the state resembling that of mice fed normal chow ad libitum, but that of light-fed mice was still significantly different from the other two groups. Together, these data indicate that for CR, restricting food consumption to the active phase brought better metabolic phenotype associated with potentially beneficial structural shifts in the gut microbiota.IMPORTANCE Aberrant feeding patterns whereby people eat more frequently throughout the day and with a bias toward late-night eating are prevalent in society today. However, whether restriction of food to daytime in comparison to nighttime, coupled with restricted calorie intake, can influence gut microbiota, metabolism, and overall health requires further investigation. We surveyed the effects of the shift in feeding time on gut microbiota and metabolic phenotype in calorie-restricted mice and found that avoiding eating during the rest period may generate more beneficial effects in mice. This work strengthens the evidence for using "when to eat" as an intervention to improve health during calorie restriction.
KEYWORDS:
anti-inflammation; calorie restriction; gut microbiota; shift of feeding time

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Dietary Interventions for Gout and Effect on Cardiovascular Risk Factors: A Systematic Review.
Vedder D, Walrabenstein W, Heslinga M, de Vries R, Nurmohamed M, van Schaardenburg D, Gerritsen M.
Nutrients. 2019 Dec 4;11(12). pii: E2955. doi: 10.3390/nu11122955. Review.
PMID: 31817107
[pdf availed free from Medline abstract.]
Abstract
Gout is one of the most prevalent inflammatory rheumatic disease. It is preceded by hyperuricemia and associated with an increased risk for cardiovascular disease, both related to unhealthy diets. The objective of this systematic review is to better define the most appropriate diet addressing both disease activity and traditional cardiovascular risk factors in hyperuricemic patients. We included clinical trials with patients diagnosed with hyperuricemia or gout, investigating the effect of dietary interventions on serum uric acid (SUA) levels, gout flares and-if available-cardiovascular risk factors. Eighteen articles were included, which were too heterogeneous to perform a meta-analysis. Overall, the risk of bias of the studies was moderate to high. We distinguished four groups of dietary interventions: Calorie restriction and fasting, purine-low diets, Mediterranean-style diets, and supplements. Overall, fasting resulted in an increase of SUA, whilst small (SUA change +0.3 to -2.9 mg/dL) but significant effects were found after low-calorie, purine-low, and Mediterranean-style diets. Studies investigating the effect on cardiovascular risk factors were limited and inconclusive. Since Mediterranean-style diets/DASH (Dietary Approach to Stop Hypertension) have shown to be effective for the reduction of cardiovascular risk factors in other at-risk populations, we recommend further investigation of such diets for the treatment of gout.
KEYWORDS:
DASH; Mediterranean diet; blood pressure; cardiovascular disease; cholesterol; diet; gout; hyperuricemia; metabolic syndrome x; purine low die

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Modulation of liver glucose output by free or restricted feeding in the adult rat is independent of litter size.
Yamada LA, Mariano IR, Sabino VLR, Rabassi RS, Bataglini C, Azevedo SCSF, Branquinho NTD, Kurauti MA, Garcia RF, Pedrosa MMD.
Nutr Metab (Lond). 2019 Dec 12;16:86. doi: 10.1186/s12986-019-0413-0. eCollection 2019.
PMID: 31857820
Abstract
BACKGROUND:
Caloric restriction since birth changes glucose metabolism by the liver in overnight-fasted rats to a fed-like pattern, in which glucose output is large but gluconeogenesis is negligible. It was investigated whether these changes could be a residual effect of the nutritional condition during lactation and what could be the mechanism of such change.
METHODS:
Newborn Wistar rat pups were arranged in litters of 6 or 12 (G6 and G12). After weaning, the male pups were divided in: G6L and G12 L, fed freely until the age of 90 days (freely-fed groups); G6R and G12R, given 50% of the GL ingestion (food-restricted groups) until 90 days of age; G6RL and G12RL, given 50% of the GL ingestion until 60 days of age and fed freely until 90 days of age (refed groups). The experimental protocols were carried out at the age of 90 days after overnight fasting. Pairs of groups were compared through t test; other statistical comparisons were made with one-way ANOVA with Tukey post hoc text.
RESULTS:
Caloric restriction was effective in decreasing body and fat weights, total cholesterol and LDL. These effects were totally or partially reversed after 30 days of refeeding (groups GRL). During liver perfusion, the high glucose output of the GRs was further enhanced by adrenaline (1 μM), but not by lactate infusion. In contrast, in groups G6L, G12 L, G6RL and G12RL glycogenolysis (basal and adrenaline-stimulated glucose output) was low and gluconeogenesis from lactate was significant. A twofold increase in liver content of PKA in group G6R suggests that liver sensitivity to glucagon and adrenaline was higher because of caloric restriction, resulting in enhanced glucose output.
CONCLUSIONS:
As glucose output was not affected by litter size, liver glucose metabolism in the adult rat, in contrast to other metabolic processes, is not a programmed effect of the nutritional condition during lactation. In addition, the increased expression of PKA points to a higher sensitivity of the animals under caloric restriction to glycogenolytic hormones, a relevant condition for glucose homeostasis during fasting.
KEYWORDS:
Caloric restriction; Gluconeogenesis; Glycogenolysis; Litter size; Liver metabolism; Metabolic programming

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Mechanisms of Calorie Restriction: A Review of Genes Required for the Life-Extending and Tumor-Inhibiting Effects of Calorie Restriction.
Komatsu T, Park S, Hayashi H, Mori R, Yamaza H, Shimokawa I.
Nutrients. 2019 Dec 16;11(12). pii: E3068. doi: 10.3390/nu11123068. Review.
PMID: 31888201
bstract
This review focuses on mechanisms of calorie restriction (CR), particularly the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis as an evolutionary conserved signal that regulates aging and lifespan, underlying the effects of CR in mammals. Topics include (1) the relation of the GH-IGF-1 signal with chronic low-level inflammation as one of the possible causative factors of aging, that is, inflammaging, (2) the isoform specificity of the forkhead box protein O (FoxO) transcription factors in CR-mediated regulation of cancer and lifespan, (3) the role for FoxO1 in the tumor-inhibiting effect of CR, (4) pleiotropic roles for FoxO1 in the regulation of disorders, and (5) sirtuin (Sirt) as a molecule upstream of FoxO. From the evolutionary view, the necessity of neuropeptide Y (Npy) for the effects of CR and the pleiotropic roles for Npy in life stages are also emphasized. Genes for mediating the effects of CR and regulating aging are context-dependent, particularly depending on nutritional states.
KEYWORDS:
FoxO transcription factor; calorie restriction; neuropeptide Y; pleiotropy of CR genes; sirtuin

Factors that affect the translation of dietary restriction into a longer life.
von Frieling J, Roeder T.
IUBMB Life. 2019 Dec 30. doi: 10.1002/iub.2224. [Epub ahead of print] Review.
PMID: 31889425
Abstract
Nutritional interventions, such as dietary or calorie restriction, are known to have a variety of health-promoting effects. The most impressive are the direct effects on life expectancy, which have been reproduced in many animal models. A variety of dietary restriction protocols have been described, which differ either in their macronutrient composition or in the time window for consumption. Mechanistically, the effects of dietary restriction are mediated mainly through signaling pathways that have central roles in the maintenance of cellular energy balance. Among these, target of rapamycin and insulin signaling appear to be the most important. Such nutritional interventions can have their effects in two different ways: either by direct interaction with the metabolism of the host organism, or by modulating the composition and performance of its endogenous microbiome. Various dietary restriction regimens have been identified that significantly alter the microbiome and thus profoundly modulate host metabolism. This review aims to discuss the mechanisms by which dietary restriction can affect life expectancy, and in particular the role of the microbiome.
KEYWORDS:
C. elegans; Drosophila; TOR; caloric restriction; dietary restriction; insulin; microbiota

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Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction.
Jiang Y, Yan F, Feng Z, Lazarovici P, Zheng W.
Cells. 2019 Dec 31;9(1). pii: E100. doi: 10.3390/cells9010100. Review.
PMID: 31906091
Abstract
Dietary restriction (DR), which is defined as a reduction of particular or total nutrient intake without causing malnutrition, has been proved to be a robust way to extend both lifespan and health-span in various species from yeast to mammal. However, the molecular mechanisms by which DR confers benefits on longevity were not yet fully elucidated. The forkhead box O transcription factors (FOXOs), identified as downstream regulators of the insulin/IGF-1 signaling pathway, control the expression of many genes regulating crucial biological processes such as metabolic homeostasis, redox balance, stress response and cell viability and proliferation. The activity of FOXOs is also mediated by AMP-activated protein kinase (AMPK), sirtuins and the mammalian target of rapamycin (mTOR). Therefore, the FOXO-related pathways form a complex network critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis and to support physiological aging. In this review, we will focus on the role of FOXOs in different DR interventions. As different DR regimens or calorie (energy) restriction mimetics (CRMs) can elicit both distinct and overlapped DR-related signaling pathways, the benefits of DR may be maximized by combining diverse forms of interventions. In addition, a better understanding of the precise role of FOXOs in different mechanistic aspects of DR response would provide clear cellular and molecular insights on DR-induced increase of lifespan and health-span.
KEYWORDS:
AMPK; FOXO; calorie restriction mimetics; dietary restriction; insulin/IGF-1 signaling pathway; longevity; mTOR; sirtuins

Energy Restriction and Colorectal Cancer: A Call for Additional Research.
Castejón M, Plaza A, Martinez-Romero J, Fernandez-Marcos PJ, Cabo R, Diaz-Ruiz A.
Nutrients. 2020 Jan 1;12(1). pii: E114. doi: 10.3390/nu12010114. Review.
PMID: 31906264
Abstract
: Colorectal cancer has the second highest cancer-related mortality rate, with an estimated 881,000 deaths worldwide in 2018. The urgent need to reduce the incidence and mortality rate requires innovative strategies to improve prevention, early diagnosis, prognostic biomarkers, and treatment effectiveness. Caloric restriction (CR) is known as the most robust nutritional intervention that extends lifespan and delays the progression of age-related diseases, with remarkable results for cancer protection. Other forms of energy restriction, such as periodic fasting, intermittent fasting, or fasting-mimicking diets, with or without reduction of total calorie intake, recapitulate the effects of chronic CR and confer a wide range of beneficial effects towards health and survival, including anti-cancer properties. In this review, the known molecular, cellular, and organismal effects of energy restriction in oncology will be discussed. Energy-restriction-based strategies implemented in colorectal models and clinical trials will be also revised. While energy restriction constitutes a promising intervention for the prevention and treatment of several malignant neoplasms, further investigations are essential to dissect the interplay between fundamental aspects of energy intake, such as feeding patterns, fasting length, or diet composition, with all of them influencing health and disease or cancer effects. Currently, effectiveness, safety, and practicability of different forms of fasting to fight cancer, particularly colorectal cancer, should still be contemplated with caution.
KEYWORDS:
colorectal cancer models; energy restriction; metabolism

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Promoting healthspan and lifespan with caloric restriction in primates.
Pifferi F, Terrien J, Perret M, Epelbaum J, Blanc S, Picq JL, Dhenain M, Aujard F.
Commun Biol. 2019 Mar 15;2(1):107. doi: 10.1038/s42003-019-0348-z. No abstract available.
PMID: 31924947
https://www.nature.com/articles/s42003-019-0348-z.pdf

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Lifestyle vs. pharmacological interventions for healthy aging.
Furrer R, Handschin C.
Aging (Albany NY). 2020 Jan 10:5-7. doi: 10.18632/aging.102741. [Epub ahead of print] No abstract available.
PMID: 31937689
https://www.aging-us.com/article/102741/text
KEYWORDS:
aging; caloric restriction; exercise; metformin; rapamycin

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Deletion of Nrf2 shortens lifespan in C57BL6/J male mice but does not alter the health and survival benefits of caloric restriction.
Pomatto LCD, Dill T, Carboneau B, Levan S, Kato J, Mercken EM, Pearson KJ, Bernier M, de Cabo R.
Free Radic Biol Med. 2020 Jan 14. pii: S0891-5849(19)32365-2. doi: 10.1016/j.freeradbiomed.2020.01.005. [Epub ahead of print]
PMID: 31953150
https://sci-hub.tw/10.1016/j.freeradbiomed.2020.01.005
Abstract
Caloric restriction (CR) is the leading non-pharmaceutical dietary intervention to improve health- and lifespan in most model organisms. A wide array of cellular pathways is induced in response to CR and CR-mimetics, including the transcriptional activator Nuclear factor erythroid-2-related factor 2 (Nrf2), which is essential in the upregulation of multiple stress-responsive and mitochondrial enzymes. Nrf2 is necessary in tumor protection but is not essential for the lifespan extending properties of CR in outbred mice. Here, we sought to study Nrf2-knockout (KO) mice and littermate controls in male C57BL6/J, an inbred mouse strain. Deletion of Nrf2 resulted in shortened lifespan compared to littermate controls only under ad libitum conditions. CR-mediated lifespan extension and physical performance improvements did not require Nrf2. Metabolic and protein homeostasis and activation of tissue-specific cytoprotective proteins were dependent on Nrf2 expression. These results highlight an important contribution of Nrf2 for normal lifespan and stress response.

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Context-Dependent Roles for SIRT2 and SIRT3 in Tumor Development Upon Calorie Restriction or High Fat Diet.
Ahmed MA, O'Callaghan C, Chang ED, Jiang H, Vassilopoulos A.
Front Oncol. 2020 Jan 8;9:1462. doi: 10.3389/fonc.2019.01462. eCollection 2019.
PMID: 31970087
Abstract
Calorie restriction (CR) is considered one of the most robust ways to extend life span and reduce the risk of age-related diseases, including cancer, as shown in many different organisms, whereas opposite effects have been associated with high fat diets (HFDs). Despite the proven contribution of sirtuins in mediating the effects of CR in longevity, the involvement of these nutrient sensors, specifically, in the diet-induced effects on tumorigenesis has yet to be elucidated. Previous studies focusing on SIRT1, do not support a critical role for this sirtuin family member in CR-mediated cancer prevention. However, the contribution of other family members which exhibit strong deacetylase activity is unexplored. To fill this gap, we aimed at investigating the role of SIRT2 and SIRT3 in mediating the anti and pro-tumorigenic effect of CR and HFD, respectively. Our results provide strong evidence supporting distinct, context-dependent roles played by these two family members. SIRT2 is indispensable for the protective effect of CR against tumorigenesis. On the contrary, SIRT3 exhibited oncogenic properties in the context of HFD-induced tumorigenesis, suggesting that SIRT3 inhibition may mitigate the cancer-promoting effects of HFD. Given the different functions regulated by SIRT2 and SIRT3, unraveling downstream targets/pathways involved may provide opportunities to develop new strategies for cancer prevention.
KEYWORDS:
SIRT2; SIRT3; aging; calorie restriction; cancer; high fat diet

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Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver.
Gensous N, Ravaioli F, Pirazzini C, Gramignoli R, Ellis E, Storci G, Capri M, Strom S, Laconi E, Franceschi C, Garagnani P, Marongiu F, Bacalini MG.
Nutrients. 2020 Jan 21;12(2). pii: E277. doi: 10.3390/nu12020277.
PMID: 31973116
Abstract
A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5' of the 18S and the 5' of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.
KEYWORDS:
DNA methylation; aging; caloric restriction; liver; ribosomal RNA

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Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity.
Tang D, Zeng T, Wang Y, Cui H, Wu J, Zou B, Tao Z, Zhang L, Garside GB, Tao S.
Gut Microbes. 2020 Jan 26:1-21. doi: 10.1080/19490976.2020.1714401. [Epub ahead of print]
PMID: 31983316
Abstract
Methotrexate (MTX) is a typical chemotherapeutic drug that is widely used in the treatment of various malignant diseases as well as autoimmune diseases, with gastrointestinal toxicity being its most prominent complication which could have a significant effect on the prognosis of patients. Yet effective ways to alleviate such complications remains to be explored. Here we show that 30% dietary restriction (DR) for 2 weeks dramatically increased the survival rate of 2-month-old female mice after lethal-dose MTX exposure. DR significantly reduced intestinal inflammation, preserved the number of basal crypt PCNA-positive cells, and protected the function of intestinal stem cells (ISCs) after MTX treatment. Furthermore, ablating intestinal microbiota by broad-spectrum antibiotics completely eliminated the protective effect achieved by DR. 16S rRNA gene deep-sequencing analysis revealed that short-term DR significantly increased the Lactobacillus genus, with Lactobacillus rhamnosus GG gavage partially mimicking the rescue effect of DR on the intestines of ad libitum fed mice exposed to lethal-dose MTX. Together, the current study reveals that DR could be a highly effective way to alleviate the lethal injury in the intestine after high-dose MTX treatment, which is functionally mediated by increasing the protective intestinal microbiota taxa in mice. Keywords: Dietary restriction, Methotrexate, Gut microbiota, Intestinal stem cells, intestinal toxicity.
KEYWORDS:
Dietary restriction; gut microbiota; intestinal stem cells; intestinal toxicity; methotrexate

UW Madison study shows calorie restriction in monkeys slows skeletal muscle aging
https://www.dailyunion.com/announcements/uw-madison-study-shows-calorie-restriction-in-monkeys-slows-skeletal/article_a2b53f5a-8a62-5278-9b49-5ea393335e0f.html
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Molecular and Functional Networks Linked to Sarcopenia Prevention by Caloric Restriction in Rhesus Monkeys.
Rhoads TW, Clark JP, Gustafson GE, Miller KN, Conklin MW, DeMuth TM, Berres ME, Eliceiri KW, Vaughan LK, Lary CW, Beasley TM, Colman RJ, Anderson RM.
Cell Syst. 2020 Jan 6. pii: S2405-4712(19)30463-6. doi: 10.1016/j.cels.2019.12.002. [Epub ahead of print]
PMID: 31982367
https://www.cell.com/cell-systems/fulltext/S2405-4712(19)30463-6
https://www.cell.com/action/showPdf?pii=S2405-4712(19)30463-6
Abstract
Caloric restriction (CR) improves survival in nonhuman primates and delays the onset of age-related morbidities including sarcopenia, which is characterized by the age-related loss of muscle mass and function. A shift in metabolism anticipates the onset of muscle-aging phenotypes in nonhuman primates, suggesting a potential role for metabolism in the protective effects of CR. Here, we show that CR induced profound changes in muscle composition and the cellular metabolic environment. Bioinformatic analysis linked these adaptations to proteostasis, RNA processing, and lipid synthetic pathways. At the tissue level, CR maintained contractile content and attenuated age-related metabolic shifts among individual fiber types with higher mitochondrial activity, altered redox metabolism, and smaller lipid droplet size. Biometric and metabolic rate data confirm preserved metabolic efficiency in CR animals that correlated with the attenuation of age-related muscle mass and physical activity. These data suggest that CR-induced reprogramming of metabolism plays a role in delayed aging of skeletal muscle in rhesus monkeys.
KEYWORDS:
caloric restriction; metabolic networks; rhesus monkeys; sarcopenia; skeletal muscle aging

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Impact of caloric restriction on AMPK and endoplasmic reticulum stress in peripheral tissues and circulating peripheral blood mononuclear cells from Zucker rats.
Vega-Martín E, González-Blázquez R, Manzano-Lista FJ, Martín-Ramos M, García-Prieto CF, Viana M, Rubio MA, Calle-Pascual AL, Lionetti L, Somoza B, Fernández-Alfonso MS, Alcalá M, Gil-Ortega M.
J Nutr Biochem. 2020 Jan 9;78:108342. doi: 10.1016/j.jnutbio.2020.108342. [Epub ahead of print]
PMID: 32004927
Abstract
The activation of endoplasmic reticulum (ER) stress and a reduction of AMP-dependent protein kinase (AMPK) phosphorylation have been described in obesity. We hypothesize that a moderate caloric restriction (CR) might contribute to reducing ER stress and increasing AMPK phosphorylation in peripheral tissues from genetically obese Zucker fa/fa rats and in peripheral blood mononuclear cells (PBMCs). Zucker Lean and Zucker fa/fa rats were fed with chow diet either ad libitum (AL) (C, as controls) or 80% of AL (CR) for 2 weeks, giving rise to four experimental groups: Lean C, Lean CR, fa/fa C and fa/fa CR. CR significantly increased AMPK phosphorylation in the liver, perirenal adipose tissue (PRAT) and PBMCs from fa/fa rats but not in the subcutaneous AT (SCAT), suggesting a reduced response of SCAT to CR. Liver samples of fa/fa rats exhibited an increased mRNA expression of PERK, EIF-2α, XBP-1(s), Chop and caspase 3, which was significantly reduced by CR. PRAT exhibited an overexpression of Edem and PDIA-4 in fa/fa rats, but only PDIA-4 expression was reduced by CR. eIF-2α phosphorylation was significantly increased in all studied tissues from fa/fa rats and reduced by CR. A negative correlation was detected between p-AMPK and p-eIF-2α in the liver, PRAT and PBMCs from fa/fa rats but not in SCAT. This study shows that a moderate CR reduces ER stress and improves AMPK phosphorylation in several peripheral tissues and in circulating PBMCs, suggesting that alterations observed in PBMCs could reflect metabolic alterations associated with obesity.
KEYWORDS:
AMPK; Caloric restriction; Circulating peripheral blood mononuclear cells; Endoplasmic reticulum stress; Obesity

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Food with calorie restriction reduces the development of atherosclerosis in apoE-deficient mice.
Yang J, Zeng P, Liu L, Yu M, Su J, Yan Y, Ma J, Hu W, Yang X, Han J, Duan Y, Chen Y.
Biochem Biophys Res Commun. 2020 Jan 29. pii: S0006-291X(20)30184-4. doi: 10.1016/j.bbrc.2020.01.109. [Epub ahead of print]
PMID: 32007274
https://sci-hub.tw/http://www.sciencedirect.com/science/article/pii/S0006291X20301844
Abstract
Calorie restriction (CR) ameliorates various diseases including cardiovascular disease. However, its protection and underlying mechanisms against atherosclerosis remain un-fully elucidated. In this study, we fed apoE deficient (apoE-/-) mice in Control group a high-fat diet (HFD, 21% fat plus 0.5% cholesterol) or in CR group a CR diet (CRD, 2% fat plus 0.5% cholesterol, ∼40% calorie restriction and same levels of cholesterol, vitamins, minerals and amino acids as in HFD). After 16 weeks feeding, compared with HFD, CRD substantially reduced atherosclerosis in mice. CRD increased SMC and collagen content but reduced macrophage content, necrotic core and vascular calcification in lesion areas. Mechanistically, CRD attenuated bodyweight gain, improved lipid profiles but had little effect on macrophage lipid metabolism. CRD also inhibited expression of inflammatory molecules in lesions. Taken together, our study demonstrates CRD effectively reduces atherosclerosis in apoE-/- mice, suggesting it as a potent and reproducible therapy for atherosclerosis management.
KEYWORDS:
Atherosclerosis; Body weight; Calorie restriction; Inflammation; Lipids profile

Short-Term Diet Restriction but Not Alternate Day Fasting Prevents Cisplatin-Induced Nephrotoxicity in Mice.
Gunebakan E, Yalcin E, Dulger EC, Yigitbasi A, Ates N, Caglayan A, Beker MC, Sahin K, Korkaya H, Kilic E.
Biomedicines. 2020 Feb 3;8(2). pii: E23. doi: 10.3390/biomedicines8020023.
PMID: 32028692
Abstract
Cisplatin (CP) is one of the most preferred platinum-containing antineoplastic drugs. However, even in nontoxic plasma concentrations, it may cause kidney injury. To be able to increase its effective pharmacological dose, its side effects need to be regarded. Diet restriction (DR) has been demonstrated to improve cellular survival in a number of disorders. In this context, we investigated the role of DR in CP-induced nephrotoxicity (CPN). Besides alternate DR, animals were exposed to DR for 3 days prior or after CP treatment. Here, we observed that both 3 days of DR reverses the nephrotoxic effect of CP, which was associated with improved physiological outcomes, such as serum creatine, blood-urea nitrogen and urea. These treatments significantly increased phosphorylation of survival kinases PI3K/Akt and ERK-1/2 and decreased the level of stress kinase JNK were noted. In addition, the activation level of signal transduction mediator p38 MAPK phosphorylation was higher particularly in both three-day DR groups. Next, animals were fed with carbohydrate-, protein- or fat-enriched diets in the presence of CP. Results indicated that not only fasting but also dietary content itself may play a determinant role in the severity of CPN. Our data suggest that DR is a promising approach to reduce CPN by regulating metabolism and cell signaling pathways.
KEYWORDS:
MAPK pathway; acute kidney injury; cisplatin; fasting; nephrotoxicity; renal protection

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Molecular Mechanism of Dietary Restriction in Neuroprevention and Neurogenesis: Involvement of Neurotrophic Factors.
Park HR, Park M, Kim HS, Lee J.
Toxicol Res. 2008 Dec;24(4):245-251. doi: 10.5487/TR.2008.24.4.245. Epub 2008 Dec 1.
PMID: 32038802
http://koreascience.or.kr/article/JAKO200804050611150.page
Abstract
Dietary restriction (DR) is the most efficacious intervention for retarding the deleterious effects of aging. DR increases longevity, decreases the occurrence and severity of age-related diseases, and retards the physiological decline associated with aging. The beneficial effects of DR have been mostly studied in non-neuronal tissues. However, several studies have showed that DR attenuate neuronal loss after several different insults including exposure to kainate, ischemia, and MPTR Moreover, administration of the non-metabolizable glucose analog 2-deoxy-D-glucose (2DG) could mimic the neuroprotective effect of DR in rodent, presumably by limiting glucose availability at the cellular level. Based on the studies of chemically induced D.R., it has been proposed that the mechanism whereby DR and 2DG protect neurons is largely mediated by stress response proteins such as HSP70 and GRP78 which are increased in neurons of rats and mice fed a DR regimen. In addition, D.R., as mild metabolic stress, could lead to the increased activity in neuronal circuits and thus induce expression of neurotrophic factors. Interestingly, such increased neuronal activities also enhance neurogenesis in the brains of adult rodents. In this review, we focus on what is known regarding molecular mechanisms of the protective role of DR in neurodegenerative diseases and aging process. Also, we propose that DR is a mild cellular stress that stimulates production of neurotrophic factors, which are major regulators of neuronal survival, as well as neurogenesis in adult brain.
KEYWORDS:
Aging; Brain; Caloric restriction; Neurodegenerative diseases; Neurogenesis

Anti-aging Effects of Calorie Restriction (CR) and CR Mimetics based on the Senoinflammation Concept.
Kim DH, Bang E, Jung HJ, Noh SG, Yu BP, Choi YJ, Chung HY.
Nutrients. 2020 Feb 6;12(2). pii: E422. doi: 10.3390/nu12020422. Review.
PMID: 32041168
https://sci-hub.tw/10.3390/nu12020422
Abstract
Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.
KEYWORDS:
aging; calorie restriction; mimetics; senescence-associated secretory phenotype; senoinflammation

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Impact of calorie restriction on energy metabolism in humans.
Most J, Redman LM.
Exp Gerontol. 2020 Feb 11:110875. doi: 10.1016/j.exger.2020.110875. [Epub ahead of print] Review.
PMID: 32057825
https://sci-hub.tw/10.1016/j.exger.2020.110875
Abstract
Calorie restriction (CR) is the most potent, non-pharmacological intervention to support metabolic health. The effects of calorie restriction exceed weight loss. Consistent throughout many studies, calorie restriction induces a reduction in energy expenditure that is larger than the loss of metabolic mass, i.e. fat-free mass and fat mass, can explain. Per prevailing theories of mammalian aging, this disproportionate reduction in metabolic rate, defined as metabolic adaptation, reduces oxidative damage and thereby delays age-associated declines in physiological function. The aim of this narrative review is to investigate the origins of CR-induced metabolic adaptation. From a physiological standpoint this likely relates to the composition of body weight loss, reductions in insulin secretion, thyroid and leptin concentrations, and increased mitochondrial energy efficiency. Behavioral factors including physical activity and eating behaviors likely also play a role, specifically to prevent weight regain. Future studies are required to understand the interindividual differences in the response to CR, e.g. by sex, physical activity, or mitochondrial capacity, and to assess the long-term implications of CR for weight regain.
KEYWORDS:
Adaptive thermogenesis; Calorie restriction; Energy efficiency; Energy requirements; Weight loss; Weight regain
 

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Long-term caloric restriction activates the myocardial SIRT1/AMPK/PGC-1α pathway in C57BL/6J male mice.
Ma L, Wang R, Wang H, Zhang Y, Zhao Z.
Food Nutr Res. 2020 Jan 29;64. doi: 10.29219/fnr.v64.3668. eCollection 2020.
PMID: 32082101
Abstract
BACKGROUND:
Caloric restriction (CR) can help in improving heart function. There is as yet no consensus on the mechanism of the effect of CR. Silent mating-type information regulation 1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK), and mTOR are key players in metabolic stress management. We aimed to explore the effect of CR on the myocardial SIRT1/AMPK/mTOR pathway in mice.
METHODS:
Thirty-six 6-week-old male C57BL/6J mice were randomly divided into three groups: normal control group (NC group, n = 12), high-energy group (HE group, n = 12) and CR group (n = 12) according to different diets. After 11 months, western blot was used to examine proteins such as p-AMPK, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), SIRT1, and p-mTOR, whereas real-time PCR was used to examine the expression of AMPK, PGC-1α, and SIRT1 transcripts.
RESULTS:
Compared to the HE group, the CR group displayed increased expression of myocardial p-AMPK protein, SIRT1 protein and mRNA, and PGC-1a mRNA. However, no difference was observed in the expression of p-mTOR protein and mTOR mRNA in the myocardium among the three groups.
CONCLUSIONS:
CR improves the SIRT1/AMPK/PGC-1α pathway in mice myocardium with no effect on the mTOR pathway.
KEYWORDS:
AMPK; SIRT1; caloric restriction; mTOR; signaling pathway

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