The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome

Derous, Davina; Mitchell, Sharon; Wang, Lu; Green, Cara L; Wang, Yingchun; Chen, Luonan; Han, Jing-Dong J.; Promislow, Daniel E. L.; Lusseau, David; Douglas, Alex; Speakman, John R.

doi:10.18632/aging.101269

Cited by 27 publications

(28 citation statements)

References 167 publications

(236 reference statements)

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“…However, restriction of both calories and protein in protein‐matched group did not lead to synergistic upregulation of liver and plasma FGF21, and the curtailed secretion of FGF21 may also have contributed to their lower energy expenditure. Our findings are in agreement with some reports on lack of liver FGF21 changes with calorie restriction in mice and a reduction in circulating FGF21 with energy restriction in humans . Prior evidence from intestinal‐derived cell lines implicates the existence of amino acid sensing mechanisms in the intestine; whether similar sensing mechanisms occur in vivo remains largely unknown.…”

Section: Discussionsupporting

confidence: 92%

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Zapata

Singh

Pezeshki

et al. 2019

Mol. Nutr. Food Res.

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Scope: Dietary protein restriction elicits hyperphagia and increases energy expenditure; however, less is known of whether these responses are a consequence of increasing carbohydrate content. The effects of protein-diluted diets with fixed carbohydrate content on energy balance, hormones, and key markers of protein sensing and thermogenesis in tissues are determined. Methods and results: Obesity-prone rats (n = 13-16 per group) are randomized to diets containing fixed carbohydrate (52% calories) and varying protein concentrations: 15% (control), 10% (mild protein restriction), 5% (moderate protein restriction) or 1% (severe protein restriction) protein calories, or protein-matched to 5% protein, for 21 days. Propranolol and ondansetron are administered to interrogate the roles of sympathetic and serotonergic systems, respectively, in diet-induced changes in energy expenditure. It is found that mild-to-moderate protein restriction promotes transient hyperphagia, whereas severe protein restriction induces hypophagia, with alterations in meal patterns. Protein restriction enhances energy expenditure that is partly attenuated by propranolol, but not ondansetron. Moderate to severe protein restriction decreases gains in body weight, lean and fat mass, decreased postprandial glucose and leptin, but increased fibroblast growth factor-21 concentrations. Protein-matching retains lean mass suggesting that intake of dietary protein, but not calories, is important for preserving lean mass. Notably, protein restriction increases the protein and/or transcript abundance of key amino acid sensing molecules in liver and intestine (PERK, eIF2α, ATF2, CHOP, 4EBP1, FGF21), and upregulated thermogenic markers (β2AR, Klotho, HADH, UCP-1) in brown adipose tissue. Conclusion: Low-protein diets promote hyperphagia and sympathetically mediated increase in energy expenditure, prevent gains in tissue reserves, and concurrently upregulate hepatic and intestinal amino acid sensing intermediaries and thermogenic markers in brown adipose tissue.

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“…Other omics studies provided evidence that CR definitively modulates aging processes and prevents or delays age-associated disease progression. Analysis of hepatic transcriptome showed that CR stimulated pathways involving IGF-1, NF-κB, mTOR, and SIRTs, which collectively contribute to reduced oxidative stress and improved metabolism, further supporting that CR promotes health and could extend lifespan by interfering with age-associated signaling pathways [85]. In addition, CR suppresses adiposity and insulin resistance, consequentially suppressing a proinflammatory status.…”

Section: Omics Big Data On Aging and Crmentioning

confidence: 83%

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

et al. 2020

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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.

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“…Derous et al studied the effects of caloric restriction (CR) on the increase in lifespan by evaluating four of the main signaling pathways involved in aging. 115 The impact of CR was consistent on IIS, nuclear factor-κB, and mammalian TOR, while sirtuins were not significantly altered (►Fig. 2).…”

Section: Aging-related Molecular Alterations In Liver Diseasesmentioning

confidence: 84%

Aging and the Biological Response to Liver Injury

et al. 2019

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Interest in understanding the aging process has recently risen in the scientific community. Aging, commonly defined as the functional decline in the function of organs and tissues, is indeed the major risk factor for the development of many chronic diseases, such as cardiovascular diseases, pathologies of nervous system, or cancer. To date, the influence of aging in the pathophysiology of liver and biliary diseases is not fully understood. Although liver cells have a high regenerative capacity, hepatocytes and cholangiocytes undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, liver cells initially activate compensatory mechanisms that, if hyperstimulated, may lead to the decline of regenerative capacity and the development of pathologies. A deeper understanding of molecular aging has undoubtedly the potential to improve the clinical management of patients, possibly unveiling new pathways for selective drug treatment.

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“…They isolated mitochondria from the livers of controls, and after 4 months of a CR schedule, they found an increase in the LC3-II/LC3-I ratio in CR livers, indicating enhanced liver mitochondrial autophagy. Derous et al found similar results when they evaluated the effect of graded levels of CR on autophagy using the hepatic transcriptome [65]. Mice were subjected to a graded level of CR (from 0% to 40% CR) for 3 months, following which a significant increase in autophagy levels was observed that correlated with increased levels of CR.…”

Section: Livermentioning

confidence: 68%

The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention

Chung

2019

Nutrients

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Autophagy is an important housekeeping process that maintains a proper cellular homeostasis under normal physiologic and/or pathologic conditions. It is responsible for the disposal and recycling of metabolic macromolecules and damaged organelles through broad lysosomal degradation processes. Under stress conditions, including nutrient deficiency, autophagy is substantially activated to maintain proper cell function and promote cell survival. Altered autophagy processes have been reported in various aging studies, and a dysregulated autophagy is associated with various age-associated diseases. Calorie restriction (CR) is regarded as the gold standard for many aging intervention methods. Although it is clear that CR has diverse effects in counteracting aging process, the exact mechanisms by which it modulates those processes are still controversial. Recent advances in CR research have suggested that the activation of autophagy is linked to the observed beneficial anti-aging effects. Evidence showed that CR induced a robust autophagy response in various metabolic tissues, and that the inhibition of autophagy attenuated the anti-aging effects of CR. The mechanisms by which CR modulates the complex process of autophagy have been investigated in depth. In this review, several major advances related to CR’s anti-aging mechanisms and anti-aging mimetics will be discussed, focusing on the modification of the autophagy response.

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“…Studies conducted using a number of different model organisms, especially yeast, Caenorhabditis elegans , Drosophila , and mice, have paved the way to an understanding of how DR and CR exert their positive effects on lifespan . In accordance with the proposition that energy restriction underpins CR, whereas protein restriction underpins DR, the cellular systems that are directly involved in maintaining energy homeostasis or in sensing protein (amino acid) status are particularly important.…”

Section: Cr Macronutrient Restriction and Time Restricted Food Intakementioning

confidence: 99%

Factors that affect the translation of dietary restriction into a longer life

Frieling

Roeder

2020

IUBMB Life

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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.

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The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome

Cited by 27 publications

References 167 publications

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

Aging and the Biological Response to Liver Injury

The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention

Factors that affect the translation of dietary restriction into a longer life

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