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      The ups and downs of caloric restriction and fasting: from molecular effects to clinical application

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          Abstract

          Age‐associated diseases are rising to pandemic proportions, exposing the need for efficient and low‐cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life‐ and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social‐behavioral limitations, CR may be challenging to implement into real life. Thus, CR‐mimicking interventions have been developed, including intermittent fasting, time‐restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages.

          Abstract

          Can dietary modulations promote better health? The current article comprehensively reviews key concepts of dietary interventions, their clinical application and the beneficial and disadvantageous effects of caloric restriction and fasting on human health.

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            DNA methylation age of human tissues and cell types

            Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.
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              Inflammaging: a new immune–metabolic viewpoint for age-related diseases

              Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self). A limited number of receptors, whose degeneracy allows them to recognize many signals and to activate the innate immune responses, sense these stimuli. In this situation, metaflammation (the metabolic inflammation accompanying metabolic diseases) is thought to be the form of chronic inflammation that is driven by nutrient excess or overnutrition; metaflammation is characterized by the same mechanisms underpinning inflammaging. The gut microbiota has a central role in both metaflammation and inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms and crosstalk with other organs and systems. We argue that chronic diseases are not only the result of ageing and inflammaging; these diseases also accelerate the ageing process and can be considered a manifestation of accelerated ageing. Finally, we propose the use of new biomarkers (DNA methylation, glycomics, metabolomics and lipidomics) that are capable of assessing biological versus chronological age in metabolic diseases.
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                Author and article information

                Contributors
                sebastian.hofer@uni-graz.at
                frank.madeo@uni-graz.at
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                15 November 2021
                11 January 2022
                : 14
                : 1 ( doiID: 10.1002/emmm.v14.1 )
                : e14418
                Affiliations
                [ 1 ] Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
                [ 2 ] BioHealth Graz Graz Austria
                [ 3 ] BioTechMed Graz Graz Austria
                Author notes
                [*] [* ] Corresponding author. Tel: +43 316 380 1498; E‐mail: sebastian.hofer@ 123456uni-graz.at

                Corresponding author. Tel: +43 316 380 8878; E‐mail: frank.madeo@ 123456uni-graz.at

                Author information
                https://orcid.org/0000-0002-0756-0014
                https://orcid.org/0000-0001-7548-7771
                https://orcid.org/0000-0002-7472-2677
                https://orcid.org/0000-0002-5070-1329
                Article
                EMMM202114418
                10.15252/emmm.202114418
                8749464
                34779138
                2e648325-ac85-458b-ab97-c6aa1d27fa89
                © 2021 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 October 2021
                : 11 April 2021
                : 08 October 2021
                Page count
                Figures: 5, Tables: 0, Pages: 20, Words: 18140
                Funding
                Funded by: Austrian Science Fund (FWF) , doi 10.13039/501100002428;
                Award ID: F3007
                Award ID: F3012
                Award ID: DK‐MCD W1226
                Award ID: P29203
                Award ID: P29262
                Award ID: P27893
                Award ID: P31727
                Funded by: Austrian Federal Ministry of Education, Science and Research (Unkonventionelle Forschung‐InterFast and Fast4Health)
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                11 January 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:11.01.2022

                Molecular medicine
                caloric restriction,fasting,healthspan,intermittent fasting,lifespan,time‐restricted eating,autophagy & cell death,metabolism

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