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      Sirtuins and their Biological Relevance in Aging and Age-Related Diseases

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          Abstract

          Sirtuins, initially described as histone deacetylases and gene silencers in yeast, are now known to have many more functions and to be much more abundant in living organisms. The increasing evidence of sirtuins in the field of ageing and age-related diseases indicates that they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. Here, we summarize some of the recent discoveries in sirtuin biology that clearly implicate the functions of sirtuins in the regulation of aging and age-related diseases. Furthermore, human sirtuins are considered promising therapeutic targets for anti-aging and ageing-related diseases and have attracted interest in scientific communities to develop small molecule activators or drugs to ameliorate a wide range of ageing disorders. In this review, we also summarize the discovery and development status of sirtuin-targeted drug and further discuss the potential medical strategies of sirtuins in delaying aging and treating age-related diseases.

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          Sirtuins in mammals: insights into their biological function.

          Shaday Michan, David. Sinclair (2007)
          Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.
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            Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

            Jill Milne, Philip Lambert, Simon Schenk … (2007)
            Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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              Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

              Kerby Shedden, Jeremy M. G. Taylor, Steven A. Enkemann … (2008)
              Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging Dis
                Journal ID (iso-abbrev): Aging Dis
                Title: Aging and Disease
                Publisher: JKL International LLC
                ISSN (Electronic): 2152-5250
                Publication date Collection: July 2020
                Publication date (Electronic): 23 July 2020
                Volume: 11
                Issue: 4
                Pages: 927-945
                Affiliations
                [1-ad-11-4-927] 1Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Beijing, China
                [2-ad-11-4-927] 2Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
                Author notes
                [* ]Correspondence should be addressed to: Dr. Limin Han ( liminhan@ 123456bjmu.edu.cn ) and Dr. Tanjun Tong ( ttj@ 123456bjmu.edu.cn ), Department of Biochemistry & Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
                Article
                Publisher ID: ad-11-4-927
                DOI: 10.14336/AD.2019.0820
                PMC ID: 7390530
                PubMed ID: 32765955
                SO-VID: 99d103a8-01ff-4f87-a0ef-6301c5e56e04
                Copyright © Copyright: © 2020 Zhao et al.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                Date received : 29 July 2019
                Date revision requested : 19 August 2019
                Date accepted : 20 August 2019
                Categories
                Subject: Review

                Keywords: sirtuins,aging,age-related diseases,cancer
                Data availability:
                Keywords: sirtuins, aging, age-related diseases, cancer

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