Introduction to Cardiovascular Aging Compendium
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 7 Linguagem: Inglês
10.1161/circresaha.118.313940
ISSN1524-4571
AutoresAli J. Marian, Aruni Bhatnagar, Roberto Bolli, Juan Carlos Izpisúa Belmonte,
Tópico(s)Cardiovascular Health and Risk Factors
ResumoHomeCirculation ResearchVol. 123, No. 7Introduction to Cardiovascular Aging Compendium Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIntroduction to Cardiovascular Aging Compendium"Aging as the Quintessential Complex Phenotype" A.J. Marian, Aruni Bhatnagar, Roberto Bolli and Juan Carlos Izpisua Belmonte A.J. MarianA.J. Marian Correspondence to A.J. Marian, MD, Center for Cardiovascular Genetics, University of Texas Health Science Center at Houston, 6770 Bertner St, DAC 900A, Houston, Texas 77030. Email E-mail Address: [email protected] From the University of Texas Health Science Center, Houston (A.J.M.) , Aruni BhatnagarAruni Bhatnagar Division of Cardiology, University of Louisville, KY (A.B., R.B.) , Roberto BolliRoberto Bolli Division of Cardiology, University of Louisville, KY (A.B., R.B.) and Juan Carlos Izpisua BelmonteJuan Carlos Izpisua Belmonte The Salk Institute for Biological Studies, La Jolla, CA (J.C.B.). Originally published13 Sep 2018https://doi.org/10.1161/CIRCRESAHA.118.313940Circulation Research. 2018;123:737–739Aging is inevitable, universal to all forms of life, and a prelude to mortality. Despite this formidable challenge, humans have long aspired to stay young forever and to achieve immortality. This fantastical theme has been explored extensively in popular art and literature throughout the ages. For example, in Oscar Wilde novel The Picture of Dorian Gray a handsome young man finds eternal youth, whereas all his vices and indulgences are transferred to his progressively aging portrait. In Goethe's play, Dr Faustus makes a pact with Mephistopheles to transform him from an old man into a handsome young doctor in exchange of his soul. In recent times, such mythical yearnings have been replaced with studies in modern molecular genetics and biology that seek to garner new insights into the mechanisms of aging—a knowledge that may be used to develop ingenious interventions to prevent, attenuate, or even reverse aging.Fantastical myths and promises, notwithstanding, human life expectancy has steadily increased during the past couple of centuries. The expected life expectancy in industrialized world has doubled since the turn of the century, with most deaths in recent years occurring after 80 years of age. There are many reasons for his remarkable increase in human longevity. These include improved nutrition, spurred by agricultural revolution, better sanitation, resulting in less infection, and superior health care, because of technological advances and economic growth. As a result, the leading causes of death have shifted from acute pathogen infections to chronic noncommunicable diseases, such as cardiovascular diseases, neuro-degeneration, metabolic disease, and chronic inflammatory conditions. Of these, cardiovascular disease has remained the leading cause of death in developed countries, every year since 1900, except for 1918–1919 when it was superseded by the Spanish flu. Clearly, the next phase of improvement in human longevity could be achieved mostly by preventing or treating chronic conditions, such as cardiovascular disease, and shifting the focus from simply living longer to healthy aging like Jeanne Louise Calment, a supercentenarian, who had the longest confirmed human lifespan of 122 years.The present Compendium offers a significant compilation of the state-of-the-art scientific discoveries that provide new insights into multiple aspects of aging, presented by the leading scientists in the field. In the compendium, Ferrucci et al1 offer a Viewpoint discussing the hierarchical changes that occur with aging at the molecular, cellular, functional, and organismal levels. The authors categorize aging metrics into 3 broad categories of biological, phenotypic, and functional aging. Hallmarks of biological aging comprise a series of genetic, genomics, and epigenetic changes that along with mitochondrial dysfunction, stem cell depletion and dysfunction, inflammation, and dysregulated homeostasis contribute to cellular senescence. Notable examples of molecular aging include telomere shortening, expression of CDKN2A (cyclin-dependent kinase inhibitor 2A) protein, and CpG methylation. Molecular changes provide the platform for phenotypic manifestations of aging, which include declining cognitive functions, fat redistribution and accumulation, and sarcopenia. Functional aging, as reflected by physical frailty or changes in vascular reactivity, is closely linked with and is a consequence of molecular and phenotypic aging. The authors envision research programs focusing on uncovering the mechanisms underlying molecular aging and integrating the findings into phenotypic and functional aging that would offer a robust platform to translational applications of discoveries.Aging could be considered an archetypical complex phenotype with variable expressivity. Consequently, genetic approaches, such as Genome-Wide Association Studies and Whole Genome Sequencing could be powerful approaches to define genetic variants that are associated with aging and longevity. In this regard, Giuliani et al2 provide a comprehensive and in-depth review discussing the genetic basis of aging and challenges that many investigators encounter in finding and defining genetic causes of healthy aging and longevity. The authors discuss not only the results of the recent genetic findings but they also point out the complex interactions between the environmental factors that play a role in the pathogenesis of aging, including the effects of such diverse factors as the microbiome and the interactions between the mitochondrial DNA with the host genome. They also point out the role of several genes that have been implicated in influencing longevity, including genes encoding protein constituents of the insulin/IGF1 (insulin-like growth factor-1)/FOXO (Forkhead box O) transcription factor pathways. A surprising number of other genes, such as those regulating the genome and metabolic stability have also been implicated in determining longevity. These include such well-known multifunctional proteins as the MTOR (mammalian target of rapamycin), sirtuins, and AMPK (adenine monophosphate-activated protein kinase). Given the complexity of the determinants of aging, the plethora of proteins involved in the process, and the relatively moderate size of estimated heritability of longevity, large-scale genome sequencing and Genome-Wide Association Studies are needed to garner further insights into the genetic basis of aging and longevity.Recent advances in genomic technologies have enabled the identification of epigenetic changes that occur in healthy aging and pathological conditions. The compendium includes an informative and comprehensive review by Liu et al,3 which provides an informative and comprehensive review of epigenetic changes associated with cardiovascular aging. The authors discuss approaches to harness this knowledge to maintain and rejuvenate the epigenetic signature in the young state. The article covers changes in CpG methylation upon aging, including the role of TET2, which has been implicated in clonal hematopoiesis in cardiovascular disease.4,5 They also discuss the contributions of various types of histone modifications, chromatin remodeling enzymes, and noncoding RNAs to cardiovascular aging. The authors note that although epigenetic regulation of gene expression during cardiac development and pathology is well substantiated, its specific role in aging is less well understood and is ripe for further development.Telomeres, the heterochromatic ends of chromosomes comprised of TTAGGG repeats, are known to shorten during cell replication and consequently have been considered by some to be the sine qua non for aging. Blasco and Martinez6 provide an in-depth and insightful discussion on the role of telomeres in maintaining chromosome stability and the mechanisms that regulate telomere length and shortening upon cell division. The authors marshal multiple lines of evidence to implicate telomere length as a key determinant of human health and longevity. This evidence includes epidemiological data showing an inverse association between telomere length and increased prevalence of age-related clinical phenotypes.7 In addition, the authors discuss germline mutations that are responsible for telomeropathies, which manifest as accelerated aging of multiple organs. It is estimated that shortening of telomere length in circulating cells by ≈1000 base pairs leads to a 3-fold increase in the risk of myocardial infarction. Mechanistically, the authors link shortening of telomere length not only to the activation of DNA damage response, induction of cell senescence programming, expression of senescence-associated secretory phenotype, and inflammation but also to impaired stem cell regeneration as well. Human data are complemented with evidence from genetically-modified mice and gene transfer studies that target telomerase, which by increasing telomere length improves phenotypes associated with aging. In sum, the authors make a compelling case for the role of telomere shortening in cardiovascular aging.The benefits of staying hungry, cold, and drunk, and taking an antidepressant, while idiomatic to longevity, are supported by scientific evidence centered primarily on the fundamental role of autophagy in aging, including cardiovascular aging.8 Kroemer et al9 provide a cogent and persuasive discussion on the critical role of autophagy in cellular homeostasis, metabolic fitness, aging, and survival. They present robust evidence in support of the notion that reduced autophagy is associated with accelerated cardiovascular aging. The authors discuss many mechanisms by which reduced autophagy accelerates aging. Notable among these are dysregulated mTOR, AMPK, and IGF1 pathways, as well as the TFEB (transcription factor E Box) and the transcription factors belonging to the FOXO family. They also discuss the role of excessive generation and accumulation of reactive oxygen species that contribute to mitochondrial dysfunction and suppress autophagy, more specifically mitophagy. The authors also enumerate the beneficial vascular effects of enhanced autophagy, whether achieved through caloric restriction or the use of SIRT1 (sirtuin 1) activators. Collectively, the authors deliver an authoritative and comprehensive review on the role of autophagy in cardiovascular aging and discuss possible interventions to enhance autophagy with the objective of slowing down and attenuating cardiovascular aging.The next 2 articles in the Compendium focus on vascular aging. Donato et al10 discusses the role of vascular system in organismal aging, while Ungvari et al11 address the underlying mechanisms. Endothelial dysfunction and arterial stiffness are common features of aging, and these changes are important contributors to cardiovascular mortality and morbidity.12 Fortunately, vascular aging, particularly in early stages, is partially reversible by several interventions that include caloric restriction and healthy diet. A number of mechanisms have been implicated in vascular aging, most of which are similar to mechanisms involved in organismal aging. Notable among such mechanisms are mitochondrial dysfunction, oxidative stress, reduced nitric oxide bioavailability, genomic/epigenetic alterations, telomere shortening, inflammation, stem cell depletion, and impaired autophagy, as well as dysregulated signaling pathways, such as mTOR, AMPK, and sirtuins. In comparison, the role of KLOTHO, an intriguing protein implicated in vascular aging, including endothelial dysfunction and medial calcification, remained unclear. KLOTHO, which is predominantly expressed in the kidney and parathyroid gland, is considered an antiaging protein whose effect is mediated by cleaved product, which is released into circulation. Another circulating hormone GDF11 (growth and differentiation factor 11) is also implicated in vascular aging. However, the role of this protein has remained controversial. An intriguing aspect of vascular aging is its effects on regulating metabolism, including obesity and insulin resistance. These effects are attributed to production of proinflammatory cytokines by the aging vasculature.Kane and Sinclair13 present an elegant discussion on the important roles of nicotinamide adenine dinucleotide and sirtuins in age-related cardiovascular and metabolic phenotypes. Sirtuins, since the recognition of their life-expanding properties in yeasts followed by the discovery of resveratrol as an activator of SIRT1, have captured the curiosity of scientists and public alike. Recognition of nicotinamide adenine dinucleotide as an important substrate of sirtuin deacetylation has rekindled the interest in this old molecule as a mediator of health and longevity. Sirtuins and nicotinamide adenine dinucleotide are implicated in almost all age-related cardiovascular and metabolic phenotypes, including endothelial dysfunction, hypertension, atherosclerosis, myocardial infarction and ischemic injury, cardiac hypertrophy and fibrosis, obesity, and insulin sensitivity. Mechanistically, sirtuins function as deacetylating enzymes that target histones, transcription factors, and other proteins and affect gene expression and protein function. The authors extend their discussion to include the results of clinical trials in humans with various sirtuin-activating compounds and nicotinamide adenine dinucleotide boosters. A number of beneficial effects have been reported. Nonetheless, the findings of the clinical trials are not yet robust enough to support specific clinical recommendations.Aging is a strong risk factor for diabetes mellitus, obesity, and other metabolic traits. Ferrucci et al14 provide an extensive review on age-related changes in glucose metabolism and obesity. The authors note the multifactorial nature of metabolic changes associated with aging. They provide a detailed discussion of the role of food intake, gut microbiota, mitochondria, adipose tissue dysfunction, endocannabinoids and inflammation in predisposing to age-related impaired glucose metabolism, and obesity. In addition, the authors provide an insightful review of recent clinical trials on cardiovascular effects of glucose-lowering agents. They note that increased mortality observed with some of the oral hypoglycemic agents and the beneficial effects found with 2 new classes of glucose-lowering agents, namely GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT (sodium-glucose transporter) inhibitors. The authors conclude their review by providing a model for aging and metabolic changes wherein multiple factors, such as excess food intake and gut microbiota contribute to mitochondrial and adipose tissue dysfunction, leading to inflammation, insulin resistance, beta cell dysfunction, and metabolic syndromes.The last article in the compendium addresses the important role of mouse models in delineating the molecular basis of aging in humans. Lopez-Otin et al15 categorize the hallmarks of aging into 9 categories, comprised of genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The authors elegantly discuss examples of gain- and loss-of-function studies in mouse models that provide insights into the molecular mechanisms involved in regulating each of these hallmarks of human aging. Equally informative is the discussion on limitations of the mouse models and the differences in aging induced by loss- and gain-of-function mutations in mouse models and healthy aging. The review offers one of the most comprehensive and informative discussion on this topic.Thus, the Cardiovascular Aging Compendium is a compilation of a series of comprehensive, insightful, authoritative articles that is expected to serve as a valuable resource for both cardiovascular and non-cardiovascular scientists, who have active research programs in aging, as well as those simply interested in the current state of aging research.DisclosuresNone.Sources of FundingThe authors acknowledge support by grants from NIH, National Heart, Lung, and Blood Institute (NHLBI, R01 HL088498 and 1R01HL132401), Leducq Foundation (14 CVD 03), The Ewing Halsell Foundation, George and Mary Josephine Hamman Foundation, and TexGen Fund from Greater Houston Community Foundation.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to A.J. Marian, MD, Center for Cardiovascular Genetics, University of Texas Health Science Center at Houston, 6770 Bertner St, DAC 900A, Houston, Texas 77030. Email ali.j.[email protected]tmc.eduReferences1. Ferrucci L, Levine M, Kuo P-L, Simonsick EM. Time and the metrics of aging.Circ Res. 2018; 123:740–744. doi: 10.1161/CIRCRESAHA.118.312816LinkGoogle Scholar2. Giuliani C, Garagnani P, Franceschi C. Genetics of human longevity within an eco-evolutionary nature-nurture framework.Circ Res. 2018; 123:745–772. doi: 10.1161/CIRCRESAHA.118.312562LinkGoogle Scholar3. Zhang W, Song M, Qu J, Liu G-H. Epigenetic modifications in cardiovascular aging and diseases.Circ Res. 2018; 123:773–786. doi: 10.1161/CIRCRESAHA.118.312497LinkGoogle Scholar4. Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease.Circ Res. 2018; 123:335–341. doi: 10.1161/CIRCRESAHA.118.313225LinkGoogle Scholar5. 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Calderón-Larrañaga A, Saadeh M, Hooshmand B, Refsum H, Smith A, Marengoni A and Vetrano D (2020) Association of Homocysteine, Methionine, and MTHFR 677C>T Polymorphism With Rate of Cardiovascular Multimorbidity Development in Older Adults in Sweden , JAMA Network Open, 10.1001/jamanetworkopen.2020.5316, 3:5, (e205316) September 14, 2018Vol 123, Issue 7 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313940PMID: 30355084 Originally publishedSeptember 13, 2018 Keywordslongevitycause of deathEditorialsmortalitylife expectancyPDF download Advertisement
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