111 results on '"Sinclair, David"'
Search Results
2. Loss of epigenetic information as a cause of mammalian aging.
- Author
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Yang JH, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, Blanchette M, Munding EM, Bhakta M, Chew YC, Guo W, Yang X, Maybury-Lewis S, Tian X, Ross JM, Coppotelli G, Meer MV, Rogers-Hammond R, Vera DL, Lu YR, Pippin JW, Creswell ML, Dou Z, Xu C, Mitchell SJ, Das A, O'Connell BL, Thakur S, Kane AE, Su Q, Mohri Y, Nishimura EK, Schaevitz L, Garg N, Balta AM, Rego MA, Gregory-Ksander M, Jakobs TC, Zhong L, Wakimoto H, El Andari J, Grimm D, Mostoslavsky R, Wagers AJ, Tsubota K, Bonasera SJ, Palmeira CM, Seidman JG, Seidman CE, Wolf NS, Kreiling JA, Sedivy JM, Murphy GF, Green RE, Garcia BA, Berger SL, Oberdoerffer P, Shankland SJ, Gladyshev VN, Ksander BR, Pfenning AR, Rajman LA, and Sinclair DA
- Subjects
- Animals, DNA Methylation, Epigenome, Mammals genetics, Nucleoproteins, Saccharomyces cerevisiae genetics, Aging genetics, Epigenesis, Genetic
- Abstract
All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging., Competing Interests: Declaration of interests D.A.S. is a consultant, inventor, board member, and in some cases an investor in Life Biosciences (developing reprogramming medicines), InsideTracker, Zymo, EdenRoc Sciences/Cantata/Dovetail/Metrobiotech, Caudalie, Galilei, Immetas, Animal Biosciences, Tally Health, and more. See https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. E.M.M., M. Blanchette, and M. Bhakta are employees of Catata Bio/Dovetail. Y.C.C., W.G., and X.Y. are employees of Zymo Research. A.J.W. advises Kate Therapeutics and Frequency Therapeutics and is a co-founder, adviser, and equity holder of Elevian, which sponsors Wagers Lab research. L.S. was an employee of Vium. Y.R.L. and L.A.R. are equity owners of Life Biosciences. M.S.B. and D.L.V. advise EdenRoc Sciences. A patent application was filed on the reprogramming methods., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
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3. Mitochondrial and metabolic dysfunction in ageing and age-related diseases.
- Author
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Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, and Sinclair DA
- Subjects
- Caloric Restriction, Energy Metabolism, Humans, Mitochondria metabolism, Aging metabolism, Metabolic Diseases metabolism
- Abstract
Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches., (© 2022. Springer Nature Limited.)
- Published
- 2022
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4. Gut Microbiota Predicts Healthy Late-Life Aging in Male Mice.
- Author
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Ke S, Mitchell SJ, MacArthur MR, Kane AE, Sinclair DA, Venable EM, Chadaideh KS, Carmody RN, Grodstein F, Mitchell JR, and Liu Y
- Subjects
- Animals, Frailty, Healthy Aging, Humans, Longevity, Longitudinal Studies, Machine Learning, Male, Mice, Mice, Inbred C57BL, Aging, Caloric Restriction methods, Gastrointestinal Microbiome
- Abstract
Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging. Here, we report findings from a small longitudinal study of male C57BL/6 mice maintained on either ad libitum or mild (15%) CR diets from 21 months of age and tracked until natural death. We demonstrate that CR results in a significantly reduced rate of increase in the frailty index (FI), a well-established indicator of aging. We observed significant alterations in diversity, as well as compositional patterns of the mouse gut microbiota during the aging process. Interrogating the FI-related microbial features using machine learning techniques, we show that gut microbial signatures from 21-month-old mice can predict the healthy aging of 30-month-old mice with reasonable accuracy. This study deepens our understanding of the links between CR, gut microbiota, and frailty in the aging process of mice.
- Published
- 2021
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5. ARDD 2020: from aging mechanisms to interventions.
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Mkrtchyan GV, Abdelmohsen K, Andreux P, Bagdonaite I, Barzilai N, Brunak S, Cabreiro F, de Cabo R, Campisi J, Cuervo AM, Demaria M, Ewald CY, Fang EF, Faragher R, Ferrucci L, Freund A, Silva-García CG, Georgievskaya A, Gladyshev VN, Glass DJ, Gorbunova V, de Grey A, He WW, Hoeijmakers J, Hoffmann E, Horvath S, Houtkooper RH, Jensen MK, Jensen MB, Kane A, Kassem M, de Keizer P, Kennedy B, Karsenty G, Lamming DW, Lee KF, MacAulay N, Mamoshina P, Mellon J, Molenaars M, Moskalev A, Mund A, Niedernhofer L, Osborne B, Pak HH, Parkhitko A, Raimundo N, Rando TA, Rasmussen LJ, Reis C, Riedel CG, Franco-Romero A, Schumacher B, Sinclair DA, Suh Y, Taub PR, Toiber D, Treebak JT, Valenzano DR, Verdin E, Vijg J, Young S, Zhang L, Bakula D, Zhavoronkov A, and Scheibye-Knudsen M
- Subjects
- Cellular Senescence, Congresses as Topic, Drug Discovery, Humans, Life Style, Pharmaceutical Preparations, Aging, Artificial Intelligence, Biomedical Research, Longevity
- Abstract
Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7
th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.- Published
- 2020
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6. Reprogramming to recover youthful epigenetic information and restore vision.
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Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, Karg MM, Schultz MB, Kane AE, Davidsohn N, Korobkina E, Chwalek K, Rajman LA, Church GM, Hochedlinger K, Gladyshev VN, Horvath S, Levine ME, Gregory-Ksander MS, Ksander BR, He Z, and Sinclair DA
- Subjects
- Aging physiology, Animals, Axons physiology, Cell Line, Tumor, Cell Survival, DNA-Binding Proteins genetics, Dependovirus genetics, Dioxygenases, Disease Models, Animal, Female, Genetic Vectors genetics, Glaucoma genetics, Glaucoma pathology, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Mice, Mice, Inbred C57BL, Octamer Transcription Factor-3 genetics, Optic Nerve Injuries genetics, Proto-Oncogene Proteins genetics, Retinal Ganglion Cells cytology, SOXB1 Transcription Factors genetics, Transcriptome genetics, Aging genetics, Cellular Reprogramming genetics, DNA Methylation, Epigenesis, Genetic, Eye cytology, Eye innervation, Eye pathology, Nerve Regeneration genetics, Vision, Ocular genetics, Vision, Ocular physiology
- Abstract
Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity
1-3 . Changes to DNA methylation patterns over time form the basis of ageing clocks4 , but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5-7 . Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.- Published
- 2020
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7. Age and life expectancy clocks based on machine learning analysis of mouse frailty.
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Schultz MB, Kane AE, Mitchell SJ, MacArthur MR, Warner E, Vogel DS, Mitchell JR, Howlett SE, Bonkowski MS, and Sinclair DA
- Subjects
- Aging genetics, Animals, Biological Clocks, Female, Frailty, Humans, Life Expectancy, Machine Learning, Male, Mice genetics, Mice growth & development, Mice, Inbred C57BL, Aging physiology, Mice physiology
- Abstract
The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.
- Published
- 2020
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8. Why does COVID-19 disproportionately affect older people?
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Mueller AL, McNamara MS, and Sinclair DA
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- Aged, Betacoronavirus isolation & purification, Betacoronavirus physiology, COVID-19, Comorbidity, Cytokine Release Syndrome etiology, Cytokine Release Syndrome immunology, Humans, Respiratory Distress Syndrome etiology, Respiratory Distress Syndrome immunology, Risk Assessment, Risk Factors, SARS-CoV-2, Severity of Illness Index, Aging physiology, Coronavirus Infections epidemiology, Coronavirus Infections immunology, Coronavirus Infections therapy, Epigenesis, Genetic physiology, Immunity physiology, Pandemics, Patient Care Management methods, Pneumonia, Viral epidemiology, Pneumonia, Viral immunology, Pneumonia, Viral therapy
- Abstract
The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.
- Published
- 2020
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9. Harvard HIV and Aging Workshop: Perspectives and Priorities from Claude D. Pepper Centers and Centers for AIDS Research.
- Author
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Montano M, Bhasin S, D'Aquila RT, Erlandson KM, Evans WJ, Funderburg NT, Justice A, Ndhlovu LC, Ojikutu B, Pahor M, Pahwa S, Ryan AS, Schrack J, Schultz MB, Sebastiani P, Sinclair DA, Tripp J, Walker B, Womack JA, Yung R, and Reeves RK
- Subjects
- Aged, Cardiovascular Diseases complications, Cognition, Comorbidity, Congresses as Topic, Frail Elderly, Geriatrics methods, Humans, Hypertension complications, Male, Aging, Biomedical Research organization & administration, HIV Infections complications, HIV Infections epidemiology
- Abstract
People aging with HIV (PAWH) infection experience greater impairments in physical and cognitive function, in addition to higher rates of peripheral comorbid conditions (e.g., renal failure, diabetes, bone fracture, hypertension, cardiovascular disease, polypharmacy, and multimorbidity). While multifactorial drivers, including HIV infection itself, antiretroviral therapy-related toxicities, disparities in care, and biobehavioral factors, likely contribute, there remains an overarching question as to what are the relevant age-related mechanisms and models that could inform interventions that promote health span and life span in PAWH? This workshop was convened to hear from experts on the biology of aging and HIV researchers studying PAWH to focus on advancing investigations at the interface of HIV and Aging. In this study, we summarize the discussions from the Harvard Center for AIDS Research and Boston Claude D. Pepper cosponsored workshop on HIV and Aging, which took place in October 2018.
- Published
- 2019
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10. NAD + in Brain Aging and Neurodegenerative Disorders.
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Lautrup S, Sinclair DA, Mattson MP, and Fang EF
- Subjects
- Animals, Cell Line, Humans, Mice, Neurodegenerative Diseases drug therapy, Neurons cytology, Neurons pathology, Rats, Aging metabolism, Brain metabolism, NAD metabolism, Neurodegenerative Diseases metabolism, Neurons metabolism
- Abstract
NAD
+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+ -dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+ -based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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11. Frailty biomarkers in humans and rodents: Current approaches and future advances.
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Kane AE and Sinclair DA
- Subjects
- Aging pathology, Animals, Biomarkers metabolism, Brain-Derived Neurotrophic Factor metabolism, Female, Frailty pathology, Humans, Interleukin-6 metabolism, Male, Mice, Rats, Aging metabolism, DNA Methylation, Epigenesis, Genetic, Frailty metabolism, Inflammation Mediators metabolism
- Abstract
Even though they would have great benefit across research and clinical fields, currently there are no accepted biomarkers of frailty. Cross-sectional studies in humans have identified promising candidates including inflammatory markers such as IL-6, immune markers such as WBC count, clinical markers such as albumin, endocrine markers such as vitamin D, oxidative stress markers such as isoprostanes, proteins such as BDNF and epigenetic markers such as DNA methylation, but there are limitations to the current state of the research. Future approaches to the identification of frailty biomarkers should include longitudinal studies, studies using animal models of frailty, studies incorporating novel biomarkers combined into composite panels, and studies investigating sex differences and potential overlap between markers of biological age and frailty., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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12. Epigenetic changes during aging and their reprogramming potential.
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Kane AE and Sinclair DA
- Subjects
- Animals, Cellular Reprogramming, Chromatin genetics, CpG Islands, DNA Methylation, Humans, Aging, Epigenesis, Genetic
- Abstract
The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. Excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors. This review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes.
- Published
- 2019
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13. Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice.
- Author
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Wahl D, Solon-Biet SM, Wang QP, Wali JA, Pulpitel T, Clark X, Raubenheimer D, Senior AM, Sinclair DA, Cooney GJ, de Cabo R, Cogger VC, Simpson SJ, and Le Couteur DG
- Subjects
- Aging drug effects, Animals, Behavior, Animal drug effects, Biomarkers metabolism, Body Composition drug effects, Brain drug effects, Brain pathology, Caloric Restriction, Cognition drug effects, Dendritic Spines drug effects, Dendritic Spines metabolism, Female, Gene Expression Regulation drug effects, Heart drug effects, Heart physiology, Inflammation pathology, Male, Memory drug effects, Mice, Aging physiology, Brain physiology, Diet, Protein-Restricted, Dietary Carbohydrates pharmacology
- Abstract
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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14. Sirtuins and NAD + in the Development and Treatment of Metabolic and Cardiovascular Diseases.
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Kane AE and Sinclair DA
- Subjects
- Age Factors, Aging pathology, Animals, Cardiovascular Diseases drug therapy, Cardiovascular Diseases pathology, Cardiovascular Diseases physiopathology, Cardiovascular System drug effects, Cardiovascular System pathology, Cardiovascular System physiopathology, Enzyme Activation, Enzyme Activators therapeutic use, Humans, Metabolic Diseases drug therapy, Metabolic Diseases pathology, Metabolic Diseases physiopathology, Up-Regulation, Aging metabolism, Cardiovascular Diseases enzymology, Cardiovascular System enzymology, Metabolic Diseases enzymology, NAD metabolism, Sirtuins metabolism
- Abstract
The sirtuin family of nicotinamide adenine dinucleotide-dependent deacylases (SIRT1-7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.
- Published
- 2018
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15. Impairment of an Endothelial NAD + -H 2 S Signaling Network Is a Reversible Cause of Vascular Aging.
- Author
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Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne B, Joshi S, Lu Y, Treviño-Villarreal JH, Kang MJ, Hung TT, Lee B, Williams EO, Igarashi M, Mitchell JR, Wu LE, Turner N, Arany Z, Guarente L, and Sinclair DA
- Subjects
- Animals, Endothelial Cells cytology, Endothelial Cells metabolism, Humans, Mice, Mice, Knockout, Microvessels metabolism, Mitochondria metabolism, Muscle, Skeletal metabolism, Neovascularization, Physiologic, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Physical Conditioning, Animal, RNA Interference, RNA, Small Interfering metabolism, Receptors, Notch metabolism, Signal Transduction, Sirtuin 1 antagonists & inhibitors, Sirtuin 1 genetics, Sirtuin 1 metabolism, Vascular Endothelial Growth Factor A metabolism, Aging, Hydrogen Sulfide metabolism, NAD metabolism
- Abstract
A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD
+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2 S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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16. A conserved NAD + binding pocket that regulates protein-protein interactions during aging.
- Author
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Li J, Bonkowski MS, Moniot S, Zhang D, Hubbard BP, Ling AJ, Rajman LA, Qin B, Lou Z, Gorbunova V, Aravind L, Steegborn C, and Sinclair DA
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- Adaptor Proteins, Signal Transducing chemistry, Adaptor Proteins, Signal Transducing genetics, Aging genetics, Animals, Conserved Sequence, DNA Damage genetics, Fibroblasts drug effects, Fibroblasts metabolism, HEK293 Cells, Humans, Mice, Models, Molecular, Neoplasms genetics, Neoplasms metabolism, Paraquat pharmacology, Poly (ADP-Ribose) Polymerase-1 chemistry, Poly (ADP-Ribose) Polymerase-1 genetics, Protein Interaction Domains and Motifs, RNA, Small Interfering genetics, Radiation Tolerance genetics, Sequence Homology, Nucleic Acid, Adaptor Proteins, Signal Transducing metabolism, Aging metabolism, DNA Repair, NAD metabolism, Poly (ADP-Ribose) Polymerase-1 metabolism
- Abstract
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD
+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+ Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging., (Copyright © 2017, American Association for the Advancement of Science.)- Published
- 2017
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17. Slowing ageing by design: the rise of NAD + and sirtuin-activating compounds.
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Bonkowski MS and Sinclair DA
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- Allosteric Regulation, Animals, Clinical Trials as Topic, Enzyme Activators pharmacology, Humans, NAD physiology, Resveratrol, Stilbenes pharmacology, Aging drug effects, Enzyme Activators therapeutic use, Sirtuins physiology, Stilbenes therapeutic use
- Abstract
The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD
+ )-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans., Competing Interests: statement The authors declare competing interests: see Web version for details.- Published
- 2016
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18. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance.
- Author
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Mohamad M, Mitchell SJ, Wu LE, White MY, Cordwell SJ, Mach J, Solon-Biet SM, Boyer D, Nines D, Das A, Catherine Li SY, Warren A, Hilmer SN, Fraser R, Sinclair DA, Simpson SJ, de Cabo R, Le Couteur DG, and Cogger VC
- Subjects
- Animals, Disease Models, Animal, Endothelial Cells metabolism, Glucose metabolism, Glycogen metabolism, Liver cytology, Liver metabolism, Male, Mice, Inbred C57BL, Poloxamer, Porosity, Rats, Inbred F344, Staining and Labeling, Aging metabolism, Insulin metabolism, Insulin Resistance, Liver blood supply, Liver ultrastructure, Microcirculation
- Abstract
While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are essential for insulin transfer across the liver sinusoidal endothelium and that age-related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metabolism and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2016
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19. Why NAD(+) Declines during Aging: It's Destroyed.
- Author
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Schultz MB and Sinclair DA
- Subjects
- ADP-ribosyl Cyclase 1 metabolism, Animals, Mice, Mitochondria metabolism, Models, Biological, Aging metabolism, NAD metabolism
- Abstract
NAD(+) is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate CD38 in the decline of NAD(+) during aging, with implications for combating age-related diseases., Competing Interests: D.A.S. is a consultant and/or inventor on patents licensed to GlaxoSmithKline, Ovascience, Metrobiotech, Caudalie, and Liberty Biosecurity., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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20. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.
- Author
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Mitchell SJ, Madrigal-Matute J, Scheibye-Knudsen M, Fang E, Aon M, González-Reyes JA, Cortassa S, Kaushik S, Gonzalez-Freire M, Patel B, Wahl D, Ali A, Calvo-Rubio M, Burón MI, Guiterrez V, Ward TM, Palacios HH, Cai H, Frederick DW, Hine C, Broeskamp F, Habering L, Dawson J, Beasley TM, Wan J, Ikeno Y, Hubbard G, Becker KG, Zhang Y, Bohr VA, Longo DL, Navas P, Ferrucci L, Sinclair DA, Cohen P, Egan JM, Mitchell JR, Baur JA, Allison DB, Anson RM, Villalba JM, Madeo F, Cuervo AM, Pearson KJ, Ingram DK, Bernier M, and de Cabo R
- Subjects
- Aging genetics, Animals, Autophagy genetics, Biomarkers metabolism, Caloric Restriction, Cluster Analysis, Female, Gene Expression Profiling, Gene Expression Regulation, Glucose metabolism, Homeostasis genetics, Hydrogen Sulfide metabolism, Islets of Langerhans anatomy & histology, Liver metabolism, Liver ultrastructure, Longevity genetics, Longevity physiology, Male, Metabolome, Metabolomics, Mice, Mice, Inbred Strains, Mitochondria metabolism, Phenotype, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism, Aging metabolism, Energy Intake genetics, Sex Characteristics
- Abstract
Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions., (Published by Elsevier Inc.)
- Published
- 2016
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21. When stem cells grow old: phenotypes and mechanisms of stem cell aging.
- Author
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Schultz MB and Sinclair DA
- Subjects
- Animals, Cell Survival physiology, Humans, Telomere Shortening physiology, Aging physiology, Cellular Senescence physiology, Longevity physiology, Stem Cells physiology
- Abstract
All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan., (© 2016. Published by The Company of Biologists Ltd.)
- Published
- 2016
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22. Interventions to Slow Aging in Humans: Are We Ready?
- Author
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Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, and Fontana L
- Subjects
- AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Aging genetics, Animals, Caloric Restriction methods, Diet, Enzyme Activation, Gene Expression Regulation, Growth Hormone antagonists & inhibitors, Growth Hormone genetics, Growth Hormone metabolism, Humans, Insulin-Like Growth Factor I antagonists & inhibitors, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Longevity genetics, Mice, Ribosomal Protein S6 Kinases antagonists & inhibitors, Ribosomal Protein S6 Kinases genetics, Ribosomal Protein S6 Kinases metabolism, Signal Transduction, Sirtuins genetics, Sirtuins metabolism, TOR Serine-Threonine Kinases antagonists & inhibitors, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Aging drug effects, Biological Factors therapeutic use, Longevity drug effects, Prescription Drugs therapeutic use
- Abstract
The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2015
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23. Oogonial stem cells as a model to study age-associated infertility in women.
- Author
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Garg N and Sinclair DA
- Subjects
- Female, Humans, Infertility, Female metabolism, Adult Germline Stem Cells metabolism, Aging metabolism, Infertility, Female etiology, Meiosis genetics, Oocytes metabolism, Oogenesis physiology, Oogonial Stem Cells metabolism
- Abstract
Fertility is the first biological process to break down during aging, thereby making it a useful tool to understand fundamental processes of aging. Reproductive aging in females is associated with a loss of ovarian function characterised by a reduction in the number and quality of oocytes. The central dogma, namely that females are born with a fixed pool of oocytes that progressively decline with increasing maternal age, has been challenged by evidence supporting postnatal oogenesis in mammals. Reports demonstrating formation of new oocytes from newly discovered germline stem cells, referred to as oogonial stem cells (OSCs), has opened new avenues for treatment of female infertility. In this review we discuss why the OSCs possibly lose their regenerative potential over time, and focus specifically on the aging process in germline stem cells as a possible mechanism for understanding female age-related infertility and how we can slow or delay ovarian aging.
- Published
- 2015
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- View/download PDF
24. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice.
- Author
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Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N, Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, and Simpson SJ
- Subjects
- Amino Acids, Branched-Chain pharmacology, Animals, Blood Pressure drug effects, Body Composition drug effects, Cardiovascular Physiological Phenomena drug effects, Energy Intake drug effects, Glucose pharmacology, Glucose Intolerance, Insulin blood, Kaplan-Meier Estimate, Leptin blood, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Phosphorylation, TOR Serine-Threonine Kinases metabolism, Aging, Diet, Longevity drug effects
- Abstract
The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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25. Small molecule SIRT1 activators for the treatment of aging and age-related diseases.
- Author
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Hubbard BP and Sinclair DA
- Subjects
- Aging metabolism, Aging pathology, Animals, Cardiovascular Diseases drug therapy, Cardiovascular Diseases metabolism, Diabetes Mellitus drug therapy, Diabetes Mellitus metabolism, Humans, Inflammation drug therapy, Inflammation metabolism, Longevity drug effects, Longevity physiology, Molecular Targeted Therapy, Neoplasms drug therapy, Neoplasms metabolism, Aging drug effects, Sirtuin 1 metabolism
- Abstract
Recent studies in mice have identified single molecules that can delay multiple diseases of aging and extend lifespan. In theory, such molecules could prevent dozens of diseases simultaneously, potentially extending healthy years of life. In this review, we discuss recent advances, controversies, opportunities, and challenges surrounding the development of SIRT1 activators, molecules with the potential to delay aging and age-related diseases. Sirtuins comprise a family of NAD⁺-dependent deacylases that are central to the body's response to diet and exercise. New studies indicate that both natural and synthetic sirtuin activating compounds (STACs) work via a common allosteric mechanism to stimulate sirtuin activity, thereby conferring broad health benefits in rodents, primates, and possibly humans. The fact that two-thirds of people in the USA who consume multiple dietary supplements consume resveratrol, a SIRT1 activator, underscores the importance of understanding the biochemical mechanism, physiological effects, and safety of STACs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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26. Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis.
- Author
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Wu LE, Gomes AP, and Sinclair DA
- Subjects
- Aging pathology, Animals, Carcinogenesis pathology, Humans, Aging metabolism, Carcinogenesis metabolism, Energy Metabolism physiology
- Abstract
Why does cancer risk increase as we age? Frequently attributed to the multi-hit hypothesis and the time required to accumulate genomic mutations, this question is a matter of ongoing debate. Here, we propose that the normal decline in oxidative metabolism during aging constitutes an early and important "hit" that drives tumorigenesis. Central to these metabolic changes are the sirtuins, a family of NAD(+)-dependent deacylases that have evolved as coordinators of physiological responses to nutrient intake and energetic demand. Thus, the modulation of sirtuins might be a fruitful approach to reversing the age-related metabolic changes that could underlie tumorigenesis., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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27. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.
- Author
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Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, and Sinclair DA
- Subjects
- AMP-Activated Protein Kinases metabolism, Animals, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mice, Muscle, Skeletal metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Reactive Oxygen Species metabolism, Sirtuin 1 metabolism, Transcription Factors metabolism, Aging pathology, Cell Nucleus metabolism, Mitochondria metabolism, NAD metabolism, Oxidative Phosphorylation
- Abstract
Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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28. Germline energetics, aging, and female infertility.
- Author
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Tilly JL and Sinclair DA
- Subjects
- Animals, Caloric Restriction, Female, Germ Cells, Humans, Menopause metabolism, Mice, Mitochondria metabolism, Oocytes, Ovary cytology, Rats, Stem Cells, Aging metabolism, Infertility, Female metabolism, Oogenesis, Ovary metabolism
- Abstract
The role of metabolism in ovarian aging is poorly described, despite the fact that ovaries fail earlier than most other organs. Growing interest in ovarian function is being driven by recent evidence that mammalian females routinely generate new oocytes during adult life through the activity of germline stem cells. In this perspective, we overview the female reproductive system as a powerful and clinically relevant model to understand links between aging and metabolism, and we discuss new concepts for how oocytes and their precursor cells might be altered metabolically to sustain or increase ovarian function and fertility in women., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
29. The intersection between aging and cardiovascular disease.
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North BJ and Sinclair DA
- Subjects
- Age Factors, Aged, Animals, Cardiovascular Diseases genetics, Cardiovascular Diseases metabolism, Cardiovascular Diseases mortality, Cardiovascular Diseases pathology, Cardiovascular Diseases physiopathology, Gene Expression Regulation, Humans, Longevity, Prognosis, Risk Assessment, Risk Factors, Aging genetics, Aging metabolism, Aging pathology, Cardiovascular Diseases etiology, Cardiovascular System metabolism, Cardiovascular System pathology, Cardiovascular System physiopathology
- Abstract
The average lifespan of humans is increasing, and with it the percentage of people entering the 65 and older age group is growing rapidly and will continue to do so in the next 20 years. Within this age group, cardiovascular disease will remain the leading cause of death, and the cost associated with treatment will continue to increase. Aging is an inevitable part of life and unfortunately poses the largest risk factor for cardiovascular disease. Although numerous studies in the cardiovascular field have considered both young and aged humans, there are still many unanswered questions as to how the genetic pathways that regulate aging in model organisms influence cardiovascular aging. Likewise, in the molecular biology of aging field, few studies fully assess the role of these aging pathways in cardiovascular health. Fortunately, this gap is beginning to close, and these two fields are merging together. We provide an overview of some of the key genes involved in regulating lifespan and health span, including sirtuins, AMP-activated protein kinase, mammalian target of rapamycin, and insulin-like growth factor 1 and their roles regulating cardiovascular health. We then discuss a series of review articles that will appear in succession and provide a more comprehensive analysis of studies carried out linking genes of aging and cardiovascular health, and perspectives of future directions of these two intimately linked fields.
- Published
- 2012
- Full Text
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30. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy.
- Author
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Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, and Sinclair DA
- Subjects
- Acetylation, Age Factors, Amino Acid Sequence, Animals, Cardiomegaly enzymology, Cardiomegaly genetics, Cardiomegaly pathology, Peptidyl-Prolyl Isomerase F, Cyclophilins chemistry, Cyclophilins genetics, Cyclosporine pharmacology, Disease Models, Animal, Humans, Lysine, Mice, Mice, 129 Strain, Mice, Knockout, Mitochondria, Heart drug effects, Mitochondria, Heart pathology, Mitochondrial Membrane Transport Proteins chemistry, Mitochondrial Permeability Transition Pore, Mitochondrial Swelling, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Protein Conformation, Sirtuin 3 deficiency, Sirtuin 3 genetics, Structure-Activity Relationship, Time Factors, Aging, Cardiomegaly prevention & control, Cyclophilins metabolism, Mitochondria, Heart enzymology, Mitochondrial Membrane Transport Proteins metabolism, Myocytes, Cardiac enzymology, Sirtuin 3 metabolism
- Abstract
Cardiac failure is a leading cause of age-related death, though its root cause remains unknown. Mounting evidence implicates a decline in mitochondrial function due to increased opening of the mitochondrial permeability transition pore (mPTP). Here we report that the NAD+-dependent deacetylase SIRT3 deacetylates the regulatory component of the mPTP, cyclophilin D (CypD) on lysine 166, adjacent to the binding site of cyclosporine A, a CypD inhibitor. Cardiac myocytes from mice lacking SIRT3 exhibit an age-dependent increase in mitochondrial swelling due to increased mPTP opening, a phenotype that is rescued by cyclosporine A. SIRT3 knockout mice show accelerated signs of aging in the heart including cardiac hypertrophy and fibrosis at 13 months of age. SIRT3 knockout mice are also hypersensitive to heart stress induced by transverse aortic constriction (TAC), as evidenced by cardiac hypertrophy, fibrosis, and increased mortality. Together, these data show for the first time that SIRT3 activity is necessary to prevent mitochondrial dysfunction and cardiac hypertrophy during aging and shed light on new pharmacological approaches to delaying aging and treating diseases in cardiac muscle and possibly other post-mitotic tissues.
- Published
- 2010
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31. Dietary restriction: standing up for sirtuins.
- Author
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Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P, Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA, Tong Q, Tsubota K, Vaquero A, and Verdin E
- Subjects
- Animals, Humans, Signal Transduction, Aging physiology, Caloric Restriction, Longevity, Sirtuins physiology
- Published
- 2010
- Full Text
- View/download PDF
32. A blueprint for developing therapeutic approaches that increase healthspan and delay death.
- Author
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Le Couteur DG and Sinclair DA
- Subjects
- Antioxidants therapeutic use, Caloric Restriction, Health, Humans, Longevity drug effects, Aging drug effects
- Published
- 2010
- Full Text
- View/download PDF
33. Impact papers on aging in 2009.
- Author
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Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, Bohr VA, Brosh RM Jr, Brunet A, Depinho RA, Donehower LA, Finch CE, Finkel T, Gorospe M, Gudkov AV, Hall MN, Hekimi S, Helfand SL, Karlseder J, Kenyon C, Kroemer G, Longo V, Nussenzweig A, Osiewacz HD, Peeper DS, Rando TA, Rudolph KL, Sassone-Corsi P, Serrano M, Sharpless NE, Skulachev VP, Tilly JL, Tower J, Verdin E, and Vijg J
- Subjects
- Adult Stem Cells physiology, Aging drug effects, Animals, Autophagy, Caloric Restriction, Cellular Reprogramming, Circadian Rhythm, DNA Damage, Humans, Mitochondria metabolism, Neoplasms metabolism, Oxidative Stress, RNA Processing, Post-Transcriptional, Telomere physiology, Aging physiology
- Abstract
The Editorial Board of Aging reviews research papers published in 2009, which they believe have or will have significant impact on aging research. Among many others, the topics include genes that accelerate aging or in contrast promote longevity in model organisms, DNA damage responses and telomeres, molecular mechanisms of life span extension by calorie restriction and pharmacological interventions into aging. The emerging message in 2009 is that aging is not random but determined by a genetically-regulated longevity network and can be decelerated both genetically and pharmacologically., ((c) Blagosklonny et al)
- Published
- 2010
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34. Mammalian sirtuins: biological insights and disease relevance.
- Author
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Haigis MC and Sinclair DA
- Subjects
- Animals, Cardiovascular Diseases physiopathology, Humans, Metabolic Diseases physiopathology, Neoplasms physiopathology, Neurodegenerative Diseases physiopathology, Aging physiology, Longevity physiology, Sirtuins physiology
- Abstract
Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
- Published
- 2010
- Full Text
- View/download PDF
35. The ageing epigenome: damaged beyond repair?
- Author
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Sinclair DA and Oberdoerffer P
- Subjects
- Aging metabolism, Animals, Chromatin genetics, DNA Repair genetics, Genomic Instability genetics, Humans, Mutation genetics, Oxidative Stress genetics, Protein Processing, Post-Translational genetics, Aging genetics, Cellular Senescence genetics, DNA Damage genetics, Epigenesis, Genetic genetics
- Abstract
Of all the proposed causes of ageing, DNA damage remains a leading, though still debated theory. Unlike most other types of age-related cellular damage, which can hypothetically be reversed, mutations in DNA are permanent. Such errors result in the accumulation of changes to RNA and protein sequences with age, and are tightly linked to cellular senescence and overall organ dysfunction. Over the past few years, an additional, more global role has emerged for the contribution of DNA damage and genomic instability to the ageing process. We, and others have found that DNA damage and the concomitant repair process can induce genome-wide epigenetic changes, which may promote a variety of age-related transcriptional and functional changes. Here, we discuss the link between DNA damage, chromatin alterations and ageing, an interplay that explains how seemingly random DNA damage could manifest in predictable phenotypic changes that define ageing, changes that may ultimately be reversible.
- Published
- 2009
- Full Text
- View/download PDF
36. Aging: past, present and future.
- Author
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Blagosklonny MV, Campisi J, and Sinclair DA
- Subjects
- Animals, Caloric Restriction, DNA Damage physiology, History, 19th Century, History, 20th Century, History, 21st Century, Humans, Longevity physiology, Selection, Genetic physiology, Signal Transduction physiology, Aging physiology, Physiology history, Physiology trends
- Published
- 2009
- Full Text
- View/download PDF
37. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging.
- Author
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Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, and Sinclair DA
- Subjects
- Animals, Brain metabolism, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Repair, Embryonic Stem Cells, Gene Knockout Techniques, Humans, Lymphoma metabolism, Mice, Molecular Sequence Data, Oxidative Stress, Sirtuin 1, Specific Pathogen-Free Organisms, Thymus Neoplasms metabolism, Yeasts cytology, Yeasts metabolism, Aging genetics, Chromatin metabolism, Genomic Instability, Sirtuins genetics
- Abstract
Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.
- Published
- 2008
- Full Text
- View/download PDF
38. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span.
- Author
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Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, and de Cabo R
- Subjects
- Age Factors, Aging genetics, Aging metabolism, Animals, Antioxidants pharmacology, Antioxidants therapeutic use, Apoptosis drug effects, Apoptosis physiology, Cardiovascular System drug effects, Cardiovascular System physiopathology, Food Deprivation physiology, Food, Formulated, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Inflammation drug therapy, Inflammation prevention & control, Longevity genetics, Male, Mice, Mice, Inbred C57BL, Osteoporosis drug therapy, Osteoporosis prevention & control, Resveratrol, Stilbenes therapeutic use, Transcription, Genetic genetics, Treatment Outcome, Aging drug effects, Caloric Restriction, Energy Intake genetics, Longevity drug effects, Stilbenes pharmacology, Transcription, Genetic drug effects
- Abstract
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.
- Published
- 2008
- Full Text
- View/download PDF
39. David A. Sinclair, Ph.D is interviewed by Vicki Glaser.
- Author
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Sinclair DA
- Subjects
- Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans physiology, Longevity genetics, Longevity physiology, Mice, Research economics, Research Support as Topic, Aging physiology
- Published
- 2008
- Full Text
- View/download PDF
40. The role of nuclear architecture in genomic instability and ageing.
- Author
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Oberdoerffer P and Sinclair DA
- Subjects
- Animals, Gene Expression, Humans, Saccharomyces cerevisiae physiology, Aging physiology, Chromatin physiology, Genomic Instability
- Abstract
Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time--a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA-protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms.
- Published
- 2007
- Full Text
- View/download PDF
41. Can we slow aging?
- Author
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Sinclair D and Komaroff AL
- Subjects
- Aging physiology, Humans, Resveratrol, United States, Wine, Aging genetics, Longevity, Stilbenes
- Published
- 2006
42. Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity?
- Author
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Yang H, Lavu S, and Sinclair DA
- Subjects
- Animals, Caloric Restriction, NAD biosynthesis, Niacinamide physiology, Nicotinamide Phosphoribosyltransferase, Saccharomyces cerevisiae physiology, Sirtuins physiology, Aging physiology, Longevity physiology, Mammals physiology, Pentosyltransferases physiology
- Abstract
Eukaryotes have evolved elaborate mechanisms to survive periods of adversity. By manipulating genes that control these mechanisms, researchers have found they can generate more stress resistant, longer-lived organisms. One of these is the PNC1 gene of Saccharomyces cerevisiae, a master "longevity regulatory gene" that translates a variety of environmental stresses into lifespan extension by activating the sirtuin family of longevity deacetylases. Master longevity genes such as PNC1 are highly adaptive because they allow organisms to respond in a concerted way to adversity and to rapidly evolve life strategies to compensate for a changing environment. Hence, they should be well conserved. We propose that there is a functional equivalent of PNC1 in mammals called Nampt (a.k.a. PBEF/Visfatin), a stress-responsive gene that would coordinately regulate metabolism, cell defenses, and resistance to diseases of aging.
- Published
- 2006
- Full Text
- View/download PDF
43. Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
- Author
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Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, and Sinclair D
- Subjects
- Aging drug effects, Alleles, Animal Feed, Animals, Caenorhabditis elegans drug effects, Drosophila melanogaster drug effects, Drosophila melanogaster genetics, Feeding Behavior drug effects, Feeding Behavior physiology, Female, Fertility drug effects, Fertility physiology, Flavonoids pharmacology, Flavonols, Genotype, Longevity drug effects, Male, Mutation genetics, Phenols pharmacology, Polyphenols, Resveratrol, Sirtuins metabolism, Stilbenes pharmacology, Survival Rate, Time Factors, Aging physiology, Caenorhabditis elegans physiology, Caloric Restriction, Drosophila melanogaster physiology, Longevity physiology, Sirtuins agonists
- Abstract
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
- Published
- 2004
- Full Text
- View/download PDF
44. Cell biology. An age of instability.
- Author
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Sinclair DA
- Subjects
- Animals, Cell Division, DNA Damage, DNA Repair, DNA Replication, DNA, Fungal metabolism, DNA, Fungal physiology, DNA, Ribosomal metabolism, Genes, rRNA, Humans, Neoplasms genetics, Aging, Cellular Senescence, Genes, Fungal, Mutation, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae physiology
- Abstract
It is well established that as we age our cancer risk increases dramatically. As Sinclair explains in his Perspective, the link between cancer and aging is now solidified by new work in budding yeast (McMurray and Gottschling). As yeast cells age there is a marked increase in their genetic instability (a hallmark of cancer), which is independent of the mechanism that determines their life-span.
- Published
- 2003
- Full Text
- View/download PDF
45. Is DNA cut out for a long life?
- Author
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Sinclair D
- Subjects
- Animals, DNA Repair, Mice, Mice, Knockout, Models, Biological, Reactive Oxygen Species, Aging genetics, DNA Damage, DNA, Fungal, Longevity genetics, Saccharomyces cerevisiae genetics
- Abstract
Much attention has been focused on the DNA repair hypothesis of aging. Studies in mammals that seek to test the validity of this model are complicated by both the functional redundancy and the essential nature of genes involved in the repair process. Compared to mammals, the study of DNA repair and aging in yeast has considerably fewer complicating factors. In this Perspective, I discuss results presented in this month's issue of Aging Cell that address whether the types of DNA damage repaired by the base excision repair pathway cause aging in yeast.
- Published
- 2003
- Full Text
- View/download PDF
46. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1.
- Author
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Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, and Sinclair DA
- Subjects
- DNA, Ribosomal genetics, Genes, Fungal, Green Fluorescent Proteins, Histone Deacetylases genetics, Humans, Life Expectancy, Luminescent Proteins genetics, Luminescent Proteins metabolism, Models, Biological, Molecular Structure, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Recombination, Genetic, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae physiology, Silent Information Regulator Proteins, Saccharomyces cerevisiae genetics, Sirtuin 1, Sirtuin 2, Sirtuins genetics, Telomere genetics, Aging physiology, Gene Silencing, Histone Deacetylases metabolism, Niacinamide pharmacology, Saccharomyces cerevisiae drug effects, Silent Information Regulator Proteins, Saccharomyces cerevisiae metabolism, Sirtuins metabolism
- Abstract
The Saccharomyces cerevisiae Sir2 protein is an NAD(+)-dependent histone deacetylase that plays a critical role in transcriptional silencing, genome stability, and longevity. A human homologue of Sir2, SIRT1, regulates the activity of the p53 tumor suppressor and inhibits apoptosis. The Sir2 deacetylation reaction generates two products: O-acetyl-ADP-ribose and nicotinamide, a precursor of nicotinic acid and a form of niacin/vitamin B(3). We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of a sir2 mutant. Nicotinamide abolishes silencing and leads to an eventual delocalization of Sir2 even in G(1)-arrested cells, demonstrating that silent heterochromatin requires continual Sir2 activity. We show that physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC(50) < 50 microm) is equal to or better than the most effective known synthetic inhibitors of this class of proteins. We propose a model whereby nicotinamide inhibits deacetylation by binding to a conserved pocket adjacent to NAD(+), thereby blocking NAD(+) hydrolysis. We discuss the possibility that nicotinamide is a physiologically relevant regulator of Sir2 enzymes.
- Published
- 2002
- Full Text
- View/download PDF
47. Sirtuin Evolution at the Dawn of Animal Life
- Author
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Gold, David A and Sinclair, David A
- Subjects
Aging ,Genetics ,Animals ,Humans ,Longevity ,NAD ,Sirtuins ,Vertebrates ,sirtuin ,PNC1 ,NAMPT ,animals ,gene evolution ,Biochemistry and Cell Biology ,Evolutionary Biology - Abstract
Sirtuins are a family of proteins that protect against cellular injury and aging; understanding their evolution should reveal fundamental mechanisms governing longevity. "Early-branching" animals such as sea sponges and jellyfish have been understudied in previous analyses of sirtuin diversity. These organisms not only hold important positions at the base of the evolutionary tree, but also have unique aging dynamics that defy convention, such as quasi-immortality and high regenerative capacity. In this study, we survey the evolution of sirtuin proteins in animals, with a focus on the oldest living lineages. We describe previously unrecognized expansions of "Class IV" and "Class I" sirtuins around the origin of animals, raising the number of sirtuin families in the last common ancestor to at least nine. Most of these undescribed sirtuins have been lost in vertebrates and other bilaterian animals. Our work also clarifies the evolution of PNC1 and NAMPT enzymes that carry out the rate-limiting step in sirtuin-related NAD+ biosynthesis. The genes for PNC1 and NAMPT enzymes were both present in the first animals, with the genes being lost a minimum of 11 and 13 times, respectively, over the course of animal evolution. We propose that species with these ancestral gene repertoires are ideal model organisms for studying the genetic regulation of animal longevity and will provide clues to increasing longevity in humans.
- Published
- 2022
48. Meeting Report: Aging Research and Drug Discovery
- Author
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Meron, Esther, Thaysen, Maria, Angeli, Suzanne, Antebi, Adam, Barzilai, Nir, Baur, Joseph A, Bekker-Jensen, Simon, Birkisdottir, Maria, Bischof, Evelyne, Bruening, Jens, Brunet, Anne, Buchwalter, Abigail, Cabreiro, Filipe, Cai, Shiqing, Chen, Brian H, Ermolaeva, Maria, Ewald, Collin Y, Ferrucci, Luigi, Florian, Maria Carolina, Fortney, Kristen, Freund, Adam, Georgievskaya, Anastasia, Gladyshev, Vadim N, Glass, David, Golato, Tyler, Gorbunova, Vera, Hoejimakers, Jan, Houtkooper, Riekelt H, Jager, Sibylle, Jaksch, Frank, Janssens, Georges, Jensen, Martin Borch, Kaeberlein, Matt, Karsenty, Gerard, de Keizer, Peter, Kennedy, Brian, Kirkland, James L, Kjaer, Michael, Kroemer, Guido, Lee, Kai-Fu, Lemaitre, Jean-Marc, Liaskos, David, Longo, Valter D, Lu, Yu-Xuan, MacArthur, Michael R, Maier, Andrea B, Manakanatas, Christina, Mitchell, Sarah J, Moskalev, Alexey, Niedernhofer, Laura, Ozerov, Ivan, Partridge, Linda, Passegué, Emmanuelle, Petr, Michael A, Peyer, James, Radenkovic, Dina, Rando, Thomas A, Rattan, Suresh, Riedel, Christian G, Rudolph, Lenhard, Ai, Ruixue, Serrano, Manuel, Schumacher, Björn, Sinclair, David A, Smith, Ryan, Suh, Yousin, Taub, Pam, Trapp, Alexandre, Trendelenburg, Anne-Ulrike, Valenzano, Dario Riccardo, Verburgh, Kris, Verdin, Eric, Vijg, Jan, Westendorp, Rudi GJ, Zonari, Alessandra, Bakula, Daniela, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten
- Subjects
Aging ,aging ,drug discovery ,conference ,AI ,longevity ,Biochemistry and Cell Biology ,Physiology ,Oncology and Carcinogenesis ,Developmental Biology - Abstract
Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery (ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community.
- Published
- 2022
49. The impact of anesthesia providers on major morbidity following screening colonoscopies
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Lubarsky, David A, Guercio, Jason R, Hanna, John W, Abreu, Maria T, Ma, Qianli, Uribe, Claudia, Birnbach, David J, Sinclair, David R, and Candiotti, Keith A
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Public Health ,Biomedical and Clinical Sciences ,Clinical Sciences ,Health Sciences ,Clinical Research ,Prevention ,Health Services ,Patient Safety ,Aging ,Colo-Rectal Cancer ,Digestive Diseases ,Cancer ,anesthesiology ,complications ,endoscopy ,myocardial infarction ,safety ,stroke ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Background and aimsFew studies evaluate the impact of anesthesia providers during procedures, such as colonoscopy, on low-risk patients. The objective of this study was to compare the effect of anesthesia providers on several outcome variables, including major morbidity, following screening colonoscopies.MethodsA propensity-matched cohort study of 14,006 patients who enrolled with a national insurer offering health maintenance organization (HMO), preferred provider organization (PPO), and Medicare Advantage plans for a screening colonoscopy between July 1, 2005 and June 30, 2007 were studied. Records were evaluated for completion of the colonoscopy, new cancer diagnosis (colon, anal, rectal) within 6 months of the colonoscopy, new primary diagnosis of myocardial infarction (MI), new primary diagnosis of stroke, hospital admission within 7 days of the colonoscopy, and adherence to guidelines for use of anesthesia providers.ResultsThe presence of an anesthesia provider did not affect major morbidity or the percent of completed exams. Overall morbidity within 7 days was very low. When an anesthesia provider was present, a nonsignificant trend toward greater cancer detection within 6 months of the procedure was observed. Adherence to national guidelines regarding the use of anesthesia providers for low-risk patients was poor.ConclusionA difference in outcome associated with the presence or absence of an anesthesia provider during screening colonoscopy in terms of MI, stroke, or hospital admission within 7 days of the procedure was not observed. Adherence to published guidelines for the use of anesthesia providers is low. The incidence of completed exams was unaffected by the presence of an anesthesia provider. However, a nonstatistically significant trend toward increased cancer detection requires further study.
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- 2015
50. Characteristics of older unpaid carers in England: a study of social patterning from the English Longitudinal Study of Ageing.
- Author
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Davies, Laurie E, Spiers, Gemma F, Sinclair, David R, Kingston, Andrew, and Hanratty, Barbara
- Subjects
ELDER care ,CROSS-sectional method ,HEALTH status indicators ,MENTAL health ,CHRONIC pain ,ENDOWMENTS ,RESEARCH funding ,SOCIOECONOMIC factors ,LOGISTIC regression analysis ,EQUALITY ,DESCRIPTIVE statistics ,LONELINESS ,AGE distribution ,BURDEN of care ,LONGITUDINAL method ,ODDS ratio ,AGING ,PSYCHOLOGY of caregivers ,CONFIDENCE intervals ,COMPARATIVE studies ,PUBLIC welfare ,INTERPERSONAL relations ,SOCIAL isolation ,ACTIVITIES of daily living ,COMORBIDITY ,OLD age - Abstract
Background A growing number of older people provide unpaid care, but contemporary research evidence on this group is limited. Aim This study aims to describe the characteristics of older people who provide unpaid care and how these vary by socioeconomic position. Methods Using recent information from the English Longitudinal Study of Ageing (ELSA wave 9, 2019), we analysed cross-sectional data on 1,282 unpaid carers aged ≥50. Data on sociodemographics, health, social wellbeing, care intensity and caregiver–recipient relationships were extracted. Total net non-pension wealth quintiles were used as a relative measure of socioeconomic position. Differences between the poorest and richest wealth quintiles were examined through logistic regression. Findings Most older carers in ELSA were female and looking after another older person. Poor mental and physical health and social isolation were common, and socially patterned. Compared with carers in the middle wealth group, the poorest group were more likely to be living with the person they cared for (odds ratio (OR) 1.56 [95% confidence interval (CI) 1.03–2.36]) and more likely to experience loneliness (OR 2.29 [95% CI 1.42–3.69]), dependency (i.e. the need for help with activities of daily living) (OR 1.62 [95% CI 1.05–2.51]), chronic pain (OR 1.81 [95% CI 1.23–2.67]), a higher number of diseases (OR 1.75 [95% CI 1.15–2.65]) and fair/poor self-rated health (OR 2.59 [95% CI 1.79–3.76]). The poorest carers were also less likely to have a high quality of life (OR 0.51 [95% CI 0.33–0.80]) or be in work (OR 0.33 [95% CI 0.19–0.59]). Conclusion Our findings suggest that financially disadvantaged unpaid carers (and their households) may have the greatest needs for intervention and support. Focussing resources on this group has potential to address social inequalities. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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