Publications by authors named "David A Sinclair"

164 Publications

Gut Microbiota Predicts Healthy Late-Life Aging in Male Mice.

Nutrients 2021 Sep 21;13(9). Epub 2021 Sep 21.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

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 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.
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http://dx.doi.org/10.3390/nu13093290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467910PMC
September 2021

Measuring PGC-1α and Its Acetylation Status in Mouse Primary Myotubes.

Methods Mol Biol 2021 ;2310:301-309

Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.

Metabolic flexibility is vital for organisms to respond to and survive changes in energy availability. A critical metabolic flexibility regulator is peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which regulates various transcription factors and nuclear receptors that, in turn, regulate mitochondrial homeostasis and fatty acid oxidation. PGC-1α is itself regulated, with one of the significant modes of regulation being acetylation. Thus, measuring the acetylation status of PGC-1α is a critical indicator of cells' metabolic flexibility. In this chapter, we describe a method of evaluating PGC-1α acetylation in primary mouse myotubes. This method can also be used with other cell types and tissues.
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http://dx.doi.org/10.1007/978-1-0716-1433-4_17DOI Listing
August 2021

Quantitative proteomic analysis of extracellular vesicle subgroups isolated by an optimized method combining polymer-based precipitation and size exclusion chromatography.

J Extracell Vesicles 2021 04 27;10(6):e12087. Epub 2021 Apr 27.

Laboratory of Cell Communication & Extracellular Vesicles Instituto Nacional de Medicina Genómica Mexico City Mexico.

The molecular characterization of extracellular vesicles (EVs) has revealed a great heterogeneity in their composition at a cellular and tissue level. Current isolation methods fail to efficiently separate EV subtypes for proteomic and functional analysis. The aim of this study was to develop a reproducible and scalable isolation workflow to increase the yield and purity of EV preparations. Through a combination of polymer-based precipitation and size exclusion chromatography (Pre-SEC), we analyzed two subsets of EVs based on their CD9, CD63 and CD81 content and elution time. EVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blot assays. To evaluate differences in protein composition between the early- and late-eluting EV fractions, we performed a quantitative proteomic analysis of MDA-MB-468-derived EVs. We identified 286 exclusive proteins in early-eluting fractions and 148 proteins with a differential concentration between early- and late-eluting fractions. A density gradient analysis further revealed EV heterogeneity within each analyzed subgroup. Through a systems biology approach, we found significant interactions among proteins contained in the EVs which suggest the existence of functional clusters related to specific biological processes. The workflow presented here allows the study of EV subtypes within a single cell type and contributes to standardizing the EV isolation for functional studies.
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http://dx.doi.org/10.1002/jev2.12087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077108PMC
April 2021

Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung.

Front Oncol 2020 2;10:602763. Epub 2021 Mar 2.

Department of Radiation Oncology, University of California, Irvine, CA, United States.

Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure of the lung to ionizing radiation. The hESC-derived EV were systemically administered to the mice the retro-orbital sinus to explore the potential therapeutic benefits following exposure to high thoracic doses of radiation (14 Gy). Data demonstrated that hESC-derived EV treatment significantly improved overall survival of the irradiated cohorts ( < 0.001). Increased survival was also associated with significant reductions in lung fibrosis as quantified by CBCT imaging ( < 0.01, 2 weeks post-irradiation). Qualitative histological analyses revealed reduced indications of radiation induced pulmonary injury in animals treated with EV. EV were then subjected to a rigorous proteomic analysis to ascertain the potential bioactive cargo that may prove beneficial in ameliorating radiation-induced normal tissue toxicities in the lung. Proteomics validated several consensus exosome markers (, CD68) and identified major classes of proteins involved in nuclear pore complexes, epigenetics, cell cycle, growth and proliferation, DNA repair, antioxidant function, and cellular metabolism (TCA cycle and oxidative phosphorylation, OXYPHOS). Interestingly, EV were also found to contain mitochondrial components (mtDNA, OXYPHOS protein subunits), which may contribute to the metabolic reprograming and recovery of radiation-injured pulmonary tissue. To evaluate the safety of EV treatments in the context of the radiotherapeutic management of tumors, mice harboring TC1 tumor xenografts were subjected to the same EV treatments shown to forestall lung fibrosis. Data indicated that over the course of one month, no change in the growth of flank tumors between treated and control cohorts was observed. In conclusion, present findings demonstrate that systemic delivery of hESC-derived EV could ameliorate radiation-induced normal tissue complications in the lung, through a variety of potential mechanisms based on EV cargo analysis.
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http://dx.doi.org/10.3389/fonc.2020.602763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962869PMC
March 2021

ARDD 2020: from aging mechanisms to interventions.

Aging (Albany NY) 2020 12 30;12(24):24484-24503. Epub 2020 Dec 30.

Blavatnik Institute, Department of Genetics, Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Boston, MA 94107, USA.

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 Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1 to 4 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 8 ARDD meeting that is scheduled for the 31 of August to 3 of September, 2021, at Columbia University, USA.
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http://dx.doi.org/10.18632/aging.202454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803558PMC
December 2020

Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment.

Aging (Albany NY) 2020 12 29;12(24):24504-24521. Epub 2020 Dec 29.

Angiogenesis Laboratory, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.

Currently, no pharmacotherapy has been proven effective in treating photoreceptor degeneration in patients. Discovering readily available and safe neuroprotectants is therefore highly sought after. Here, we investigated nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), in a retinal detachment (RD) induced photoreceptor degeneration. NMN administration after RD resulted in a significant reduction of TUNEL photoreceptors, CD11b macrophages, and GFAP labeled glial activation; a normalization of protein carbonyl content (PCC), and a preservation of the outer nuclear layer (ONL) thickness. NMN administration significantly increased NAD levels, SIRT1 protein expression, and heme oxygenase-1 (HO-1) expression. Delayed NMN administration still exerted protective effects after RD. Mechanistic studies using 661W cells revealed a SIRT1/HO-1 signaling as a downstream effector of NMN-mediated protection under oxidative stress and LPS stimulation. In conclusion, NMN administration exerts neuroprotective effects on photoreceptors after RD and oxidative injury, suggesting a therapeutic avenue to treating photoreceptor degeneration.
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http://dx.doi.org/10.18632/aging.202453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803565PMC
December 2020

Reprogramming to recover youthful epigenetic information and restore vision.

Nature 2020 12 2;588(7836):124-129. Epub 2020 Dec 2.

Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.

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. Changes to DNA methylation patterns over time form the basis of ageing clocks, 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 capacity. 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.
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http://dx.doi.org/10.1038/s41586-020-2975-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134PMC
December 2020

Publisher Correction: Age and life expectancy clocks based on machine learning analysis of mouse frailty.

Nat Commun 2020 Oct 8;11(1):5143. Epub 2020 Oct 8.

Blavatnik Institute, Department of Genetics, Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Boston, MA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-19046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546720PMC
October 2020

Age and life expectancy clocks based on machine learning analysis of mouse frailty.

Nat Commun 2020 09 15;11(1):4618. Epub 2020 Sep 15.

Blavatnik Institute, Department of Genetics, Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41467-020-18446-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492249PMC
September 2020

The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function.

Int J Mol Sci 2020 Jul 11;21(14). Epub 2020 Jul 11.

Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal.

Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I/R injury.
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http://dx.doi.org/10.3390/ijms21144896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402335PMC
July 2020

Can artificial intelligence identify effective COVID-19 therapies?

EMBO Mol Med 2020 08 7;12(8):e12817. Epub 2020 Jul 7.

Paul F. Glenn Center for Biology of Aging Research, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

In this issue of EMBO Molecular Medicine, Stebbing et al (2020b) validate an artificial intelligence-assisted prediction that a drug used to treat rheumatoid arthritis could be a potent weapon against COVID-19. Using liver organoids infected with SARS-CoV-2, they confirm dual antiviral and anti-inflammatory activities and show that its administration in four COVID-19 patients is correlated with disease improvement, paving the way for more rigorous placebo-controlled trials.
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http://dx.doi.org/10.15252/emmm.202012817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361072PMC
August 2020

Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.

J Gerontol A Biol Sci Med Sci 2020 10;75(11):2037-2041

Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

SRT1720, a sirtuin1-activator, and metformin (MET), an antidiabetic drug, confer health and life-span benefits when administered individually. It is unclear whether combination of the two compounds could lead to additional benefits. Groups of 56-week-old C57BL/6J male mice were fed a high-fat diet (HFD) alone or supplemented with either SRT1720 (2 g/kg food), a high dose of MET (1% wt/wt food), or a combination of both. Animals were monitored for survival, body weight, food consumption, body composition, and rotarod performance. Mice treated with MET alone did not have improved longevity, and life span was dramatically reduced by combination of MET with SRT1720. Although all groups of animals were consuming similar amounts of food, mice on MET or MET + SRT1720 showed a sharp reduction in body weight. SRT1720 + MET mice also had lower percent body fat combined with better performance on the rotarod compared to controls. These data suggest that co-treatment of SRT1720 with MET is detrimental to survival at the doses used and, therefore, risk-benefits of combining life-span-extending drugs especially in older populations needs to be systematically evaluated.
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http://dx.doi.org/10.1093/gerona/glaa148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750506PMC
October 2020

Why does COVID-19 disproportionately affect older people?

Aging (Albany NY) 2020 05 29;12(10):9959-9981. Epub 2020 May 29.

Glenn Center for Biology of Aging Research, Blavatnik Institute, Harvard Medical School, Boston, MA 20115, USA.

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.
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http://dx.doi.org/10.18632/aging.103344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963PMC
May 2020

Administration of Nicotinamide Mononucleotide (NMN) Reduces Metabolic Impairment in Male Mouse Offspring from Obese Mothers.

Cells 2020 03 25;9(4). Epub 2020 Mar 25.

Department of Pharmacology, School of Medical Sciences, UNSW Sydney NSW 2052, Australia.

Maternal obesity impacts offspring metabolism. We sought to boost mitochondrial energy metabolism using the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide mononucleotide (NMN) to treat metabolic impairment induced by maternal and long-term post weaning over-nutrition. Male offspring of lean or obese mothers, fed chow or high fat diet (HFD) for 30 weeks post-weaning, were given NMN injection, starting at 31 weeks of age, daily for 3 weeks before sacrifice. Glucose tolerance was tested at 10, 29 and 32 weeks of age to measure short and long term effects of post-weaning HFD, and NMN treatment. Plasma insulin and triglycerides, liver triglycerides and expression of mitochondrial metabolism-related genes were measured at 34 weeks. Impaired glucose tolerance due to maternal and post weaning HFD was significantly improved by only 8 days of NMN treatment. Furthermore, in offspring of obese mothers hepatic lipid accumulation was reduced due to NMN treatment by 50% and 23% in chow and HFD fed offspring respectively. Hepatic genes involved in fat synthesis, transport and uptake were reduced, while those involved in fatty acid oxidation were increased by NMN. Overall this finding suggests short term administration of NMN could be a therapeutic approach for treating metabolic disease due to maternal and post weaning over-nutrition, even in late adulthood.
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http://dx.doi.org/10.3390/cells9040791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226525PMC
March 2020

NAD Repletion Rescues Female Fertility during Reproductive Aging.

Cell Rep 2020 02;30(6):1670-1681.e7

Human Reproduction Unit, Kolling Institute, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia.

Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD). Treatment with the NAD metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD levels represents an opportunity to rescue female reproductive function in mammals.
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http://dx.doi.org/10.1016/j.celrep.2020.01.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063679PMC
February 2020

Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage.

Nat Commun 2019 12 3;10(1):5501. Epub 2019 Dec 3.

Cancer & Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT), Brisbane, Queensland, Australia.

The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor-Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD-dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions.
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http://dx.doi.org/10.1038/s41467-019-13167-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890647PMC
December 2019

NAD in Brain Aging and Neurodegenerative Disorders.

Cell Metab 2019 10;30(4):630-655

Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway; The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cmet.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787556PMC
October 2019

Voluntary exercise normalizes the proteomic landscape in muscle and brain and improves the phenotype of progeroid mice.

Aging Cell 2019 12 6;18(6):e13029. Epub 2019 Sep 6.

Department of Neuroscience, Biomedicum, Karolinska Institutet, Stockholm, Sweden.

The accumulation of mitochondrial DNA (mtDNA) mutations is a suspected driver of aging and age-related diseases, but forestalling these changes has been a major challenge. One of the best-studied models is the prematurely aging mtDNA mutator mouse, which carries a homozygous knock-in of a proofreading deficient version of the catalytic subunit of mtDNA polymerase-γ (PolgA). We investigated how voluntary exercise affects the progression of aging phenotypes in this mouse, focusing on mitochondrial and protein homeostasis in both brain and peripheral tissues. Voluntary exercise significantly ameliorated several aspects of the premature aging phenotype, including decreased locomotor activity, alopecia, and kyphosis, but did not have major effects on the decreased lifespan of mtDNA mutator mice. Exercise also decreased the mtDNA mutation load. In-depth tissue proteomics revealed that exercise normalized the levels of about half the proteins, with the majority involved in mitochondrial function and nuclear-mitochondrial crosstalk. There was also a specific increase in the nuclear-encoded proteins needed for the tricarboxylic acid cycle and complex II, but not in mitochondrial-encoded oxidative phosphorylation proteins, as well as normalization of enzymes involved in coenzyme Q biosynthesis. Furthermore, we found tissue-specific alterations, with brain coping better as compared to muscle and with motor cortex being better protected than striatum, in response to mitochondrial dysfunction. We conclude that voluntary exercise counteracts aging in mtDNA mutator mice by counteracting protein dysregulation in muscle and brain, decreasing the mtDNA mutation burden in muscle, and delaying overt aging phenotypes.
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http://dx.doi.org/10.1111/acel.13029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826127PMC
December 2019

Harvard HIV and Aging Workshop: Perspectives and Priorities from Claude D. Pepper Centers and Centers for AIDS Research.

AIDS Res Hum Retroviruses 2019 Nov/Dec;35(11-12):999-1012. Epub 2019 Sep 23.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts.

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.
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http://dx.doi.org/10.1089/AID.2019.0130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862961PMC
September 2020

Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins.

Free Radic Biol Med 2019 09 24;141:483-491. Epub 2019 Jul 24.

Department of Life Sciences, University of Coimbra, Portugal; Center for Neurosciences and Cell Biology, University of Coimbra, Portugal. Electronic address:

The key role of mitochondria in oxidative metabolism and redox homeostasis explains the link between mitochondrial dysfunction and the development of metabolic disorders. Mitochondria's highly dynamic nature, based on alterations in biogenesis, mitophagy, fusion and fission, allows adjusting sequential redox reactions of the electron transport chain (ETC) and dissipation of the membrane potential by ATP synthase, to different environmental cues. With reactive oxygen species being an inevitable by-product of oxidative phosphorylation (OXPHOS), alterations on mitochondrial oxidative rate with a consequent excessive load of reactive oxygen species have been traditionally associated with pathological conditions. However, reactive oxygen species have also been suggested as promoters of mitohormesis, a process in which low, non-cytotoxic concentrations of reactive oxygen species promote mitochondrial homeostasis. Therefore, signaling systems involved in the regulation of mitochondrial homeostasis are attractive candidates for drug development for metabolic diseases triggered by mitochondrial dysfunction. Reversible phosphorylation downstream the cyclic AMP (cAMP) signaling cascade and deacetylation mediated by sirtuins are recognized as major mitochondrial regulators.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718302PMC
September 2019

Sex differences in the response to dietary restriction in rodents.

Curr Opin Physiol 2018 Dec 27;6:28-34. Epub 2018 Mar 27.

Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Dietary restriction (DR) remains the most reproducible and consistent laboratory intervention to extend lifespan and improve health in mammals. DR has been primarily characterized in males due to issues of cost, perceived heightened variability amongst females, and the misconception that the reproductive system is the only important difference between sexes in mammals. In reality, existing data point to clear sex differences in mammalian responses to DR. Here we discuss recent advances in our understanding of sex differences in the responses to DR in rodent models.
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http://dx.doi.org/10.1016/j.cophys.2018.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588196PMC
December 2018

Impacts of obesity, maternal obesity and nicotinamide mononucleotide supplementation on sperm quality in mice.

Reproduction 2019 08;158(2):169-179

Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.

Male fertility and sperm quality are negatively impacted by obesity. Furthermore, recent evidence has shown that male offspring from obese rat mothers also have reduced sperm quality and fertility. Here, we extend work in this area by comparing the effects of both maternal obesity and offspring post-weaning diet-induced obesity, as well as their combination, on sperm quality in mice. We additionally tested whether administration of the NAD+-booster nicotinamide mononucleotide (NMN) can ameliorate the negative effects of obesity and maternal obesity on sperm quality. We previously showed that intraperitoneal (i.p.) injection of NMN can reduce the metabolic deficits induced by maternal obesity or post-weaning dietary obesity in mice. In this study, female mice were fed a high-fat diet (HFD) for 6 weeks until they were 18% heavier than a control diet group. Thereafter, HFD and control female mice were mated with control diet males, and male offspring were weaned into groups receiving control or HFD. At 30 weeks of age, mice received 500 mg/kg body weight NMN or vehicle PBS i.p. for 21 days. As expected, adiposity was increased by both maternal and post-weaning HFD but reduced by NMN supplementation. Post-weaning HFD reduced sperm count and motility, while maternal HFD increased offspring sperm DNA fragmentation and levels of aberrant sperm chromatin. There was no evidence that the combination of post-weaning and maternal HFD exacerbated the impacts in sperm quality suggesting that they impact spermatogenesis through different mechanisms. Surprisingly NMN reduced sperm count, vitality and increased sperm oxidative DNA damage, which was associated with increased NAD+ in testes. A subsequent experiment using oral NMN at 400 mg/kg body weight was not associated with reduced sperm viability, oxidative stress, mitochondrial dysfunction or increased NAD+ in testes, suggesting that the negative impacts on sperm could be dependent on dose or mode of administration.
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http://dx.doi.org/10.1530/REP-18-0574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589912PMC
August 2019

Molecular and Cellular Characterization of SIRT1 Allosteric Activators.

Methods Mol Biol 2019 ;1983:133-149

Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA.

SIRT1 is an NAD-dependent lysine deacetylase that promotes healthy aging and longevity in diverse organisms. Small molecule allosteric activators of SIRT1 such as resveratrol and SRT2104 directly bind to the N-terminus of SIRT1 and lower the K for the protein substrate. In rodents, sirtuin-activating compounds (STACs) protect from age-related diseases and extend life span. In human clinical trials, STACs have a high safety profile and anti-inflammatory activities. Here, we describe methods for identifying and characterizing STACs, including production of recombinant protein, in vitro assays with recombinant protein, and cellular assays based on mitochondrial dynamics. The methods described in this chapter will facilitate this discovery of improved STACs, natural and synthetic, in the pursuit of interventions to treat age-related diseases.
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http://dx.doi.org/10.1007/978-1-4939-9434-2_8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567996PMC
January 2020

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.

Redox Biol 2019 06 10;24:101192. Epub 2019 Apr 10.

Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary; Department of Public Health, Semmelweis University, Budapest, Hungary; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address:

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).
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http://dx.doi.org/10.1016/j.redox.2019.101192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477631PMC
June 2019

Frailty biomarkers in humans and rodents: Current approaches and future advances.

Mech Ageing Dev 2019 06 17;180:117-128. Epub 2019 Apr 17.

Department of Genetics, Harvard Medical School, Boston, MA, USA; Department of Pharmacology, The University of New South Wales, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.mad.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581034PMC
June 2019

Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.

Cell Metab 2019 06 28;29(6):1274-1290.e9. Epub 2019 Mar 28.

Department of Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.
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http://dx.doi.org/10.1016/j.cmet.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657508PMC
June 2019

Multiple basal cell carcinomas in a patient with myotonic dystrophy type 1.

BMJ Case Rep 2019 Mar 8;12(3). Epub 2019 Mar 8.

Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

A man in his early 60s with myotonic dystrophy type 1 (DM1) and an extensive history of non-melanoma skin cancer presented with multiple pearly, erythematous papules on his face, head, trunk and extremities, clinically consistent with basal cell carcinoma (BCC). Due to the numerous BCC and history of multiple and early-onset BCC, examination was concerning for a hereditary BCC syndrome. Subsequent histopathology confirmed BCC. Genetic testing was negative for basal cell nevus syndrome and clinical findings were inconsistent with other known hereditary BCC syndromes. There have been reports of an association between DM1 and BCC, however, it is not well known among clinicians. We hope to raise awareness among clinicians about this association.
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http://dx.doi.org/10.1136/bcr-2018-227233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441996PMC
March 2019

Epigenetic changes during aging and their reprogramming potential.

Crit Rev Biochem Mol Biol 2019 02 1;54(1):61-83. Epub 2019 Mar 1.

a Department of Genetics , Harvard Medical School , Boston , MA , USA.

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.
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http://dx.doi.org/10.1080/10409238.2019.1570075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424622PMC
February 2019
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