Publications by authors named "Danica Chen"

36 Publications

The therapeutic promises of NAD boosters.

Cell Metab 2021 Jul;33(7):1274-1275

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Numerous preclinical studies implicate the decline in NAD signaling in developing aging- and obesity-associated metabolic disorders. Yoshino et al. (2021) now provide the clinical evidence that an NAD booster increases muscle insulin sensitivity in postmenopausal prediabetic women, validating the therapeutic promises of NAD boosters in humans.
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http://dx.doi.org/10.1016/j.cmet.2021.06.008DOI Listing
July 2021

Redox signaling in stem cells and implications for regenerative medicine.

Authors:
Danica Chen

Free Radic Biol Med 2021 08 24;172:330. Epub 2021 Jun 24.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA. Electronic address:

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http://dx.doi.org/10.1016/j.freeradbiomed.2021.06.022DOI Listing
August 2021

Stem Cell Metabolism and Diet.

Curr Stem Cell Rep 2020 Dec 28;6(4):119-125. Epub 2020 Oct 28.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, 119 Morgan Hall, University of California, Berkeley, CA 94720.

Purpose Of Review: Diet has profound impacts on health and longevity. Evidence is emerging to suggest that diet impinges upon the metabolic pathways in tissue-specific stem cells to influence health and disease. Here, we review the similarities and differences in the metabolism of stem cells from several tissues, and highlight the mitochondrial metabolic checkpoint in stem cell maintenance and aging. We discuss how diet engages the nutrient sensing metabolic pathways and impacts stem cell maintenance. Finally, we explore the therapeutic implications of dietary and metabolic regulation of stem cells.

Recent Findings: Stem Cell transition from quiescence to proliferation is associated with a metabolic switch from glycolysis to mitochondrial OXPHOS and the mitochondrial metabolic checkpoint is critically controlled by the nutrient sensors SIRT2, SIRT3, and SIRT7 in hematopoietic stem cells. Intestine stem cell homeostasis during aging and in response to diet is critically dependent on fatty acid metabolism and ketone bodies and is influenced by the niche mediated by the nutrient sensor mTOR.

Summary: Nutrient sensing metabolic pathways critically regulate stem cell maintenance during aging and in response to diet. Elucidating the molecular mechanisms underlying dietary and metabolic regulation of stem cells provides novel insights for stem cell biology and may be targeted therapeutically to reverse stem cell aging and tissue degeneration.
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http://dx.doi.org/10.1007/s40778-020-00180-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992378PMC
December 2020

The mitochondrial metabolic checkpoint in stem cell aging and rejuvenation.

Mech Ageing Dev 2020 06 25;188:111254. Epub 2020 Apr 25.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA. Electronic address:

Stem cell aging contributes to aging-associated tissue degeneration and dysfunction. Recent studies reveal a mitochondrial metabolic checkpoint that regulates stem cell quiescence and maintenance, and dysregulation of the checkpoint leads to functional deterioration of aged stem cells. Here, we present the evidence supporting the mitochondrial metabolic checkpoint regulating stem cell aging and demonstrating the feasibility to target this checkpoint to reverse stem cell aging. We discuss the mechanisms by which mitochondrial stress leads to stem cell deterioration. We speculate the therapeutic potential of targeting the mitochondrial metabolic checkpoint for rejuvenating aged stem cells and improving aging tissue functions.
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http://dx.doi.org/10.1016/j.mad.2020.111254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375904PMC
June 2020

An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance.

Cell Metab 2020 03 6;31(3):580-591.e5. Epub 2020 Feb 6.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA. Electronic address:

It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.
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http://dx.doi.org/10.1016/j.cmet.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104778PMC
March 2020

Latest advances in aging research and drug discovery.

Aging (Albany NY) 2019 11 21;11(22):9971-9981. Epub 2019 Nov 21.

Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6 annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7 annual ARDD exhibition will transpire 2-4 of September, 2020, in Basel.
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http://dx.doi.org/10.18632/aging.102487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914421PMC
November 2019

The Epigenetics of Stem Cell Aging Comes of Age.

Trends Cell Biol 2019 07 25;29(7):563-568. Epub 2019 Apr 25.

Division of Aging Biology, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Emerging evidence indicates that epigenetic regulators are critically required for the maintenance of tissue-specific stem cells and that the epigenetic marks are altered in stem cells during physiological aging. Intriguingly, aging-associated stem cell functional decline can be reversed by manipulating epigenetic factors that become dysregulated during aging. These observations lend support to the stem cell theory of aging, which postulates that aging is the result of the inability of tissue-specific stem cells to replenish the tissues with functional differentiated cells that maintain the function of a tissue, and open a new era of research on the epigenetics of stem cell aging that may represent therapeutic potential. Recent advances in single cell technologies are revolutionizing our mechanistic understanding of rare populations of cells, such as stem cells, and offer an unprecedented opportunity to address this challenge.
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http://dx.doi.org/10.1016/j.tcb.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144731PMC
July 2019

Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging.

Cell Rep 2019 01;26(4):945-954.e4

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA. Electronic address:

Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the NLRP3 inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the NLRP3 inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that SIRT2, a cytosolic NAD-dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the NLRP3 inflammasome in HSCs cell autonomously. With age, reduced SIRT2 expression and increased mitochondrial stress lead to aberrant activation of the NLRP3 inflammasome in HSCs. SIRT2 overexpression, NLRP3 inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging.
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http://dx.doi.org/10.1016/j.celrep.2018.12.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371804PMC
January 2019

The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence.

Aging Cell 2018 06 24;17(3):e12756. Epub 2018 Mar 24.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.

The mitochondrial unfolded protein response (UPR ), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues. Despite the emerging genetic evidence implicating the UPR in stem cell maintenance, the underlying molecular mechanism is unknown. While it has been speculated that the UPR is activated upon stem cell transition from quiescence to proliferation, the direct evidence is lacking. In this study, we devised three experimental approaches that enable us to monitor quiescent and proliferating hematopoietic stem cells (HSCs) and provided the direct evidence that the UPR is activated upon HSC transition from quiescence to proliferation, and more broadly, mitochondrial integrity is actively monitored at the restriction point to ensure metabolic fitness before stem cells are committed to proliferation.
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http://dx.doi.org/10.1111/acel.12756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946069PMC
June 2018

Aging: rewiring the circadian clock.

Nat Struct Mol Biol 2017 09;24(9):687-688

Program in Metabolic Biology, Nutritional Sciences &Toxicology, University of California, Berkeley, Berkeley, California, USA.

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http://dx.doi.org/10.1038/nsmb.3461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153569PMC
September 2017

The Intersection of Aging Biology and the Pathobiology of Lung Diseases: A Joint NHLBI/NIA Workshop.

J Gerontol A Biol Sci Med Sci 2017 Oct;72(11):1492-1500

University of Alabama at Birmingham, Birmingham, Alabama.

Death from chronic lung disease is increasing and chronic obstructive pulmonary disease has become the third leading cause of death in the United States in the past decade. Both chronic and acute lung diseases disproportionately affect elderly individuals, making it likely that these diseases will become more frequent and severe as the worldwide population ages. Chronic lung diseases are associated with substantial morbidity, frequently resulting in exercise limiting dyspnea, immobilization, and isolation. Therefore, effective strategies to prevent or treat lung disease are likely to increase healthspan as well as life span. This review summarizes the findings of a joint workshop sponsored by the NIA and NHLBI that brought together investigators focused on aging and lung biology. These investigators encouraged the use of genetic systems and aged animals in the study of lung disease and the development of integrative systems-based platforms that can dynamically incorporate data sets that describe the genomics, transcriptomics, epigenomics, metabolomics, and proteomics of the aging lung in health and disease. Further research was recommended to integrate benchmark biological hallmarks of aging in the lung with the pathobiology of acute and chronic lung diseases with divergent pathologies for which advanced age is the most important risk factor.
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http://dx.doi.org/10.1093/gerona/glx090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861849PMC
October 2017

Nutrient Sensing and the Oxidative Stress Response.

Trends Endocrinol Metab 2017 06 15;28(6):449-460. Epub 2017 Mar 15.

Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA. Electronic address:

The simplicity and effectiveness of calorie restriction (CR) in lifespan and healthspan extension have fascinated generations searching for the Fountain of Youth. CR reduces levels of oxidative stress and damage, which have been postulated in the free radical theory of aging as a major cause of aging and diseases of aging. This reduction has long been viewed as a result of passive slowing of metabolism. Recent advances in nutrient sensing have provided molecular insights into the oxidative stress response and suggest that CR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Physiological studies have provided strong support for oxidative stress in the development of aging-associated conditions and diseases but have also revealed the surprising requirement for oxidative stress to support normal physiological functions and, in some contexts, even slow aging and prevent the progression of cancer. Deciphering the molecular mechanisms and physiological implications of the oxidative stress response during CR will increase our understanding of the basic biology of aging and pave the way for the design of CR mimetics to improve healthspan.
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http://dx.doi.org/10.1016/j.tem.2017.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438757PMC
June 2017

Molecular, Cellular, and Physiological Characterization of Sirtuin 7 (SIRT7).

Methods Mol Biol 2016 ;1436:271-7

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA.

Sirtuin 7 (SIRT7), a histone 3 lysine 18 (H3K18) deacetylase, functions at chromatin to suppress endoplasmic reticulum (ER) stress and mitochondrial protein folding stress (PFS(mt)), and prevent the development of fatty liver disease and hematopoietic stem cell aging. In this chapter, we provide a methodology to characterize the molecular, cellular, and physiological functions of SIRT7.
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http://dx.doi.org/10.1007/978-1-4939-3667-0_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233270PMC
December 2017

The mitochondrial metabolic checkpoint and aging of hematopoietic stem cells.

Curr Opin Hematol 2016 07;23(4):318-24

aProgram in Metabolic Biology, Nutritional Sciences and Toxicology, University of California bCalico Life Sciences, South San Francisco, California, USA.

Purpose Of Review: Cell-cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. We review recent advances in hematopoietic stem cell (HSC) biology, highlighting a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state.

Recent Findings: As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced, which is associated with increased mitochondrial protein folding stress and mitochondrial oxidative stress. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. Other mitochondrial maintenance mechanisms include mitophagy and asymmetric segregation of aged mitochondria.

Summary: Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions.
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http://dx.doi.org/10.1097/MOH.0000000000000244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891268PMC
July 2016

Reversing stem cell aging.

Oncotarget 2015 Jun;6(17):14723-4

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558105PMC
http://dx.doi.org/10.18632/oncotarget.4403DOI Listing
June 2015

Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging.

Science 2015 Mar;347(6228):1374-7

Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.

Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR(mt)), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS(mt)), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR(mt)-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.
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http://dx.doi.org/10.1126/science.aaa2361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447312PMC
March 2015

Physiology. Partitioning the circadian clock.

Science 2014 Sep;345(6201):1122-3

Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.

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http://dx.doi.org/10.1126/science.1259601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447309PMC
September 2014

SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.

Cell Rep 2013 Nov 7;5(3):654-665. Epub 2013 Nov 7.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.

Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD(+)-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.
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http://dx.doi.org/10.1016/j.celrep.2013.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888240PMC
November 2013

Sirtuins, tissue maintenance, and tumorigenesis.

Genes Cancer 2013 Mar;4(3-4):76-81

University of California, Berkeley, CA, USA.

Aging is a degenerative process resulting in compromised tissue maintenance and increased susceptibility to diseases, such as cancer. Recent advancements support the notion that aging is a highly regulated process governed by evolutionarily conserved pathways. In mammals, tissue-specific adult stem cells (ASCs) persist throughout the lifetime to maintain and repair tissues. While reduced ASC self-renewal is thought to contribute to compromised tissue maintenance, increased self-renewal of cancer stem cells (CSCs) may lead to tumorigenesis. It is speculated that genetic regulators of aging, such as sirtuins, are likely to impinge upon the ASC compartments to regulate tissue maintenance and tumorigenesis. In this review, we discuss the emerging evidence linking sirtuins to normal and malignant ASC self-renewal, tissue maintenance, and tumorigenesis.
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http://dx.doi.org/10.1177/1947601912474930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764468PMC
March 2013

The sirtuins, oxidative stress and aging: an emerging link.

Aging (Albany NY) 2013 Mar;5(3):144-50

Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.

Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice. Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629286PMC
http://dx.doi.org/10.18632/aging.100544DOI Listing
March 2013

SIRT3 reverses aging-associated degeneration.

Cell Rep 2013 Feb 31;3(2):319-27. Epub 2013 Jan 31.

Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.

Despite recent controversy about their function in some organisms, sirtuins are thought to play evolutionarily conserved roles in lifespan extension. Whether sirtuins can reverse aging-associated degeneration is unknown. Tissue-specific stem cells persist throughout the entire lifespan to repair and maintain tissues, but their self-renewal and differentiation potential become dysregulated with aging. We show that SIRT3, a mammalian sirtuin that regulates the global acetylation landscape of mitochondrial proteins and reduces oxidative stress, is highly enriched in hematopoietic stem cells (HSCs) where it regulates a stress response. SIRT3 is dispensable for HSC maintenance and tissue homeostasis at a young age under homeostatic conditions but is essential under stress or at an old age. Importantly, SIRT3 is suppressed with aging, and SIRT3 upregulation in aged HSCs improves their regenerative capacity. Our study illuminates the plasticity of mitochondrial homeostasis controlling stem cell and tissue maintenance during the aging process and shows that aging-associated degeneration can be reversed by a sirtuin.
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http://dx.doi.org/10.1016/j.celrep.2013.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582834PMC
February 2013

Protein post-translational modification analyses using on-chip immunoprobed isoelectric focusing.

Anal Chem 2013 Mar 15;85(5):2882-90. Epub 2013 Feb 15.

The UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, Berkeley, California 94720, United States.

Post-translational modifications play a critical role in regulating protein function. Increasingly, determination of protein identity, estimation of abundance, and characterization of post-translational modifications are required for analysis of protein-mediated cell signaling networks. As such, we report an integrated and rapid multispectral immunoprobed isoelectric focusing technique for identifying specific proteins bearing post-translational modifications. Immunoprobed isoelectric focusing is composed of isoelectric focusing in a large pore-size polyacrylamide gel to determine protein pI followed by immobilization of pI-resolved proteins. Proteins are immobilized via covalent attachment to a channel-filling benzophenone-functionalized polyacrylamide gel via brief UV exposure (photoblot), followed by multispectral antibody-based detection. The assay correlates observed post-translational modifications to pI shifts relative to the unmodified protein of interest. During the electrokinetically driven antibody probing stage, we observed nonuniform electrophoretic probe mobility along the channel axis. The spatially varying mobility is attributed to nonuniform charge arising from covalent attachment of ampholytes to the benzophenone-functionalized gel matrix during the photoblotting step. Using the multistep microfluidic assay, phosphorylated and acetylated forms of heat shock protein 27 and superoxide dismutase 2 were detected, respectively. The assay reported protein isoforms in immune-purified sample and raw cell lysate in 2 hours with sample volume requirements of 2 μL. This new assay is well-matched to systems biology frameworks for study of protein post-translational modifications.
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http://dx.doi.org/10.1021/ac3035053DOI Listing
March 2013

Reversible acetylation of metabolic enzymes celebration: SIRT2 and p300 join the party.

Mol Cell 2011 Jul;43(1):3-5

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.

Compelling evidence suggests that metabolic pathways are coordinated through reversible acetylation of metabolic enzymes in response to nutrient availability. In this issue of Molecular Cell, Jiang et al. (2011) show that the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase 1, is regulated through reversible acetylation by SIRT2 and p300.
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http://dx.doi.org/10.1016/j.molcel.2011.06.010DOI Listing
July 2011

SIRT-ain relief from age-inducing stress.

Aging (Albany NY) 2011 Feb;3(2):158-61

Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA.

Aging is one of the most fundamental biological processes. It results in a decline in physiological function and an increased risk for pernicious diseases such as cancer. Oxidative stress has been proposed as a major cause of aging, but experimental tests of this hypothesis have been discouraging. Calorie restriction (CR) prevents age-related decline, but there are still gaps in our knowledge of the exact mechanisms underlying this feat. Finally, a tenuous balance exists between aging and cancer, calling for a search for interventions that prevent both aging and cancer. Recent work on the mammalian sirtuin SIRT3 has shed light on these long-standing issues and suggested new approaches to ameliorate the ravages of aging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082010PMC
http://dx.doi.org/10.18632/aging.100283DOI Listing
February 2011

SIRT3: Striking at the heart of aging.

Aging (Albany NY) 2011 Jan;3(1):1-2

Department of Molecular and Cell Biology, University of California, Berkeley, 94720, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047127PMC
http://dx.doi.org/10.18632/aging.100256DOI Listing
January 2011

Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation.

Cell Metab 2010 Dec;12(6):662-7

Department of Nutritional Science & Toxicology, University of California, Berkeley, CA 94720, USA.

A major cause of aging and numerous diseases is thought to be cumulative oxidative stress, resulting from the production of reactive oxygen species (ROS) during respiration. Calorie restriction (CR), the most robust intervention to extend life span and ameliorate various diseases in mammals, reduces oxidative stress and damage. However, the underlying mechanism is unknown. Here, we show that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase. SIRT3 reduces cellular ROS levels dependent on superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. SIRT3 deacetylates two critical lysine residues on SOD2 and promotes its antioxidative activity. Importantly, the ability of SOD2 to reduce cellular ROS and promote oxidative stress resistance is greatly enhanced by SIRT3. Our studies identify a defense program that CR provokes to reduce oxidative stress and suggest approaches to combat aging and oxidative stress-related diseases.
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http://dx.doi.org/10.1016/j.cmet.2010.11.015DOI Listing
December 2010

Sirtuin regulation in calorie restriction.

Biochim Biophys Acta 2010 Aug 24;1804(8):1576-83. Epub 2009 Sep 24.

Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.

The beneficial effects of calorie restriction diet in extending lifespan and preventing diseases have long been recognized. Recent genetic and molecular studies in model organisms began to uncover the molecular regulation of calorie restriction response, with the gene SIR2 playing an essential role. This article summarizes the latest development on how mammalian SIR2 homologs coordinately regulate the calorie restriction response.
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http://dx.doi.org/10.1016/j.bbapap.2009.09.015DOI Listing
August 2010
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