The role of mitochondria in aging

The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.

[1]  Cole M. Haynes,et al.  UPRmt regulation and output: a stress response mediated by mitochondrial-nuclear communication , 2018, Cell Research.

[2]  A. Prescott,et al.  Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand , 2018, Cell metabolism.

[3]  R. Bernabei,et al.  Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia , 2018, Biological chemistry.

[4]  A. Whitworth,et al.  Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin , 2018, bioRxiv.

[5]  R. Bernabei,et al.  Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders. , 2018, Rejuvenation research.

[6]  C. D. Dela Cruz,et al.  Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases. , 2017, Mitochondrion.

[7]  R. Youle,et al.  PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol , 2018, BMC Biology.

[8]  P. van Epps,et al.  Human Immunodeficiency Virus and Aging in the Era of Effective Antiretroviral Therapy. , 2017, Infectious disease clinics of North America.

[9]  J. Auwerx,et al.  Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity , 2017, Nature.

[10]  R. Collins,et al.  Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial , 2017, The Lancet.

[11]  P. Libby,et al.  Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease , 2017, The New England journal of medicine.

[12]  V. Velagapudi,et al.  mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression. , 2017, Cell metabolism.

[13]  T. Finkel,et al.  Autophagy as a regulator of cardiovascular redox homeostasis , 2017, Free radical biology & medicine.

[14]  D. Chan,et al.  Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells. , 2017, Cell metabolism.

[15]  Robert W. Williams,et al.  Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals , 2017, The Journal of cell biology.

[16]  S. Snapper,et al.  Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages , 2017, Science.

[17]  L. O’Neill,et al.  Mitochondria are the powerhouses of immunity , 2017, Nature Immunology.

[18]  M. Haigis,et al.  Mitochondrial Sirtuins and Molecular Mechanisms of Aging. , 2017, Trends in molecular medicine.

[19]  V. Korolchuk,et al.  Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link? , 2017, EBioMedicine.

[20]  M. Palacín,et al.  Mitochondrial Dynamics: Coupling Mitochondrial Fitness with Healthy Aging. , 2017, Trends in molecular medicine.

[21]  K. DeBalsi,et al.  Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases , 2017, Ageing Research Reviews.

[22]  Junlei Chang,et al.  Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states , 2017, Nature Medicine.

[23]  Prashant Mishra,et al.  Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor , 2017, Cell.

[24]  N. Larsson,et al.  Mammalian Mitochondria and Aging: An Update. , 2017, Cell metabolism.

[25]  Stephan J Sigrist,et al.  Cardioprotection and lifespan extension by the natural polyamine spermidine , 2016, Nature Medicine.

[26]  Morgan Sheng,et al.  Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. , 2016, Free radical biology & medicine.

[27]  G. Sergi,et al.  Inflammation and frailty in the elderly: A systematic review and meta-analysis , 2016, Ageing Research Reviews.

[28]  Patricia A. Lovelace,et al.  Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans. , 2016, Cell systems.

[29]  R. de Cabo,et al.  Clinical Interventions in Aging Dovepress Animal Models of Frailty: Current Applications in Clinical Research Sarah N Hilmer 2–4 , 2022 .

[30]  Li-Wa Shao,et al.  Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response , 2016, Cell Research.

[31]  R. Xavier,et al.  Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages , 2016, Cell.

[32]  A. Dillin,et al.  Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis , 2016, Cell.

[33]  Cole M. Haynes,et al.  The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR , 2016, Current Biology.

[34]  Michael J. Munson,et al.  mito-QC illuminates mitophagy and mitochondrial architecture in vivo , 2016, The Journal of cell biology.

[35]  Evan G. Williams,et al.  Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents , 2016, Nature Medicine.

[36]  R. Aebersold,et al.  NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice , 2016, Science.

[37]  V. Dixit,et al.  Inflammasomes: mechanism of assembly, regulation and signalling , 2016, Nature Reviews Immunology.

[38]  B. Meyer,et al.  Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPRmt , 2016, Cell.

[39]  Evan G. Williams,et al.  Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity , 2016, Cell.

[40]  Tim König,et al.  Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt , 2016, EMBO reports.

[41]  P. Navas,et al.  Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan , 2016, Cell metabolism.

[42]  E. Calabrese,et al.  The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease , 2016, Molecular Neurodegeneration.

[43]  Mark Ellisman,et al.  NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria , 2016, Cell.

[44]  J. Walston,et al.  Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse , 2016, Experimental Gerontology.

[45]  F. Marincola,et al.  Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. , 2016, Cell metabolism.

[46]  E. Ballestar,et al.  Autophagy maintains stemness by preventing senescence , 2016, Nature.

[47]  Y. Yoo,et al.  Measuring In Vivo Mitophagy. , 2015, Molecular cell.

[48]  Christopher J. Murakami,et al.  A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging. , 2015, Cell metabolism.

[49]  Nancy W Glynn,et al.  Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults. , 2015, The journals of gerontology. Series A, Biological sciences and medical sciences.

[50]  B. Vaes,et al.  Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study , 2015, Experimental Gerontology.

[51]  J. Burman,et al.  The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy , 2015, Nature.

[52]  Scott R. Kennedy,et al.  Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress , 2015, Neuron.

[53]  K. Anderson,et al.  Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ , 2015, Proceedings of the National Academy of Sciences.

[54]  M. Boes,et al.  Mitochondria in autoinflammation: cause, mediator or bystander? , 2015, Trends in Endocrinology & Metabolism.

[55]  V. Dixit,et al.  Drivers of age‐related inflammation and strategies for healthspan extension , 2015, Immunological reviews.

[56]  Nektarios Tavernarakis,et al.  Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans , 2015, Nature.

[57]  R. Youle,et al.  The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease , 2015, Neuron.

[58]  R. Means,et al.  Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response , 2014, Nature.

[59]  Jiujiu Yu,et al.  Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy , 2014, Proceedings of the National Academy of Sciences.

[60]  H. McBride,et al.  A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles , 2014, The EMBO journal.

[61]  G. López-Lluch,et al.  Mitochondrial ultrastructure and markers of dynamics in hepatocytes from aged, calorie restricted mice fed with different dietary fats , 2014, Experimental Gerontology.

[62]  P. Chinnery,et al.  HIV Treatment and Associated Mitochondrial Pathology , 2014, Toxicologic pathology.

[63]  D. Kirkpatrick,et al.  The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy , 2014, Nature.

[64]  B. Braeckman,et al.  Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2 , 2014, Proceedings of the National Academy of Sciences.

[65]  C. Franceschi,et al.  Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for “inflamm‐aging” , 2014, European journal of immunology.

[66]  D. Walker,et al.  Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia , 2014, Molecular and Cellular Neuroscience.

[67]  D. Green,et al.  To Be or Not to Be? How Selective Autophagy and Cell Death Govern Cell Fate , 2014, Cell.

[68]  M. Kaeberlein,et al.  Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans , 2014, Nature Communications.

[69]  D. Ingram,et al.  Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. , 2013, Cell metabolism.

[70]  F. Sutterwala,et al.  Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. , 2013, Immunity.

[71]  Barry J. Hoffer,et al.  Germline mtDNA mutations aggravate ageing and can impair brain development , 2016 .

[72]  D. Walker,et al.  Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan , 2013, Proceedings of the National Academy of Sciences.

[73]  Robert W. Williams,et al.  Mitonuclear protein imbalance as a conserved longevity mechanism , 2013, Nature.

[74]  R. Germain,et al.  The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation , 2013, Cell.

[75]  Liang Zheng,et al.  Succinate is an inflammatory signal that induces IL-1β through HIF-1α , 2013, Nature.

[76]  John Canfield,et al.  Malate and Fumarate Extend Lifespan in Caenorhabditis elegans , 2013, PloS one.

[77]  Y. Kikkawa,et al.  Mitochondrial DNA Mutations in Mutator Mice Confer Respiration Defects and B-Cell Lymphoma Development , 2013, PloS one.

[78]  David C. Samuels,et al.  Universal heteroplasmy of human mitochondrial DNA , 2012, Human molecular genetics.

[79]  Cole M. Haynes,et al.  Mitochondrial Import Efficiency of ATFS-1 Regulates Mitochondrial UPR Activation , 2012, Science.

[80]  Reinhard Guthke,et al.  Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. , 2012, Cell metabolism.

[81]  Moshe Arditi,et al.  Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. , 2012, Immunity.

[82]  Michele Burns Ewald,et al.  Toxicity of Weight Loss Agents , 2012, Journal of Medical Toxicology.

[83]  E. Latz,et al.  NLRP3 inflammasomes link inflammation and metabolic disease. , 2011, Trends in immunology.

[84]  M. Ristow,et al.  Extending life span by increasing oxidative stress. , 2011, Free Radical Biology & Medicine.

[85]  B. Grubeck‐Loebenstein,et al.  Persistent viral infections and immune aging , 2011, Ageing Research Reviews.

[86]  David C Samuels,et al.  Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations , 2011, Nature Genetics.

[87]  A. Theiss,et al.  The role and therapeutic potential of prohibitin in disease. , 2011, Biochimica et biophysica acta.

[88]  B. Lambrecht,et al.  Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. , 2011, Trends in immunology.

[89]  S. Ryter,et al.  Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. , 2011, Nature immunology.

[90]  J. Tschopp,et al.  A role for mitochondria in NLRP3 inflammasome activation , 2011, Nature.

[91]  A. Dillin,et al.  The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity , 2011, Cell.

[92]  Siegfried Hekimi,et al.  A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans , 2010, PLoS biology.

[93]  K. Moore,et al.  NLRP3 inflamasomes are required for atherogenesis and activated by cholesterol crystals that form early in disease , 2010, Nature.

[94]  Ivan Dikic,et al.  Nix is a selective autophagy receptor for mitochondrial clearance , 2010, EMBO reports.

[95]  W. Junger,et al.  Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury , 2009, Nature.

[96]  R. Youle,et al.  Mechanisms of mitophagy , 2010, Nature Reviews Molecular Cell Biology.

[97]  M. Komatsu,et al.  Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy , 2009, Aging.

[98]  T. Junt,et al.  Triggering the succinate receptor GPR91 on dendritic cells enhances immunity , 2008, Nature Immunology.

[99]  H. Sandoval,et al.  Essential role for Nix in autophagic maturation of erythroid cells , 2008, Nature.

[100]  J. Opferman,et al.  NIX is required for programmed mitochondrial clearance during reticulocyte maturation , 2007, Proceedings of the National Academy of Sciences.

[101]  Cole M. Haynes,et al.  ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. , 2007, Developmental cell.

[102]  E. Colman.  Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. , 2007, Regulatory toxicology and pharmacology : RTP.

[103]  Massimo Zeviani,et al.  Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. , 2007, Human molecular genetics.

[104]  G. Castellani,et al.  Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans , 2007, Mechanisms of Ageing and Development.

[105]  T. Kirkwood,et al.  Caloric restriction does not enhance longevity in all species and is unlikely to do so in humans , 2006, Biogerontology.

[106]  Siegfried Hekimi,et al.  Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. , 2005, Genes & development.

[107]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[108]  J. Speakman,et al.  Body size, energy metabolism and lifespan , 2005, Journal of Experimental Biology.

[109]  Polly Matzinger,et al.  Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses , 2004, Nature Reviews Immunology.

[110]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[111]  Gary Ruvkun,et al.  A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity , 2003, Nature Genetics.

[112]  Andrew G Fraser,et al.  Rates of Behavior and Aging Specified by Mitochondrial Function During Development , 2002, Science.

[113]  Suzanne G. Leveille,et al.  Change in Muscle Strength Explains Accelerated Decline of Physical Function in Older Women With High Interleukin‐6 Serum Levels , 2002, Journal of the American Geriatrics Society.

[114]  L. Fried,et al.  Associations of subclinical cardiovascular disease with frailty. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[115]  P. Esselman,et al.  Oxidative capacity and ageing in human muscle , 2000, The Journal of physiology.

[116]  N. Arnheim,et al.  Detection of a specific mitochondrial DNA deletion in tissues of older humans. , 1990, Nucleic acids research.

[117]  L. Sagan.  On the origin of mitosing cells , 1967, Journal of theoretical biology.

[118]  D. Harman.  Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.