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http://dx.doi.org/10.5483/BMBRep.2019.52.1.300

Mitochondria: multifaceted regulators of aging  

Son, Jyung Mean (Leonard Davis School of Gerontology, University of Southern California)
Lee, Changhan (Leonard Davis School of Gerontology, University of Southern California)
Publication Information
BMB Reports / v.52, no.1, 2019 , pp. 13-23 More about this Journal
Abstract
Aging is accompanied by a time-dependent progressive deterioration of multiple factors of the cellular system. The past several decades have witnessed major leaps in our understanding of the biological mechanisms of aging using dietary, genetic, pharmacological, and physical interventions. Metabolic processes, including nutrient sensing pathways and mitochondrial function, have emerged as prominent regulators of aging. Mitochondria have been considered to play a key role largely due to their production of reactive oxygen species (ROS), resulting in DNA damage that accumulates over time and ultimately causes cellular failure. This theory, known as the mitochondrial free radical theory of aging (MFRTA), was favored by the aging field, but increasing inconsistent evidence has led to criticism and rejection of this idea. However, MFRTA should not be hastily rejected in its entirety because we now understand that ROS is not simply an undesired toxic metabolic byproduct, but also an important signaling molecule that is vital to cellular fitness. Notably, mitochondrial function, a term traditionally referred to bioenergetics and apoptosis, has since expanded considerably. It encompasses numerous other key biological processes, including the following: (i) complex metabolic processes, (ii) intracellular and endocrine signaling/communication, and (iii) immunity/inflammation. Here, we will discuss shortcomings of previous concepts regarding mitochondria in aging and their emerging roles based on recent advances. We will also discuss how the mitochondrial genome integrates with major theories on the evolution of aging.
Keywords
Aging; Communication; Mitochondria; Mitochondrial DNA; Signaling;
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1 Perez VI, Bokov A, Van Remmen H et al (2009) Is the oxidative stress theory of aging dead? Biochim Biophys Acta 1790, 1005-1014   DOI
2 Fabrizio P, Liou LL, Moy VN et al (2003) SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163, 35-46   DOI
3 Cabreiro F, Ackerman D, Doonan R et al (2011) Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic Biol Med 51, 1575-1582   DOI
4 Melov S, Ravenscroft J, Malik S et al (2000) Extension of Life-Span with Superoxide Dismutase/Catalase Mimetics. Science 289, 1567-1569   DOI
5 Curtis C, Landis GN, Folk D et al (2007) Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophilareveals a species-general network of aging and metabolic genes. Genome Biol 8, R262   DOI
6 Sun J, Folk D, Bradley TJ, Tower J (2002) Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 161, 661-672   DOI
7 Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL (1998) Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 19, 171-174   DOI
8 Schriner SE, Linford NJ, Martin GM et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909-1911   DOI
9 Bua E, Johnson J, Herbst A et al (2006) Mitochondrial DNA-Deletion Mutations Accumulate Intracellularly to Detrimental Levels in Aged Human Skeletal Muscle Fibers. Am J Hum Genet 79, 469-480   DOI
10 Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11, 298-300   DOI
11 Harman D (2009) Origin and evolution of the free radical theory of aging: a brief personal history, 1954-2009. Biogerontology 10, 773   DOI
12 Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20, 145-147   DOI
13 Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 94, 514-519   DOI
14 Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39, 359-407   DOI
15 Lee HY, Choi CS, Birkenfeld AL et al (2010) Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 12, 668-674   DOI
16 Brooks AR, Harkins RN, Wang P, Qian HS, Liu P, Rubanyi GM (2004) Transcriptional silencing is associated with extensive methylation of the CMV promoter following adenoviral gene delivery to muscle. J Gene Med 6, 395-404   DOI
17 Cortopassi GA, Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18, 6927-6933   DOI
18 Bender A, Krishnan KJ, Morris CM et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38, 515-517   DOI
19 Vermulst M, Wanagat J, Kujoth GC et al (2008) DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40, 392-394   DOI
20 Sarsour EH, Kalen AL, Goswami PC (2014) Manganese superoxide dismutase regulates a redox cycle within the cell cycle. Antioxid Redox Signal 20, 1618-1627   DOI
21 Ristow M (2014) Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med 20, 709-711   DOI
22 Sun N, Youle RJ, Finkel T (2016) The Mitochondrial Basis of Aging. Mol Cell 61, 654-666   DOI
23 Shadel GS, Horvath TL (2015) Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560-569   DOI
24 Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 33, 40-48   DOI
25 Dillin A, Hsu AL, Arantes-Oliveira N et al (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398-2401   DOI
26 Sullivan LB, Gui DY, Vander Heiden MG (2016) Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer 16, 680-693   DOI
27 Kazak L, Reyes A, Holt IJ (2012) Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat Rev Mol Cell Biol 13, 659-671   DOI
28 Kang D, Kim SH, Hamasaki N (2007) Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 7, 39-44   DOI
29 Liu X, Jiang N, Hughes B, Bigras E, Shoubridge E, Hekimi S (2005) Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev 19, 2424-2434   DOI
30 Frezza C (2017) Mitochondrial metabolites: undercover signalling molecules. Interface Focus 7, 20160100   DOI
31 Kim SJ, Xiao J, Wan J, Cohen P, Yen K (2017) Mitochondrially derived peptides as novel regulators of metabolism. J Physiol 595, 6613-6621   DOI
32 Pinti M, Cevenini E, Nasi M et al (2014) Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for "inflamm-aging". Eur J Immunol 44, 1552-1562   DOI
33 Furman D, Chang J, Lartigue L et al (2017) Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 23, 174-184   DOI
34 Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14, 576-590   DOI
35 Hashimoto Y, Niikura T, Tajima H et al (2001) A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A 98, 6336-6341   DOI
36 Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M (2014) The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 15, 536-550   DOI
37 Tranah GJ (2011) Mitochondrial-nuclear epistasis: Implications for human aging and longevity. Ageing Res Rev 10, 238-252   DOI
38 Menzies KJ, Zhang H, Katsyuba E, Auwerx J (2016) Protein acetylation in metabolism-metabolites and cofactors. Nat Rev Endocrinol 12, 43-60   DOI
39 Sutendra G, Kinnaird A, Dromparis P et al (2014) A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 158, 84-97   DOI
40 Shi L, Tu BP (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33, 125-131   DOI
41 Xie Z, Dai J, Dai L et al (2012) Lysine succinylation and lysine malonylation in histones. Mol Cell Proteomics 11, 100-107   DOI
42 Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16, 593-610   DOI
43 Schultz MB, Sinclair DA (2016) Why NAD+ Declines during Aging: It's Destroyed. Cell Metab 23, 965-966   DOI
44 Camacho-Pereira J, Tarrago MG, Chini CCS et al (2016) CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab 23, 1127-1139   DOI
45 Zarse K, Ristow M (2015) A mitochondrially encoded hormone ameliorates obesity and insulin resistance. Cell Metab 21, 355-356   DOI
46 Ikonen M, Liu B, Hashimoto Y et al (2003) Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A 100, 13042-13047   DOI
47 Guo B, Zhai D, Cabezas E et al (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423, 456-461   DOI
48 Cobb LJ, Lee C, Xiao J et al (2016) Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging 8, 796-809   DOI
49 Lee C, Zeng J, Drew BG et al (2015) The mitochondrialderived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 21, 443-454   DOI
50 McManus MJ, Picard M, Chen HW et al (2018) Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy. Cell Metab [Epub ahead of print]
51 Deuse T, Wang D, Stubbendorff M et al (2015) SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts. Cell Stem Cell 16, 33-38   DOI
52 Betancourt AM, King AL, Fetterman JL et al (2014) Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice. Biochemical J 461, 223-232   DOI
53 Fetterman JL, Zelickson BR, Johnson LW et al (2013) Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. Biochemical J 455, 157-167   DOI
54 Raimundo N, Krisko A (2018) Cross-organelle communication at the core of longevity. Aging 10, 15-16   DOI
55 Rieusset J (2018) The role of endoplasmic reticulummitochondria contact sites in the control of glucose homeostasis: an update. Cell Death Dis 9, 388   DOI
56 Janikiewicz J, Szymanski J, Malinska D et al (2018) Mitochondria-associated membranes in aging and senescence: structure, function, and dynamics. Cell Death Dis 9, 332   DOI
57 Wang CH, Chen YF, Wu CY et al (2014) Cisd2 modulates the differentiation and functioning of adipocytes by regulating intracellular Ca2+ homeostasis. Hum Mol Genet 23, 4770-4785   DOI
58 Rand DM (2017) Fishing for adaptive epistasis using mitonuclear interactions. PLoS Genet 13, e1006662   DOI
59 Chen YF, Kao CH, Chen YT et al (2009) Cisd2 deficiency drives premature aging and causes mitochondriamediated defects in mice. Genes Dev 23, 1183-1194   DOI
60 Murley A, Sarsam RD, Toulmay A, Yamada J, Prinz WA, Nunnari J (2015) Ltc1 is an ER-localized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts. J Cell Biol 209, 539-548   DOI
61 Honscher C, Mari M, Auffarth K et al (2014) Cellular metabolism regulates contact sites between vacuoles and mitochondria. Dev Cell 30, 86-94   DOI
62 Durieux J, Wolff S, Dillin A (2011) The cell-nonautonomous nature of electron transport chain-mediated longevity. Cell 144, 79-91   DOI
63 Woo DK, Shadel GS (2011) Mitochondrial stress signals revise an old aging theory. Cell 144, 11-12   DOI
64 Zhang Q, Wu X, Chen P et al (2018) The mitochondrial unfolded protein response is mediated cell-nonautonomously by retromer-dependent Wnt signaling. Cell 174, 870-883.e817   DOI
65 Shao L-W, Niu R, Liu Y (2016) Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res 26, 1182-1196   DOI
66 Stewart JB, Chinnery PF (2015) The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet 16, 530-542   DOI
67 Kauppila TES, Kauppila JHK, Larsson NG (2017) Mammalian Mitochondria and Aging: An Update. Cell Metab 25, 57-71   DOI
68 Owusu-Ansah E, Song W, Perrimon N (2013) Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699-712   DOI
69 Kim KH, Jeong YT, Oh H et al (2012) Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19, 83-92   DOI
70 Berendzen KM, Durieux J, Shao LW et al (2016) Neuroendocrine coordination of mitochondrial stress signaling and proteostasis. Cell 166, 1553-1563.e1510   DOI
71 da Cunha FM, Torelli NQ, Kowaltowski AJ (2015) Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes. Oxid Med Cell Longev 2015, 482582
72 Lee C, Kim KH, Cohen P (2016) MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 100, 182-187   DOI
73 Doonan R, McElwee JJ, Matthijssens F et al (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22, 3236-3241   DOI
74 Pomatto LCD, Davies KJA (2018) Adaptive homeostasis and the free radical theory of ageing. Free Radic Biol Med 124, 420-430   DOI
75 Unlu ES, Koc A (2007) Effects of deleting mitochondrial antioxidant genes on life span. Ann N Y Acad Sci 1100, 505-509   DOI
76 Longo VD, Gralla EB, Valentine JS (1996) Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae Mitochondrial production of toxic oxygen species in vivo. J Biol Chem 271, 12275-12280   DOI
77 Kirby K, Hu J, Hilliker AJ, Phillips JP (2002) RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. Proc Natl Acad Sci U S A 99, 16162-16167   DOI
78 Martin I, Jones MA, Rhodenizer D et al (2009) Sod2 knockdown in the musculature has whole-organism consequences in Drosophila. Free Radic Biol Med 47, 803-813   DOI
79 Duttaroy A, Paul A, Kundu M, Belton A (2003) A Sod2 null mutation confers severely reduced adult life span in Drosophila. Genetics 165, 2295-2299   DOI
80 Wicks S, Bain N, Duttaroy A, Hilliker AJ, Phillips JP (2009) Hypoxia rescues early mortality conferred by superoxide dismutase deficiency. Free Radic Biol Med 46, 176-181   DOI
81 Kennedy SR, Salk JJ, Schmitt MW, Loeb LA (2013) Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 9, e1003794   DOI
82 Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17, 1195-1214   DOI
83 Vermulst M, Bielas JH, Kujoth GC (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39, 540-543   DOI
84 Ameur A, Stewart JB, Freyer C et al (2011) Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet 7, e1002028   DOI
85 Trifunovic A, Hansson A, Wredenberg A et al (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci U S A 102, 17993-17998   DOI
86 Trifunovic A, Wredenberg A, Falkenberg M et al (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423   DOI
87 Edgar D, Shabalina I, Camara Y et al (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10, 131-138   DOI
88 Kujoth GC, Hiona A, Pugh TD et al (2005) Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging. Science 309, 481-484   DOI
89 Logan A, Shabalina IG, Prime TA et al (2014) In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice. Aging Cell 13, 765-768   DOI
90 DeBalsi KL, Hoff KE, Copeland WC (2017) Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev 33, 89-104   DOI
91 Rando TA, Chang HY (2012) Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46-57   DOI
92 Zarse K, Schmeisser S, Groth M et al (2012) Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab 15, 451-465   DOI
93 Lee SJ, Hwang AB, Kenyon C (2010) Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 20, 2131-2136   DOI
94 Munoz-Najar U, Sedivy JM (2011) Epigenetic control of aging. Antioxid Redox Signal 14, 241-259   DOI
95 Schroeder EA, Raimundo N, Shadel GS (2013) Epigenetic silencing mediates mitochondria stressinduced longevity. Cell Metab 17, 954-964   DOI
96 Shpilka T, Haynes CM (2018) The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 19, 109-120   DOI
97 Wong W (2018) Going nuclear with stress. Science Signaling 11, eaav4285   DOI
98 Lee C, Kim KH, Cohen P (2016) MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 100, 182-187   DOI
99 Kim KH, Son JM, Benayoun BA, Lee C (2018) The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab 28, 516-524   DOI
100 Mangalhara KC, Shadel GS (2018) A Mitochondrial-Derived Peptide Exercises the Nuclear Option. Cell Metab 28, 330-331   DOI
101 Pickles S, Vigie P, Youle RJ (2018) Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance. Curr Biol 28, R170-R185   DOI
102 Lee SR, Han J (2017) Mitochondrial nucleoid: shield and switch of the mitochondrial genome. Oxid Med Cell Longev 2017 [Epub ahead of print]
103 Chen H, Vermulst M, Wang YE et al (2010) Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations. Cell 141, 280-289   DOI
104 Prevost CT, Peris N, Seger C et al (2018) The influence of mitochondrial dynamics on mitochondrial genome stability. Curr Genet 64, 199-214   DOI
105 Felkai S, Ewbank JJ, Lemieux J, Labbe JC, Brown GG, Hekimi S (1999) CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. EMBO J 18, 1783-1792   DOI
106 Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR mt. Mol Cell 58, 123-133   DOI
107 Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587-590   DOI
108 Tian Y, Garcia G, Bian Q et al (2016) Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR(mt). Cell 165, 1197-1208   DOI
109 Mouchiroud L, Houtkooper RH, Moullan N et al (2013) The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430-441   DOI
110 Gomes AP, Price NL, Ling AJ et al (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624-1638   DOI
111 Yoshino J, Mills KF, Yoon MJ, Imai S (2011) Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice. Cell Metab 14, 528-536   DOI
112 Quiros PM, Mottis A, Auwerx J (2016) Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 17, 213-226   DOI
113 Mammucari C, Gherardi G, Zamparo I et al (2015) The mitochondrial calcium uniporter controls skeletal muscle trophism in vivo. Cell Rep 10, 1269-1279   DOI
114 Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14, 576-590   DOI
115 Davis BK, Wen H, Ting JP (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29, 707-735   DOI
116 Wenceslau CF, McCarthy CG, Szasz T et al (2014) Mitochondrial damage-associated molecular patterns and vascular function. Eur Heart J 35, 1172-1177   DOI
117 Zhang Q, Raoof M, Chen Y et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104-107   DOI
118 Fuku N, Pareja-Galeano H, Zempo H et al (2015) The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell 14, 921-923   DOI
119 Muzumdar RH, Huffman DM, Atzmon G et al (2009) Humanin: a novel central regulator of peripheral insulin action. PLoS One 4, e6334   DOI
120 Lee C, Wan J, Miyazaki B et al (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13, 958-961   DOI
121 Zempo H, Fuku N, Nishida Y et al (2016) Relation between type 2 diabetes and m. 1382 A> C polymorphism which occurs amino acid replacement (K14Q) of mitochondria-derived MOTS-c. FASEB J 30, 956.1
122 Price NL, Gomes AP, Ling AJ et al (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15, 675-690   DOI
123 Canto C, Gerhart-Hines Z, Feige JN et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-1060   DOI
124 Dunham-Snary KJ, Ballinger SW (2015) GENETICS. Mitochondrial-nuclear DNA mismatch matters. Science 349, 1449-1450   DOI
125 Santos MJ, Quintanilla RA, Toro A et al (2005) Peroxisomal proliferation protects from ${\beta}$-amyloid neurodegeneration. J Biol Chem 280, 41057-41068   DOI
126 Titorenko VI, Terlecky SR (2011) Peroxisome metabolism and cellular aging. Traffic 12, 252-259   DOI
127 Sebastian D, Palacin M, Zorzano A (2017) Mitochondrial dynamics: coupling mitochondrial fitness with healthy aging. Trends Mol Med 23, 201-215   DOI
128 Koepke JI, Nakrieko KA, Wood CS et al (2007) Restoration of peroxisomal catalase import in a model of human cellular aging. Traffic 8, 1590-1600   DOI
129 Nell HJ, Au JL, Giordano CR et al (2017) Targeted Antioxidant, Catalase-SKL, Reduces Beta-Amyloid Toxicity in the Rat Brain. Brain Pathol 27, 86-94   DOI
130 Yoboue ED, Sitia R, Simmen T (2018) Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages. Cell Death Dis 9, 331   DOI
131 Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C (2016) The crucial impact of lysosomes in aging and longevity. Ageing Res Rev 32, 2-12   DOI
132 Soto-Heredero G, Baixauli F, Mittelbrunn M (2017) Interorganelle communication between mitochondria and the endolysosomal system. Front Cell Dev Biol 5, 95   DOI
133 Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1, 642-645
134 Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M et al (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3, 70ra13   DOI
135 Cortopassi GA, Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18, 6927-6933   DOI
136 Piko L, Hougham AJ, Bulpitt KJ (1988) Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: evidence for an increased frequency of deletions/additions with aging. Mech Ageing Dev 43, 279-293   DOI
137 Larsson NG (2010) Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem 79, 683-706   DOI
138 Payne BA, Wilson IJ, Yu-Wai-Man P et al (2013) Universal heteroplasmy of human mitochondrial DNA. Hum Mol Genet 22, 384-390   DOI
139 Khrapko K, Vijg J (2009) Mitochondrial DNA mutations and aging: devils in the details? Trends Genet 25, 91-98   DOI
140 Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. Biochem J 370, 751-762   DOI
141 Bachar AR, Scheffer L, Schroeder AS et al (2010) Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc Res 88, 360-366   DOI
142 Imai S-I, Guarente L (2016) It takes two to tango: NAD+ and sirtuins in aging/longevity control. NPJ Aging Mech Dis 2, 16017   DOI
143 Grazioli S, Pugin J (2018) Mitochondrial Damage-Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases. Front Immunol 9, 832   DOI
144 Hughes AL, Gottschling DE (2012) An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261-265   DOI
145 Elbaz-Alon Y, Rosenfeld-Gur E, Shinder V, Futerman AH, Geiger T, Schuldiner M (2014) A dynamic interface between vacuoles and mitochondria in yeast. Dev Cell 30, 95-102   DOI
146 Klecker T, Westermann B (2014) Mitochondria Are Clamped to Vacuoles for Lipid Transport. Dev Cell 30, 1-2   DOI
147 Cobb LJ, Lee C, Xiao J et al (2016) Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging 8, 796-809   DOI