Reconsidering the Role of Mitochondria in Aging

Journals of Gerontology - Series A Biological Sciences and Medical Sciences

Volumn 70, Issue 11, 2015, Pages 1334-1342

  Gonzalez Freire, Marta ^a   De Cabo, Rafael ^a   Bernier, Michel ^a   Sollott, Steven J ^a   Fabbri, Elisa ^a,b   Navas, Placido ^c   Ferrucci, Luigi ^a  

^a NATIONAL INSTITUTE ON AGING   (United States)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

Aging; Lifespan; Mitochondria

Indexed keywords

REACTIVE OXYGEN METABOLITE;

AGING; ENERGY METABOLISM; GENETIC EPIGENESIS; HUMAN; METABOLISM; MITOCHONDRION; PHYSIOLOGY;

AGING; ENERGY METABOLISM; EPIGENESIS, GENETIC; HUMANS; MITOCHONDRIA; REACTIVE OXYGEN SPECIES;

EID: 84946551669     PISSN: 10795006     EISSN: 1758535X     Source Type: Journal    
DOI: 10.1093/gerona/glv070     Document Type: Review

References (102)

1. DiMauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol. 2013;9(8):429-444. doi:10.1038/nrneurol.2013.126
2. Harman D. Free radical theory of aging: dietary implications. Am J Clin Nutr. 1972;25(8):839-843.
3. Larsson N-G. Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem. 2010;79:683-706. doi:10.1146/annurev-biochem- 060408-093701
4. Wanagat J, Cao Z, Pathare P, Aiken JM. Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J. 2001;15(2):322-332.
5. Bua E, Johnson J, Herbst A, et al. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am J Hum Genet. 2006;79(3):469-480. doi:10.1086/507132
6. Pak JW, Aiken JM. Low levels of mtDNA deletion mutations in ETS normal fibers from aged rats. Ann N Y Acad Sci. 2004;1019:289-293.
7. Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429(6990), 417-423.
8. Umanskaya A, Santulli G, Xie W, Andersson DC, Reiken SR, Marks AR. Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging. Proc Natl Acad Sci U S A. 2014;111(42), 15250-15255. doi:10.1073/pnas.1412754111
9. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6), 1194-1217. doi:10.1016/j. cell.2013.05.039
10. Newgard CB, Pessin JE. Recent progress in metabolic signaling pathways regulating aging and life span. J Gerontol A Biol Sci. 2014;69(1), S21-S27. doi:10.1093/gerona/glu058
11. Coen PM, Jubrias SA, Distefano G, et al. Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J Gerontol A Biol Sci Med Sci. 2013;68(4), 447-455. doi:10.1093/gerona/gls196
12. Peterson CM, Johannsen DL, Ravussin E. Skeletal muscle mitochondria and aging: a review. J Aging Res. 2012;194821. doi:10.1155/2012/194821
13. Sevini F, Giuliani C, Vianello D, et al. mtDNA mutations in human aging and longevity: controversies and new perspectives opened by highthroughput technologies. Exp Gerontol. 2014;56, 234-244. doi:10.1016/j. exger.2014.03.022
14. Owusu-Ansah E, Song W, Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell. 2013;155(3), 699-712. doi:10.1016/j.cell.2013.09.021
15. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi:10.1038/ncomms3192
16. Shi Y, Ivannikov MV, Walsh ME, et al. The lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice. PloS One. 2014;9(6), e100834.
17. Azzu V, Brand MD. Degradation of an intramitochondrial protein by the cytosolic proteasome. J Cell Sci. 2010;123(Pt 4), 578-585. doi:10.1242/jcs.060004
18. Divakaruni AS, Brand MD. The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda, MD). 2011; 26(3), 192-205. doi:10.1152/physiol.00046.2010
19. Amara CE, Shankland EG, Jubrias SA, Marcinek DJ, Kushmerick MJ, Conley KE. Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proc Natl Acad Sci U S A. 2007;104(3), 1057-1062. doi:10.1073/pnas.0610131104
20. Mookerjee SA, Divakaruni AS, Jastroch M, Brand MD. Mitochondrial uncoupling and lifespan. Mec Ageing Dev. 2010;131(7-8), 463-472. doi:10.1016/j.mad.2010.03.010
21. Lawless C, Jurk D, Gillespie CS, Shanley D, Saretzki G, von Zglinicki T, Passos JF. A stochastic step model of replicative senescence explains ROS production rate in ageing cell populations. PloS One. 2012;7(2), e32117.
22. Passos JF, Saretzki G, Ahmed S, et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 2007;5(5), e110. doi:10.1371/journal.pbio.0050110
23. López-Lluch G, Irusta, PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Exp Gerontol. 2008;43(9), 813-819. doi:10.1016/j. exger.2008.06.014
24. Ding W-X, Yin X-M. Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem. 2012;393(7), 547-564. doi:10.1515/hsz-2012-0119
25. Rambold AS, Kostelecky B, Lippincott-Schwartz J. Fuse or die: shaping mitochondrial fate during starvation. Commun Integr Biol. 2011;4(6):752-754.
26. Joseph A-M, Adhihetty PJ, Wawrzyniak NR, et al. Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PloS One. 2013;8(7), e69327.
27. Rajawat YS, Hilioti Z, Bossis, I. Aging: central role for autophagy and the lysosomal degradative system. Mech Ageing Dev. 2009;8(3), 199-213. doi:10.1016/j.arr.2009.05.001
28. Gouspillou G, Sgarioto N, Kapchinsky S, et al. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 2014;28(4):1621-1633. doi:10.1096/fj.13-242750
29. Rodriguez-Hernandez A, Cordero MD, Salviati L, et al. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy. 2009;5(1):19-32.
30. Hirota Y, Kang D, Kanki T. The physiological role of mitophagy: new insights into phosphorylation events. Int J Cell Biol. 2012;(3):354914-354918. doi:10.1155/2012/354914
31. Zhao J, Brault JJ, Schild A, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6(6):472-483. doi:10.1016/j. cmet.2007.11.004
32. Guarente L. Aging research-where do we stand and where are we going? Cell. 2014;159(1):15-19. doi:10.1016/j.cell.2014.08.041
33. Sgarbi G, Matarrese P, Pinti M, et al. Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. Aging (Albany NY). 2014;6(4):296-310.
34. Sandri M. Autophagy in skeletal muscle. FEBS Lett. 2010;584(7):1411-1416. doi:10.1016/j.febslet.2010.01.056
35. O'Leary MF, Vainshtein A, Iqbal S, Ostojic O, Hood DA. Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle. Am J Physiol Cell Physiol. 2013;304(5):C422-30. doi:10.1152/ajpcell. 00240.2012
36. Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 2004;18(4):357-368.
37. Virbasius JV, Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A. 1994;91(4):1309-1313.
38. Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev. 2006;27(7):728-735. doi:10.1210/er.2006-0037
39. Gouspillou G, Sgarioto N, Norris B, et al. The relationship between muscle fiber type-specific PGC-1alpha content and mitochondrial content varies between rodent models and humans. PLoS One. 2014;9(8):e103044.
40. Short KR, Bigelow ML, Kahl J, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A. 2005;102(15):5618-5623. doi:10.1073/pnas.0501559102
41. Conley KE, Jubrias SA, Esselman PC. Oxidative capacity and ageing in human muscle. J Physiol (Lond). 2000;526(Pt 1):203-210.
42. Jaskelioff M, Muller FL, Paik J-H, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011;469(7328):102-106. doi:10.1038/nature09603
43. Sahin E, Colla S, Liesa M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470(7334):359-365. doi:10.1038/nature09787
44. Sahin E, De Pinho RA. Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol. 2012;13(6):397-404. doi:10.1038/nrm3352
45. Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007;104(29):12017-12022. doi:10.1073/pnas.0705070104
46. Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1alpha. J Biol Chem. 2005;280(16):16456-16460. doi:10.1074/jbc.M501485200
47. Li L, Muhlfeld C, Niemann B, et al. Mitochondrial biogenesis and PGC- 1alpha deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle. Basic Res Cardiol. 2011;106(6):1221-1234. doi:10.1007/s00395-011-0213-9
48. McCarty MF. Chronic activation of AMP-activated kinase as a strategy for slowing aging. Med Hypotheses. 2004;63(2):334-339.
49. Reznick RM, Zong H, Li J, et al. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 2007;5(2):151-156. doi:10.1016/j.cmet.2007.01.008
50. Baker MJ, Tatsuta T, Langer T. Quality control of mitochondrial proteostasis. Cold Spring Harb Perspect Biol. 2011;3(7). doi:10.1101/cshperspect. a007559
51. Maharjan S, Oku M, Tsuda M, Hoseki J, Sakai Y. Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition. Sci Rep. 2014;4:5896. doi:10.1038/srep05896
52. Jensen MB, Jasper H. Mitochondrial proteostasis in the control of aging and longevity. Cell Metab. 2014;20(2):214-225. doi:10.1016/j. cmet.2014.05.006
53. Bernales S, Soto MM, McCullagh E. Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration. Front Aging Neurosci. 2012;4:5. doi:10.3389/fnagi.2012.00005
54. Mouchiroud L, Houtkooper RH, Moullan N, et al. The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 2013;154(2):430-441. doi:10.1016/j. cell.2013.06.016
55. Ngo JK, Pomatto LCD, Davies KJA. Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging. Redox Biol. 2013;1(1):258-264.
56. Bota DA, Van Remmen H, Davies KJA. Modulation of Lon protease activity and aconitase turnover during aging and oxidative stress. FEBS Lett. 2002;532(1-2):103-106.
57. Ngo JK, Davies KJA. Mitochondrial Lon protease is a human stress protein. Free Radic Biol Med. 2009;46(8):1042-1048. doi:10.1016/j.freeradbiomed. 2008.12.024
58. Rizzuto R, Pinton P, Carrington W, et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science. 1998;280(5370):1763-1766.
59. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171(8):2017-2028. doi:10.1111/bph.12468.
60. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029-2050. doi:10.1111/bph.12461.
61. Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014;96(6):672-683. doi:10.1038/clpt.2014.174.
62. Liu S, Soong Y, Seshan SV, Szeto HH. Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis. Am J Physiol Renal Physiol. 2014;306(9):F970-F980. doi:10.1152/ajprenal.00697.2013.
63. Pamplona R, Barja G, Portero-Otin M. Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation? Ann N Y Acad Sci. 2002;959:475-490.
64. Chen Y, Hagopian K, McDonald RB, et al. The influence of dietary lipid composition on skeletal muscle mitochondria from mice following 1 month of calorie restriction. J Gerontol A Biol Sci Med Sci. 2012;67(11):1121-1131. doi:10.1093/gerona/gls113.
65. Pamplona R, Prat J, Cadenas S, et al. Low fatty acid unsaturation protects against lipid peroxidation in liver mitochondria from long-lived species: the pigeon and human case. Mech Ageing Dev. 1996;86(1): 53-66.
66. Gomez A, Sanchez-Roman I, Gomez J, et al. Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity. Aging Cell. 2014;13(3):551-560. doi:10.1111/acel.12205.
67. López-Domínguez JA, Ramsey JJ, Tran D, et al. The influence of dietary fat source on life span in calorie restricted mice. J Gerontol A Biol Sci Med Sci. 2014;1-8. doi:10.1093/gerona/glu177
68. Van Vliet AR, Verfaillie T, Agostinis P. New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta. 2014;1843(10):2253-2262. doi:10.1016/j.bbamcr.2014.03.009.
69. Takeuchi A, Kim B, Matsuoka S. The destiny of Ca(2+) released by mitochondria. J Physiol Sci. 2015;65(1):11-24. doi:10.1007/s12576-014-0326-7.
70. Mitochondrial Control of Apoptosis Signaling Pathway-Web Cell Signaling. http://www.cellsignal.com/contents/science-pathway-research-apoptosis/mitochondrial-control-of-apoptosis-signaling-pathway/pathwaysapoptosis-control. Acceesed March 2015.
71. Fernandez-Sanz C, Ruiz-Meana M, Castellano J, et al. Altered FoF1 ATP synthase and susceptibility to mitochondrial permeability transition pore during ischaemia and reperfusion in aging cardiomyocytes. Thromb Haemost. 2015;113(3), 441-451. doi:10.1160/TH14-10-0901.
72. Yee C, Yang W, Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 2014;157(4), 897-909. doi:10.1016/j.cell.2014.02.055.
73. Hiona A, Sanz A, Kujoth GC, et al. Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One. 2010;5(7):e11468. doi:10.1371/journal.pone.0011468.
74. Seo AY, Joseph A-M, Dutta D, Hwang JCY, Aris JP, Leeuwenburgh C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci. 2010;123(Pt 15):2533-2542. doi:10.1242/jcs.070490.
75. Lapuente-Brun E, Moreno-Loshuertos R, Acin-Perez R, et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science. 2013;340(6140):1567-1570. doi:10.1126/science.1230381.
76. Kitazoe Y, Kishino H, Hasegawa M, Matsui A, Lane N, Tanaka M. Stability of mitochondrial membrane proteins in terrestrial vertebrates predicts aerobic capacity and longevity. Genome Biol Evol. 2011;3:1233-1244. doi:10.1093/gbe/evr079.
77. Maranzana E, Barbero G, Falasca AI, Lenaz G, Genova ML. Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal. 2013;19(13):1469-1480. doi:10.1089/ars.2012.4845.
78. Lenaz G, Genova ML. Supramolecular organisation of the mitochondrial respiratory chain: a new challenge for the mechanism and control of oxidative phosphorylation. Adv Exp Med Biol. 2012;748:107-144. doi:10.1007/978-1-4614-3573-0-5.
79. Rosca MG, Vazquez EJ, Kerner J, et al. Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. Cardiovasc Res. 2008;80(1):30-39. doi:10.1093/cvr/cvn184.
80. Frenzel M, Rommelspacher H, Sugawa MD, Dencher NA. Ageing alters the supramolecular architecture of OxPhos complexes in rat brain cortex. Exp Gerontol. 2010;45(7-8):563-572. doi:10.1016/j.exger.2010.02.003.
81. Petrosillo G, Matera M, Moro N, Ruggiero FM, Paradies G. Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin. Free Radic Biol Med. 2009;46(1):88-94. doi:10.1016/j.freeradbiomed.2008.09.031.
82. Paradies G, Paradies V, De Benedictis V, Ruggiero FM, Petrosillo G. Functional role of cardiolipin in mitochondrial bioenergetics. Biochim Biophys Acta. 2014;1837(4):408-417. doi:10.1016/j.bbabio.2013.10.006.
83. López-Lluch G, Rodriguez-Aguilera JC, Santos-Ocana C, Navas P. Is coenzyme Q a key factor in aging? Mech Ageing Dev. 2010;131(4):225-235. doi:10.1016/j.mad.2010.02.003.
84. Crescenzo R, Bianco F, Mazzoli A, Giacco A, Liverini G, Iossa S. Alterations in proton leak, oxidative status and uncoupling protein 3 content in skeletal muscle subsarcolemmal and intermyofibrillar mitochondria in old rats. BMC Geriatr. 2014;14:79. doi:10.1186/1471-2318-14-79.
85. Fabbri E, An Y, Schrack JA, et al. Energy metabolism and the burden of multimorbidity in older adults: results from the Baltimore longitudinal study of aging. J Gerontol A Biol Sci Med Sci. 2014;1-7. doi:10.1093/gerona/glu209.
86. Houtkooper RH, Williams RW, Auwerx J. Metabolic networks of longevity. Cell. 2010;142(1):9-14. doi:10.1016/j.cell.2010.06.029.
87. Hepple RT, Baker DJ, McConkey M, Murynka T, Norris R. Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles. Rejuvenation Res. 2006;9(2):219-222. doi:10.1089/rej.2006.9.219.
88. Ruas JL, White JP, Rao RR, et al. A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell. 2012;151(6):1319-1331. doi:10.1016/j.cell.2012.10.050.
89. Gomes AP, Price NL, Ling AJY, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624-1638. doi:10.1016/j.cell.2013.11.037.
90. Mendelsohn AR, Larrick JW. Partial reversal of skeletal muscle aging by restoration of normal NAD(+) levels. Rejuvenation Res. 2014;17(1):62-69. doi:10.1089/rej.2014.1546.
91. Prolla TA, Denu JM. NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab. 2014;19(2):178-180. doi:10.1016/j. cmet.2014.01.005.
92. Rotig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17(2):215-217. doi:10.1038/ng1097-215.
93. Isaya G. Mitochondrial iron-sulfur cluster dysfunction in neurodegenerative disease. Front Pharmacol. 2014;5:29. doi:10.3389/fphar.2014.00029.
94. Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM-Y. Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 2005;25(3):689-698. doi:10.1523/jneurosci.4265-04.2005.
95. Weiss N, Andrianjafiniony T, Dupré-Aucouturier S, Pouvreau S, Desplanches D, Jacquemond V. Altered myoplasmic Ca(2+) handling in rat fast-twitch skeletal muscle fibres during disuse atrophy. Pflugers Arch. 2010;459(4):631-644. doi:10.1007/s00424-009-0764-x.
96. Bhattacharya A, Lustgarten M, Shi Y, et al. Increased mitochondrial matrix-directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria. Free Radic Biol Med. 2011;50(5):592-601. doi:10.1016/j.freeradbiomed.2010.12.014.
97. Salminen A, Kaarniranta K, Hiltunen M, Kauppinen A. Krebs cycle dysfunction shapes epigenetic landscape of chromatin: novel insights into mitochondrial regulation of aging process. Cell Signal. 2014;26(7):1598-1603. doi:10.1016/j.cellsig.2014.03.030.
98. Shaughnessy DT, McAllister K, Worth L, et al. Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress. Environ Health Perspect. 2014;122:1271-1278. doi:10.1289/ehp.1408418.
99. Li M, Schroder R, Ni S, Madea B, Stoneking M. Extensive tissue-related and allele-related mt DNA heteroplasmy suggests positive selection for somatic mutations. Proc Natl Acad Sci U S A. 2015;112(8), 2491-2496. doi:10.1073/pnas.1419651112.
100. Giuliani C, Barbieri C, Li M, et al. Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing. Aging. 2014;6(6), 454-467.
101. Rose G, Romeo G, Dato S, et al. Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study. PloS One. 2010;5(10), e13395. doi:10.1371/journal.pone.0013395.
102. Ashar FN, Moes A, Moore AZ, et al. Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med (Berl). 2015;93(2), 177-186. doi:10.1007/s00109-014-1233-3.