, 36:9626 | Cite as

p62/SQSTM1 at the interface of aging, autophagy, and disease

  • Alessandro Bitto
  • Chad A. Lerner
  • Timothy Nacarelli
  • Elizabeth Crowe
  • Claudio Torres
  • Christian SellEmail author


Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/SQSTM1 as a novel target for aging studies and age-extending interventions.


Aging Autophagy Mitochondria Senescence p62 


  1. Adam T, Opie LH, Essop MF (2010) AMPK activation represses the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase: role of nuclear respiratory factor-1. Biochem Biophys Res Commun 398(3):495–499PubMedGoogle Scholar
  2. Alcorta DA et al (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 93(24):13742–13747PubMedCentralPubMedGoogle Scholar
  3. Alvers A et al (2009) Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5(6):847–849PubMedCentralPubMedGoogle Scholar
  4. Anello M et al (2005) Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48(2):282–289PubMedGoogle Scholar
  5. Askanas V, Engel W (2002) Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms. Curr Opin Neurol 15(5):525–531PubMedGoogle Scholar
  6. Babu J, Geetha T, Wooten M (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 94(f27f4e63-a010-5926-f8b4-116f27f87842):192–395PubMedGoogle Scholar
  7. Baker D et al (2011) Clearance of p16(Ink4a)-positive senescent cells delays ageing-associated disorders. Nature 479:232–236PubMedCentralPubMedGoogle Scholar
  8. Barone M, Sykiotis G, Bohmann D (2011) Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease. Dis Models Mech 4(29b98216-6e5f-44c2-693d-1f4bd0dc641e):701–708Google Scholar
  9. Bhat R et al (2012) Astrocyte senescence as a component of Alzheimer's disease. PLoS One 7(9)Google Scholar
  10. Bitto A et al (2010a) Stress-induced senescence in human and rodent astrocytes. Exp Cell Res 316:2961–2968PubMedGoogle Scholar
  11. Bitto A et al (2010b) Long-term IGF-I exposure decreases autophagy and cell viability. PLoS One 5(9)Google Scholar
  12. Bjorkoy G et al (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171(4):603–614PubMedCentralPubMedGoogle Scholar
  13. Burman J et al (2012) Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants. Proc Natl Acad Sci U S A 109(26):10438–10443PubMedCentralPubMedGoogle Scholar
  14. Buttner S et al (2008) Functional mitochondria are required for alpha-synuclein toxicity in aging yeast. J Biol Chem 283(12):7554–7560PubMedGoogle Scholar
  15. Cao K et al (2011) Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med 3(89)Google Scholar
  16. Chaudhary K, El-Sikhry H, Seubert J (2011) Mitochondria and the aging heart. JGC 8(3):159–167PubMedCentralPubMedGoogle Scholar
  17. Cheong H et al (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell 19(2):668–681PubMedCentralPubMedGoogle Scholar
  18. Choi A, Ryter S, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368(7):651–662PubMedGoogle Scholar
  19. Copple I et al (2010) Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway. J Biol Chem 285(81009124-2876-05da-270c-84b2eb4bf664):16782–16790PubMedCentralPubMedGoogle Scholar
  20. Cuervo A (2008) Autophagy and aging: keeping that old broom working. TIG 24(12):604–612PubMedCentralPubMedGoogle Scholar
  21. Dalakas M (1991) Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 325(21):1487–1498PubMedGoogle Scholar
  22. Del Roso A et al (2003) Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis. Exp Gerontol 38(5):519–527PubMedGoogle Scholar
  23. Demidenko ZN et al (2009) Rapamycin decelerates cellular senescence. Cell Cycle 8(12):1888–1895PubMedGoogle Scholar
  24. Du Y et al (2009a) Age-associated oxidative damage to the p62 promoter: implications for Alzheimer disease. Free Radic Biol Med 46(23d068fb-0594-c642-03d0-07ddf3c86ab0):492–993PubMedCentralPubMedGoogle Scholar
  25. Du Y, Wooten M, Wooten M (2009b) Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol Dis 35(685e8d56-503b-eab5-c2b8-07dd602f3f7f):302–312PubMedCentralPubMedGoogle Scholar
  26. Dubourg O et al (2011) Diagnostic value of markers of muscle degeneration in sporadic inclusion body myositis. Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases. 30(2):103-108Google Scholar
  27. Duran A et al (2011) p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 44(1):134–146PubMedCentralPubMedGoogle Scholar
  28. Fan W et al (2010) Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. Autophagy 6(a2b5697d-a785-653c-42b7-84b2eb17c4d1)Google Scholar
  29. Frenzel H, Feimann J (1984) Age-dependent structural changes in the myocardium of rats. A quantitative light- and electron-microscopic study on the right and left chamber wall. Mech Ageing Dev 27(1):29–41PubMedGoogle Scholar
  30. Geetha T, Wooten M (2002) Structure and functional properties of the ubiquitin binding protein p62. FEBS Lett 512(24344ce0-5262-a90c-1802-fc2e2b0a525f):19–43PubMedGoogle Scholar
  31. Geetha T, Jiang J, Wooten M (2005) Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell 20(1db9e0fb-5676-7dcd-89aa-116f27f72f5c):301–313PubMedGoogle Scholar
  32. Geetha T et al (2008) p62 serves as a shuttling factor for TrkA interaction with the proteasome. Biochem Biophys Res Commun 374(f569f091-6fb4-2905-c0a9-1b280377cbcc):33–40PubMedCentralPubMedGoogle Scholar
  33. Geisler S et al (2010a) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12(2):119–131PubMedGoogle Scholar
  34. Geisler S et al (2010b) The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6(7):871–878PubMedGoogle Scholar
  35. Geng J, Klionsky D (2008) The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep 9(9):859–864PubMedCentralPubMedGoogle Scholar
  36. Gilkerson R, et al. (2011) Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition. Human Mol Genet 21(5):978–990Google Scholar
  37. Gong Z, Muzumdar R (2012) Pancreatic function, type 2 diabetes, and metabolism in aging. Int J Endocrinol 2012(94bf4f10-7e61-8f0d-47cb-395213c68671):320482PubMedCentralPubMedGoogle Scholar
  38. Goode A, Layfield R (2010) Recent advances in understanding the molecular basis of Paget disease of bone. J Clin Pathol 63(e67bfe6b-8256-f35a-f589-fc0dcd60d5a1):199–402PubMedGoogle Scholar
  39. Handayaningsih A-E et al. (2012) IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway. Biochem Biophys Res Commun 425(2):478–484Google Scholar
  40. Hansen M et al (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4(2):e24PubMedCentralPubMedGoogle Scholar
  41. Harman D (2003) The free radical theory of aging. Antioxid Redox Signal 5(5):557–561PubMedGoogle Scholar
  42. He C, Klionsky D (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93PubMedCentralPubMedGoogle Scholar
  43. Hughes A, Gottschling D (2012) An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492(7428):261–265PubMedCentralPubMedGoogle Scholar
  44. Inamori Y et al (2012) Inclusion body myositis coexisting with hypertrophic cardiomyopathy: an autopsy study. NMD 22(8):747–754PubMedGoogle Scholar
  45. Itakura E, Mizushima N (2011) p62 Targeting to the autophagosome formation site requires self-oligomerization but not LC3 binding. J Cell Biol 192(35dd33bb-6bd5-d6ad-3d10-fcbe10fbbcb6):17–44PubMedCentralPubMedGoogle Scholar
  46. Itakura E et al (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19(12):5360–5372PubMedCentralPubMedGoogle Scholar
  47. Jain A et al (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285(29):22576–22591PubMedCentralPubMedGoogle Scholar
  48. Jang Y, Van Remmen H (2011) Age-associated alterations of the neuromuscular junction. Exp Gerontol 46(2–3):193–198PubMedCentralPubMedGoogle Scholar
  49. Jin Z et al (2009) Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137(4):721–735PubMedGoogle Scholar
  50. Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7(3):279–296PubMedCentralPubMedGoogle Scholar
  51. Joung I, Strominger J, Shin J (1996) Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Proc Natl Acad Sci U S A 93(529cf5e6-37c8-49cb-37e6-008f126febd7):5991–5996PubMedCentralPubMedGoogle Scholar
  52. Jung C et al (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20(7):1992–2003PubMedCentralPubMedGoogle Scholar
  53. Kang HT et al (2011) Autophagy impairment induces premature senescence in primary human fibroblasts. PLoS One 6(8):e23367PubMedCentralPubMedGoogle Scholar
  54. Kaushik S, Cuervo A (2008) Chaperone-mediated autophagy. Methods Mol Biol (Clifton, NJ) 445:227–244Google Scholar
  55. Kim E et al (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10(552acb39-f20a-30f5-80fb-6f46f5589ac8):935–980PubMedCentralPubMedGoogle Scholar
  56. Kim J et al (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141PubMedCentralPubMedGoogle Scholar
  57. Kirkin V et al (2009) A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell 33(4):505–516PubMedGoogle Scholar
  58. Kitzman D, Edwards W (1990) Age-related changes in the anatomy of the normal human heart. J Gerontol 45(2):9Google Scholar
  59. Klass M (1977) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6(6):413–429PubMedGoogle Scholar
  60. Koga H, Kaushik S, Cuervo A (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10(2):205–215PubMedCentralPubMedGoogle Scholar
  61. Komatsu M et al (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131(6):1149–1163PubMedGoogle Scholar
  62. Komatsu M et al (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12(3):213–223PubMedGoogle Scholar
  63. Komatsu M, Kageyama S, Ichimura Y (2012) p62/SQSTM1/A170: physiology and pathology. Pharmacol Res Off J Ital Pharmacol Soc 66(6):457–462Google Scholar
  64. Korolchuk V et al (2009) Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 33(47c733bb-2560-6596-2d60-07bda3a4c8b9):517–544PubMedCentralPubMedGoogle Scholar
  65. Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport 12(10):2085–2090PubMedGoogle Scholar
  66. Kuusisto E, Salminen A, Alafuzoff I (2002) Early accumulation of p62 in neurofibrillary tangles in Alzheimer's disease: possible role in tangle formation. Neuropathol Appl Neurobiol 28(3bceda89-d3ed-f98e-1484-07daef4daadc):228–265PubMedGoogle Scholar
  67. Kwon J et al (2012) Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade. EMBO Rep 13(e6cd8e22-20d2-22e1-d21d-e3874e265257):150–156PubMedCentralPubMedGoogle Scholar
  68. Lalley P (2013) The aging respiratory system—pulmonary structure, function and neural control. Respir Physiol Neurobiol 187:199–210PubMedGoogle Scholar
  69. Lamark T et al (2003) Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins. J Biol Chem 278(4a65a5a4-71cb-2ade-e9ee-fc2e2b09dbc8):34568–34649PubMedGoogle Scholar
  70. Landfield P et al (1981) Hippocampal aging in rats: a morphometric study of multiple variables in semithin sections. Neurobiol Aging 2(4):265–275PubMedGoogle Scholar
  71. Lau A et al (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30(13):3275–3285PubMedCentralPubMedGoogle Scholar
  72. Laurin N et al (2002) Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70(6):1582–1588PubMedCentralPubMedGoogle Scholar
  73. Lecoultre V, Ravussin E (2011) Brown adipose tissue and aging. Curr Opin Clin Nutr Metab Care 14(1):1–6PubMedGoogle Scholar
  74. Lee S et al (2010) PKCzeta-regulated inflammation in the nonhematopoietic compartment is critical for obesity-induced glucose intolerance. Cell Metab 12(64b8228e-3e87-bfd5-890a-3e48b17b5d2c):65–142PubMedCentralPubMedGoogle Scholar
  75. Lee J et al (2012) Autophagy suppresses interleukin-1β (IL-1β) signaling by activation of p62 degradation via lysosomal and proteasomal pathways. J Biol Chem 287(21aff234-8231-4f10-7d43-1535e01980f9):4033–4073PubMedCentralPubMedGoogle Scholar
  76. Leiser S, Miller R (2010) Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol 30(f6928770-a92a-c84b-70bf-3f502d906abb):871–955PubMedCentralPubMedGoogle Scholar
  77. Lerner C et al (2013) Reduced mTOR activity facilitates mitochondrial retrograde signaling and increases lifespan in normal fibroblasts. Aging Cell (In press)Google Scholar
  78. Li W-W, Li J, Bao J-K (2012) Microautophagy: lesser-known self-eating. CMLS 69(7):1125–1136PubMedGoogle Scholar
  79. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795PubMedGoogle Scholar
  80. Longo V (1999) Mutations in signal transduction proteins increase stress resistance and longevity in yeast, nematodes, fruit flies, and mammalian neuronal cells. Neurobiol Aging 20(5):479–486PubMedGoogle Scholar
  81. Mamidipudi V, Li X, Wooten M (2002) Identification of interleukin 1 receptor-associated kinase as a conserved component in the p75-neurotrophin receptor activation of nuclear factor-kappa B. J Biol Chem 277(48659987-f63a-21a3-c089-152bf7a64ec3):28010–28018PubMedGoogle Scholar
  82. Mammucari C et al (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6(6):458–471PubMedGoogle Scholar
  83. Mansouri A et al (2006) Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging. Mech Ageing Dev 127(3):298–306PubMedGoogle Scholar
  84. Marcus S et al (1996) A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor. J Biol Chem 271(b9b0da87-fccd-43cc-0095-0174c302442e):27197–27397PubMedGoogle Scholar
  85. Matsumoto G et al (2011) Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 44(75e058b6-11c7-0417-c1eb-374a0a09fa5f):279–368PubMedGoogle Scholar
  86. Mattson MP (2010) Perspective: does brown fat protect against diseases of aging? Ageing Res Rev 9(1):69–76PubMedCentralPubMedGoogle Scholar
  87. Mizuno Y et al (2006) Immunoreactivities of p62, an ubiquitin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. J Neurol Sci 249(1):13–18PubMedGoogle Scholar
  88. Mizushima N et al (2003) Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 116(Pt 9):1679–1688PubMedGoogle Scholar
  89. Mizushima N et al (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075PubMedCentralPubMedGoogle Scholar
  90. Moscat J, Diaz-Meco M (2011) Feedback on fat: p62-mTORC1-autophagy connections. Cell 147(7fe468c7-09ee-421a-bbe5-0fa750b8a785)Google Scholar
  91. Narendra D et al (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183(89cd27ab-ae69-8528-c6f4-1f3f639dc970):795–1598PubMedCentralPubMedGoogle Scholar
  92. Narendra D et al (2010a) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6(8):1090–1106PubMedCentralPubMedGoogle Scholar
  93. Narendra DP et al (2010b) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8(1):e1000298PubMedCentralPubMedGoogle Scholar
  94. Nezis I, Stenmark H (2012) p62 at the interface of autophagy, oxidative stress signaling, and cancer. Antioxid Redox Signal 17(5):786–793PubMedGoogle Scholar
  95. Nezis I et al (2008) Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol 180(6):1065–1071PubMedCentralPubMedGoogle Scholar
  96. Nogalska A et al (2009) p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis. Acta Neuropathol 118(3):407–413PubMedGoogle Scholar
  97. Nogalska A et al (2010) Novel demonstration of amyloid-β oligomers in sporadic inclusion-body myositis muscle fibers. Acta Neuropathol 120(5):661–666PubMedGoogle Scholar
  98. Nogalska A et al (2011) Novel demonstration of conformationally modified tau in sporadic inclusion-body myositis muscle fibers. Neurosci Lett 503(3):229–233PubMedGoogle Scholar
  99. Okatsu K et al (2010) p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15(8):887–900PubMedCentralPubMedGoogle Scholar
  100. Ozawa T (1998) Mitochondrial DNA mutations and age. Ann N Y Acad Sci 854:128–154PubMedGoogle Scholar
  101. Pankiv S et al (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131–24145PubMedGoogle Scholar
  102. Pankiv S et al (2010) Nucleocytoplasmic shuttling of p62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. J Biol Chem 285(3c704f44-98ab-1180-47d3-0682c131049e):5941–5994PubMedCentralPubMedGoogle Scholar
  103. Pattingre S et al (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122(6):927–939PubMedGoogle Scholar
  104. Piantadosi CA et al (2008) Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103(11):1232–1240PubMedCentralPubMedGoogle Scholar
  105. Polak P et al (2008) Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 8(84e93330-7322-b853-cd6e-3a6ea7481b27):399–809PubMedGoogle Scholar
  106. Porta EA (1991) Advances in age pigment research. Arch Gerontol Geriatr 12(2–3):303–320PubMedGoogle Scholar
  107. Rachubinski R, Marcus S, Capone J (1999) The p56(lck)-interacting protein p62 stimulates transcription via the SV40 enhancer. J Biol Chem 274(5ae492ce-035d-a8aa-4ee9-fc2e2b0a2e07):18278–18362PubMedGoogle Scholar
  108. Ramesh Babu J et al (2008) Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J Neurochem 106(27a74d97-a739-d297-646d-16c8da17e322):107–127PubMedGoogle Scholar
  109. Ramsey C et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66(6a48f324-2d51-2aa2-8725-1b0928e05358):75–160PubMedCentralPubMedGoogle Scholar
  110. Ravikumar B et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36(6):585–595PubMedGoogle Scholar
  111. Ringel S et al (1987) Spectrum of inclusion body myositis. Arch Neurol 44(11):1154–1157PubMedGoogle Scholar
  112. Robida-Stubbs S et al (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15(5):713–724PubMedCentralPubMedGoogle Scholar
  113. Rodriguez A et al (2006) Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metab 3(0a30ac0c-ca9e-5ee9-59ec-24cbc90092cf):211–233PubMedGoogle Scholar
  114. Salminen A et al (2011) Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 34(1):3–11PubMedGoogle Scholar
  115. Salmon A et al (2005) Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab 289(1):9Google Scholar
  116. Sancak Y et al (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Sci (New York, NY) 320(56ca5f23-896a-b94e-de3e-0c4be356193c):1496–1997Google Scholar
  117. Sancak Y et al (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(01f0f45f-84d6-a5ce-e325-0c4b1f2cde36):290–593PubMedCentralPubMedGoogle Scholar
  118. Sanchez P et al (1998) Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62. Mol Cell Biol 18(6abf35eb-a291-e542-7256-008f126e35a9):3069–3149PubMedCentralPubMedGoogle Scholar
  119. Sanz L et al (1999) The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J 18(28a44be7-14d0-4c74-cc5a-01ea9df668a3):3044–3097PubMedCentralPubMedGoogle Scholar
  120. Sanz L et al (2000) The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J 19(dec466e5-a9e0-db20-d2db-01c4befea22f):1576–1662PubMedCentralPubMedGoogle Scholar
  121. Schmucker D (2005) Age-related changes in liver structure and function: implications for disease ? Exp Gerontol 40(8–9):650–659PubMedGoogle Scholar
  122. Schmucker D, Sachs H (2002) Quantifying dense bodies and lipofuscin during aging: a morphologist's perspective. Arch Gerontol Geriatr 34(3):249–261PubMedGoogle Scholar
  123. Seibenhener ML et al (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24(18):8055–8068PubMedCentralPubMedGoogle Scholar
  124. Seo A et al (2010) New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 123(Pt 15):2533–2542PubMedCentralPubMedGoogle Scholar
  125. Sinclair D, Guarente L (1997) Extrachromosomal rDNA circles—a cause of aging in yeast. Cell 91(7):1033–1042PubMedGoogle Scholar
  126. Spilman P et al (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One 5(4):e9979PubMedCentralPubMedGoogle Scholar
  127. Steinbaugh M et al (2012) Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am J Physiol Endocrinol Metab 303(4):95Google Scholar
  128. Stępkowski T, Kruszewski M (2011) Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. Free Radic Biol Med 50(36577d97-5454-ace8-d631-84b2eb1acb05):1186–1281PubMedGoogle Scholar
  129. Szweda P et al (2003) Aging, lipofuscin formation, and free radical-mediated inhibition of cellular proteolytic systems. Ageing Res Rev 2(4):383–405PubMedGoogle Scholar
  130. Tan J, et al (2008) Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy 4:251–253Google Scholar
  131. Tan JM et al (2008b) Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum Mol Genet 17(3):431–439PubMedGoogle Scholar
  132. Tang F et al (2011) RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates autophagy through interaction with BNIP1. PLoS One 6(2caa5a85-183c-3c9d-537c-84b2eb293c9e)Google Scholar
  133. Toth SE (1968) The origin of lipofuscin age pigments. Exp Gerontol 3(1):19–30PubMedGoogle Scholar
  134. Tóth M et al (2008) Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4(3):330–338PubMedGoogle Scholar
  135. Um S et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431(1ae7851e-f1fe-5adc-6b8c-3a5109b98611):200–205PubMedGoogle Scholar
  136. Um S, D'Alessio D, Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3(fb9365a2-b3f2-6ed9-7322-3edcb615be48):393–795PubMedGoogle Scholar
  137. Vadlamudi R, Shin J (1998) Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein. FEBS Lett 435(2–3):138–142PubMedGoogle Scholar
  138. Vadlamudi R et al (1996) p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J BiolChem 271(e002a393-07b2-a95e-5354-fc56877148c3):20235–20242Google Scholar
  139. Vaughan D, Peters A (1974) Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J Neurocytol 3(4):405–429PubMedGoogle Scholar
  140. von Otter M et al (2010) Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease. BMC Med Genet 11(ea342ab4-65bd-117a-1b99-1f4bd0e008b2):36Google Scholar
  141. Wang M, Miller R (2012) Fibroblasts from long-lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress. Aging Cell 11(4):668–674PubMedCentralPubMedGoogle Scholar
  142. Watanabe Y, Tanaka M (2011) p62/SQSTM1 in autophagic clearance of a non-ubiquitylated substrate. J Cell Sci 124(Pt 16):2692–2701PubMedGoogle Scholar
  143. Wei M et al (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4(1)Google Scholar
  144. Wooten M et al (2001) The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem 276(95729bab-6726-13b1-9482-01c430398cd6):7709–7721PubMedGoogle Scholar
  145. Wooten M et al (2005) The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem 280(2978358a-d99d-7f3a-c8da-01c23fc80840):35625–35634PubMedGoogle Scholar
  146. Xie Z, Nair U, Klionsky D (2008) Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell 19(8):3290–3298PubMedCentralPubMedGoogle Scholar
  147. Young A et al (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23(7):798–803PubMedCentralPubMedGoogle Scholar
  148. Zhang Y et al (2009) Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci U S A 106(f900c956-7e9b-e365-2109-3a67f3160fb4):19860–19865PubMedCentralPubMedGoogle Scholar
  149. Zhao J et al (2007) FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6(6):472–483PubMedGoogle Scholar
  150. Zheng YT et al (2009) The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J Immunol 183(9):5909–5916PubMedGoogle Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Alessandro Bitto
    • 1
  • Chad A. Lerner
    • 2
  • Timothy Nacarelli
    • 3
  • Elizabeth Crowe
    • 3
  • Claudio Torres
    • 3
  • Christian Sell
    • 3
    Email author
  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA
  2. 2.University of RochesterRochesterUSA
  3. 3.Department of PathologyDrexel University College of MedicinePhiladelphiaUSA

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