Ana Maria Cuervo and J. Fred Dice

Department of Physiology Tufts University School of Medicine, Boston, USA

Received 12/5/97 Accepted 12/9/97

8. REFERENCES

1. DA Jurivich, L Qiu & JF Welk: Attenuated stress responses in young and old human lymphocytes. Mech Ageing Develop 94, 233-249, (1997)

2. G Pawelec & R Solana: Immunosenescence. Trends Immunol 18, 514-516, (1997)

3. R Yanishevsky, ML Mendelsohn, BH Mayall & VJ Cristofalo: Proliferative capacity and DNA content of aging

human diploid cells in culture: A cytophotometric and autoradiographic analysis. J Cell Physiol 84, 165-170, (1974)

4. T Seshadri & J Campisi: Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247, 205-209, (1990)

5. GP Dimri & J Campisi: Altered profile of transcription factor-binding activities in senescent human fibroblasts. Exp Cell Res 212, 132-140, (1994)

6. CA Afshari & JC Barrett: Molecular genetics of in vitro cellular senescence. In: Cellular Aging and Cell Death. Eds: Holbrook NJ, Martin GR, Lockshin, RA.Wiley-Liss, Inc. NY. 109-121, (1996)

7. Y Ning, JL Weber, AM Killary, DH Ledbetter, JR Smith & OM Pereira-Smith: Genetic Analysis of indefinite division in human cells: Evidence for a senescence-related gene(s) on human chromosome 4. Proc Natl Acad Sci USA 88, 5635-5639, (1991)

8. CF van Bezooijen, FR Leeuw-Israel & CF Hollander: On the role of hepatic cell ploidy in changes in liver function with age and following partial hepatectomy. Mech Ageing Develop 1, 351-356, (1973)

9. R Schoenheimer: Dynamic State of Body Constituents. Harvard University Press, Cambridge, (1942)

10. RT Schimke: Regulation of protein degradation in mammalian tissues. In: Mammalian Protein Metabolism. Ed: Munro, HN. Academic Press, NY, 177-277, (1970)

11. AL Goldberg & JF Dice: Intracellular protein degradation in mammalian and bacterial cells. Annu Rev Biochem 34, 835-869, (1974)

12. FJ Doherthy & RJ Mayer: Intracellular Protein Degradation. Oxford University Press, New York, (1992)

13. JF Dice: Cellular and molecular mechanisms of aging. Physiol Rev 73, 149-159, (1993)

14. J Papaconstantinou: Unifying model of the programmed (intrinsic) and stochastic (extrinsic) theories of aging. The stress response genes, signal transduction-redox pathways and aging. Ann New York Acad Sci 719, 195-211, (1994)

15. JA Knight: The process and theories of aging. Ann Clinic Lab Sci 25, 1-12, (1995)

16. J Vijg & JY Wei: Understanding the biology of aging: the key to prevention and therapy. J Am Geriat Soc 43, 426-434, (1995)

17. S Makrides: Protein synthesis and degradation during aging and senescence. Biol Rev 83, 393-422, (1983)

18. DF Goldspink & FJ Kelly: Protein turnover and growth in the whole body, liver, and kidney of the rat from foetus to senility. Biochem J 217, 507-516, (1984)

19. JF Dice: Altered intracellular protein degradation in aging: A possible cause of proliferative arrest. Exp Gerontol 24, 451-459, (1989)

20. JF Dice: Altered degradation of proteins microinjected into senescent human fibroblasts. J Biol Chem 257, 14624-14627, (1982)

21. RW Gracy, KU Yuksel, ML Chapman, JK Cini, M Jahani, HS Lu, B Gray & JM Talent: Impaired protein degradation may account for the accumulation of abnormal proteins in aging cells. In: Modifications of Proteins during Aging. Eds: Adelman RC, Dekker, EE. Alan R. Liss, NY, 1-18, (1985)

22. A Taylor & KJ Davies: Protein oxidation and loss of protease activity may cause cataract formation in the aged lens. Free Radic Biol Med 3, 371-377, (1987)

23. AM Cuervo, SA Hayes & JF Dice: Molecular chaperones and intracellular protein degradation with emphasis on a selective lysosomal pathway of proteolysis. In: Molecular Chaperones in the Life Cycle of Proteins. Eds: Fink, AL and Goto, Y. Marcel Dekker, Inc. NY, 491-510, (1997)

24. I Jariel-Encontre, C Salvat, AM Steff, M Pariat, C Acquaviva, O Furstoss & M Piechaczyk: Complex mechanisms for c-fos and c-jun degradation. Mol Biol Rep 24, 51-56, (1997)

25. F Chen, Y Lu, DC Kuhn, M Maki, X Shi, SC Sun & LM Demers: Calpain contributes to silica-induced I kappa B-alpha degradation and nuclear factor-kappa B activation. Arch Biochem Biophys 342, 383-388, (1997)

26. TJ Jensen, MA Loo, S Pind, DB Williams, AL Goldberg & JR Riordan: Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83, 129-135, (1995)

27. AL Schwartz, JS Trausch, A Ciechanover, JW Slot & H Geuze: Immunoelectron microscopic localization of the ubiquitin-activating enzyme E1 in HepG2 cells. Proc Natl Acad Sci USA 89, 5542-5546, (1992)

28. P Low, FJ Doherty, E Fellinger, M Sass, RJ Mayer & L Laszlo: Related organelles of the endosome-lysosome system contain a different repertoire of ubiquitinated proteins in sf9 insect cells. FEBS Lett 368, 125-131, (1995)

29. RJ Mayer, C Tipler, J Arnold, L Laszlo, A Al-Khedhairy, J Lowe & M Landon: Endosome-lysosomes, ubiquitin and neurodegeneration. Adv Exp Med Biol 389:261-269, (1996)

30. EF Blommaart, JJ Luiken & AJ Meijer: Autophagic proteolysis: control and specificity. Histochem J 29, 365-385, (1997)

31. JD Burek: Pathology of Aging Rats. CRC Press, Inc., Boca Raton, FL (1978)

32. BJ Cohen, MR Anver, DH Ringler & RC Adelman: Age-associated pathological changes in male rats. Fed Proc

37, 2848-2850, (1978)

33. RL Sprott: Mouse and rat genotype choices. Exp Gerontol. 32, 79-86, (1997)

34. T Takeda, M Hosokawa, S Takeshita, M Irino, K Higuchi, T Matsushita, Y Tomita, K Yasuhira, H Hamamoto, K Shimizu, M Ishii & T Yamamuro: A new murine model of accelerated senescence. Mech Ageing Develop 17,183-194, (1981)

35. B Sass, LS Rabstein, R Madison, RM Nims, RL Peters & GJ Kelloff: Incidence of spontaneous neoplasms in F344 rats throughout the natural life span. J Natl Cancer Inst 54, 1449-1456, (1975)

36. GL Coleman, W Barthold, GW Osbaldiston, SJ Foster & AM Jonas: Pathologic changes during aging in barrier-reared Fischer 344 male rats. J Gerontol 32, 258-278, (1977)

37. JM Ward & H Reznik-Schuller: Morphological and histochemical characteristics of pigments in aging F344 rats. Vet Pathol 17, 678-685, (1980)

38. JB Nold & GA Parker: Diseases and Neoplasms of the Aging Rat. 42nd Annual Pathology of Laboratory Animals Course, (1995). http://vetpath1.afip.mil/ POLA95

39. HJ Martus, ME Dolle, JA Gossen, ME Boerrigter & J Vijg: Use of transgenic mouse models for studying somatic mutations in aging. Mut Res 338, 203-213, (1995)

40. M Kuro, Y Matsumura, H Aizawa, h Kawaguchi, T Suga, T Utsug, Y Ohyama, M Kurabayashi, T Kaname, E Kume, H Iwasaki, A Iida, T Shiraki-Iida, S Nishikawa, R Nagai & YI Nabeshima: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45-51, (1997)

41. CE Finch: Longevity, Senescence and the Genome. The University of Chicago Press, Chicago, IL.(1990)

42. VJ Cristofalo & RJ Pignolo: Molecular markers of senescence in fibroblast-like cultures. Exp Gerontol 31, 111-123, (1996)

43. L Hayflick & PS Moorhead: The serial cultivation of human diploid cell strains. Exp Cell Res 25, 585-621, (1961)

44. L Hayflick: The cell biology of human aging. New Engl J Med 295, 1302-1308, (1976)

45. EL Schneider & Y Mitsui: The relationship between in vitro cellular aging and in vivo human age. Proc Natl Acad Sci USA 73, 3584-3588, (1976)

46. S Goldstein: Aging in vitro. Growth of cultured cells from the Galapagos turtle. Exp Cell Res 83, 297-302, (1974)

47. S Goldstein, S Murano, H Benes, EJ Moerman, RA Jones, R Thweatt, RJ Shmookler- Reis & BH Howard: Studies on the molecular genetic basis of replicative senescence in Werner syndrome and normal fibroblasts. Exp Gerontol 24, 461-468, (1989)

48. VJ Cristofalo & RJ Pignolo: Replicative senescence of human fibroblast-like cells in culture. Physiol Rev 73, 617-638, (1993)

49. GP Dimri, X Lee, G Basile, M Acosta, G Scott, C Roskelley, EE Medrano, M Linskens, I Rubelj, O Pereira-Smith & M Peacocke: A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92, 9363-9367, (1995)

50. SM Russell, CJ Wilde, DA White, HR Hasan & RJ Mayer: Characteristics of protein degradation in liver and mammary gland. Acta Biologic Medic Germ 40, 1397-1406, (1981)

51. MA McElligott & JF Dice: Erythrocyte-mediated microinjection, a technique to study protein degradation in muscle cells. Biochem J 216, 559-566, (1983)

52. PO Hasselgren, P Pedersen, HC Sax, BW Warner & JE Fischer: Methods for studying protein synthesis and degradation in liver and skeletal muscle. J Surg Res 45, 389-415,

53. A Okada & JF Dice: Altered degradation of intracellular proteins in aging human fibroblasts. Mech Ageing Dev 26, 341-356, (1984)

54. T Tamura, K Tanaka, N Tanahashi & A Ichihara: Improved method for preparation of ubiquitin-ligated lysozyme as substrate of ATP-dependent proteolysis. FEBS Lett 292, 154-158, (1991)

55. SK Kong & PB Chock: Protein ubiquitination is regulated by phosphorylation. An in vitro study. J Biol Chem 267, 14189-14192, (1992)

56. S Ugai, T Tamura, N Tanahashi, S Takai, N Komi, CH Chung, K Tanaka & A Ichihara: Purification and characterization of the 26S proteasome complex catalyzing ATP-dependent breakdown of ubiquitin-ligated proteins from rat liver. J Biochem 113, 754-768, (1993)

57. T Shibatani & WF Ward: Sodium dodecyl sulfate (SDS) activation of the 20S proteasome in rat liver. Arch Biochem & Biophys 321, 160-166, (1995)

58. Y Goda & SR Pfeffer: Cell-free systems to study vesicular transport along the secretory and endocytic pathways. FASEB J 3, 2488-2495, (1989)

59. SR Terlecky & JF Dice: Polypeptide import and degradation by isolated lysosomes. J Biol Chem 268, 23490-23495, (1993)

60. F Aniento, E Roche, AM Cuervo & E Knecht: Uptake and degradation of glyceraldehyde-3-phosphate dehydrogenase by rat liver lysosomes. J Biol Chem 268, 10463-10470, (1993)

61. AM Cuervo, E Knecht, SR Terlecky & JF Dice: Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation Am J Physiol 269, C1200-C1208, (1995)

62. JM Peters, Z Cejka, JR Harris, JA Kleinschmidt & W Baumeister: Structural features of the 26 S proteasome complex. J Mol Biol 234, 932-937, (1993)

63. A Lupas, HM Flanagan, T Tamura & W Baumeister: Self-compartmentalizing proteases. Trends Biochem Sci 22, 399-404, (1997)

64. O Coux, K Tanaka & AL Goldberg: Structure and functions of the 20S and 26S proteaseomes. Annu Rev Biochem 65, 801-847, (1996)

65. M Orlowski: The mutlticatalytic proteinase complex, a major extralysosomal proteolytic system. Biochemistry 29, 10289-10297, (1990)

66. D Krappmann, FG Wulczyn & C Scheidereit: Different mechanisms control signal-induced degradation and basal turnover of the NF-kappaB inhibitor IkappaB alpha in vivo. EMBO J 15, 6716-6726, (1996)

67. EJ Wiertz, D Tortorella, M Bogyo, J Yu, W Mothes, TR Jones, TA Rapoport & HL Ploegh: Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432-438, (1996)

68. A Varshavsky: The ubiquitin system. Trends Biochem Sci 22, 383-387, (1997)

69. M Hochstrasser: Ubiquitin-dependent protein degradation Annu Rev Genet 30, 405-439, (1996)

70. V Chau, JW Tobias, A Bachmair, D Marriott, DJ Ecker, DK Gonda & A Varshavsky: A multiubiquitin chain is confined to a specific lysine in a targeted short-lived protein. Science 243, 1576-1583, (1989)

71. Q Deveraux, V Ustrell, C Pickart & M Rechsteiner: A 26 S protease subunit that binds ubiquitin conjugates. J Biol Chem 269, 7059-7061, (1994)

72. S van Nocker, S Sadis, DM Rubin, M Glickman, H Fu, O Coux, I Wefes, D Finley & RD Vierstra: The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover. Mol Cell Biol 16, 6020-6028, (1996)

73. RT Baker, JW Tobias & A Varshavsky: Ubiquitin-specific proteases of Saccharomyces cerevisiae. Cloning of UBP3, and functional analysis of the UBP gene family. J Biol Chem 267, 23364-23375, (1992)

74. KD Wilkinson, VL Tashayev, LB O'Connor, CN Larsen, E Kasperek & CM Pickart: Metabolism of the polyubiquitin degradation signal: structure, mechanism, and role of isopeptidase T. Biochemistry 34, 14535-14546, (1995)

75. F Tokunaga, T Goto, T Koide, Y Murakami, S Hayashi, T Tamura, K Tanaka & A Ichihara: ATP-and antizyme-dependent endoproteolysis of ornithine decarboxylase to oligopeptides by the 26 S proteasome. J Biol Chem 269, 17382-17385, (1994)

76. L Hicke & H Riezman: Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84, 277-287, (1996)

77. J Horak & DH Wolf: Catabolite inactivation of the galactose transporter in the yeast Saccharomyces cerevisiae: ubiquitination, endocytosis, and degradation in the vacuole. J Bacteriol 179, 1541-1549, (1997)

78. K Tanaka, K Ii, A Ichihara, L Waxman, & AL Goldberg: A high molecular weight protease in the cytosol of rat ) liver. I. Purification, enzymological properties, and tissue distribution. J Biol Chem 261, 15197-15203, (1986

79. CV Harding, J France, R Song, JM Farah, S Chatterjee, M Iqbal & R Siman: Novel dipeptide aldehydes are proteasome inhibitors and block the MHC-I antigen-processing pathway. J Immunol 155, 1767-1775, (1995)

80. DH Lee & AL Goldberg: Selective inhibitors of the proteasome-dependent and vacuolar pathway of protein degradation in Saccharomyces cerevisiae. J Biol Chem 271, 27280-27284, (1996)

81. L Ditzel, D Stock & J Lowe: Structural investigation of proteasome inhibition. Biol Chem 378, 239-247, (1997)

82. H Djaballah, AJ Rowe, SE Harding & AJ Rivett: The multicatalytic proteinase complex (proteasome): structure conformational changes associated with changes in proteolytic activity. Biochem J 292, 857-862, (1993)

83. M Groettrup, A Soza, M Eggers, L Kuehn, TP Dick, H Schild, HG Rammensee, UH Koszinowski & PM Kloetzel: A role for the proteasome regulator PA28alpha in antigen presentation. Nature, 381, 166-168, (1996)

84. CD Smith, JM Carney, PE Starke-Reed, CN Oliver, ER Stadtman, RA Floyd & WR Markesbery: Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer's disease. Proc Natl Acad Sci USA 88, 10540-10543, (1991)

85. PE Starke-Reed & CN Oliver: Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys 275, 559-567, (1989)

86. T Shibatani & WF Ward: Effect of age and food restriction on alkaline protease activity in rat liver. J Gerontol 51, B316-B322, (1996)

87. W Heinemeyer, JA Kleinschmidt, J Saidowsky, C Escher & DH Wolf: Proteinase yscE, the yeast proteasome/multicatalytic-multifunctional proteinase: mutants unravel its function in stress induced proteolysis and uncover its necessity for cell survival. EMBO J 10, 555-562, (1991)

88. W Hilt, C Enenkel, A Gruhler, T Singer & DH Wolf: The PRE4 gene codes for a subunit of the yeast proteasome necessary for peptidylglutamyl-peptide-hydrolyzing activity. Mutations link the proteasome to stress-and ubiquitin-dependent proteolysis. J Biol Chem 268, 3479-3486, (1993)

89. JA Sahakian, LI Szweda, B Friguet, K Kitani, & RL Levine: Aging of the liver: Proteolysis of oxidatively modified glutamine synthetase. Arch Biochem Biophys 318, 411-417, (1995)

90. S Agarwal & RS Sohal: Age and proteolysis of oxidized proteins. Arch Biochem Biophys 309, 24-28, (1994)

91. JX Pan, SR Short, SA Goff & JF Dice: Ubiquitin pools, ubiquitin mRNA levels, and ubiquitin-mediated proteolysis in aging human fibroblasts. Exp Gerontol 28, 39-49, (1993)

92. JH Jahngen, RD Lipman, DA Eisenhauer, EG Jahngen & A Taylor: Aging and cellular maturation cause changes in ubiquitin-eye lens conjugates. Arch Biochem Biophys 276, 32-37, (1990)

93. GO Ivy, K Kitani & Y Ihara: Anomalous accumulation of tau and ubiquitin immunoreactivities in rat brain caused by protease inhibition and by normal aging: a clue to PHF pathogenesis?. Brain Research 498, 360-365, (1989)

94. D Finley & V Chau: Ubiquitination. Annu Rev Cell Biol 7, 25-69, (1991)

95. M Hochstrasser: Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol 7, 215-223, (1995)

96. H Kawahara & K Tanaka: Proteasomes: The protein death machinery. In: Molecular Chaperones in the Life Cycle of Proteins. Eds: Fink, AL and Goto, Y. Marcel Dekker, Inc. NY, 511-531, (1997)

97. F Shang, X Gong, HJ Palmer, TR Nowell & A Taylor: Age-related decline in ubiquitin conjugation in response to oxidative stress in the lens. Exp Eye Res 64, 21-30, (1997)

98. RL Mellgren & T Murachi: Intracellular Calcium-Dependent Proteolysis. CRC Press, Inc., Boca Raton, FL. (1990)

99. T Murachi: Calcium-dependent proteinases and specific inhibitors: calpain and calpastatin. Biochem Soc Symp 49, 149-167, (1984)

100. P Cottin, S Poussard, JG Desmazes, D Georgescauld & A Ducastaing: Free calcium and calpain I activity. Biochim Biophys Acta 1079, 139-145, (1991)

101. RD Lane, DM Allan & RL Mellgren: A comparison of the intracellular distribution of m-calpain, m-calpain, and calpastatin in proliferating human A431 cells. Exp Cell Res 203, 5-16, (1992)

102. RL Mellgren: Calcium-dependent proteases: an enzyme system active at cellular membranes?. FASEB J 1, 110-115, (1987)

103. AH Schmaier, HN Bradford, D Lundberg, A Farber & RW Colman: Membrane expression of platelet calpain. Blood 75, 1273-1281, (1990)

104. DE Croall & GN DeMartino: Calcium-activated neutral protease (calpain) system: structure, function, and regulation, Physiol Rev 71, 813-847, (1991)

105. T Glaser & NS Kosower: Calpain-calpastatin and fusion. Fusability of erythrocytes is determined by a protease-protease inhibitor [calpain-calpastatin] balance. FEBS Lett 206, 115-120, (1986)

106. A Kishimoto, K Mikawa, K Hashimoto, I Yasuda, S Tanaka, M Tominaga, T Kuroda & Y Nishizuka: Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain). J Biol Chem 264, 4088-4092, (1989)

107. N Schwarz-Ben Meir, T Glaser & NS Kosower: Band 3 protein degradation by calpain is enhanced in erythrocytes of old people. Biochem J 275, 47-52, (1991)

108. D Harman: The aging process: major risk factor for disease and death. Proc Natl Acad Sci USA 88, 5360-5363, (1991)

109. T Glaser, N Schwarz-Ben Meir, S Barnoy, S Barak, Z Eshhar & NS Kosower: Calpain (Ca+2-dependent thiol protease) in erythrocytes of young and old individuals. Proc Natl Acad Sci USA 91, 7879-7883, (1994)

110. K Saito, JS Elce, JE Hamos & RA Nixon: Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer's disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci USA 90, 2628-2632, (1993)

111. GG Sahagian & PM Novikoff: Lysosomes. In: Liver: Biology and Pathobiology. Ed: Arias, IM. Raven Press, NY. 275-291, (1994)

112. P Bohley & PO Seglen: Proteases and proteolysis in the lysosome. Experientia 48, 151-157, (1992)

113. L Lavie, AZ Reznick & D Gershon: Decreased protein and puromycinyl-peptide degradation in livers of senescent mice. Biochem J 202, 47-51, (1982)

114. L Hayflick: Recent advances in the cell biology of aging. Mech Ageing Develop 14, 59-79, 1980

115. GO Ivy, F Schottler, J Wenzel, M Baudry & G Lynch: Inhibitors of lysosomal enzymes: accumulation of lipofuscin-like dense bodies in the brain. Science 226, 985-987, (1984)

116. H Glaumann: Crinophagy as a means for degrading excess secretory proteins in rat liver. In: Current Trends in the Study of Intracellular Protein Degradation. Eds: Knecht E, Grisolia, S. Springer International, Vizcaya, Spain, 97-110, (1989)

117. SE Lenk, DL Fisher & WA Dunn Jr: Regulation of protein secretion by crinophagy in perfused rat liver. Eur J Cell Biol 56, 201-209, (1991)

118. JK Angleson & WJ Betz: Monitoring secretion in real time: capacitance, amperometry and fluorescence compared. Trends Neurosci 20, 281-287, (1997)

119. S Mukherjee, RN Ghosh & FR Maxfield: Endocytosis. Physiol Rev 77, 759-803, (1997)

120. JA Koenig & JM Edwardson: Endocytosis and recycling of G protein-coupled receptors. Trends Pharmacol Sci 18, 276-287, (1997)

121. GJ Horbach, R Van Leeuwen, SH Yap & CF van Bezooijen: Changes in fluid-phase endocytosis in the rat with age and their relation to total albumin elimination. Mech Ageing Dev 33, 305-312, (1986)

122. A Brouwer, RJ Barelds & DL Knook: Age-related changes in the endocytic capacity of rat liver Kupffer and endothelial cells. Hepatology 5, 362-366, (1985)

123. RP Edwards, HI Georgescu & CH Evans: Enhanced endocytosis by aging chondrocytes and fibroblasts. Exp Gerontol 19, 185-190, (1984)

124. J Michl, M Tolar, V Spurna & D Rezacova: Growth-promoting alpha-globulin and ageing. In: Cell Impairment in Aging and Development. Eds: Cristofalo, V and Holeckova, E. Plenum Press, NY, 137-146, (1975)

125. A Brouwer, MA Horan, RJ Barelds & DL Knook: Cellular aging of the reticuloendothelial system. Arch Gerontol Geriatr 5, 317-324, (1986)

126. HC Lee, MA Paz & PM Gallop: Low density lipoprotein receptor binding in aging human diploid fibroblasts in culture. J Biol Chem 257, 8912-8918, (1982)

127. P Phillips & V Cristofalo: A review of recent research on cellular aging in culture. In: Review of Biological Research in Aging. Ed: Rothstein, M. Vol. 3 Alan R. Liss, NY, 385-415, (1987)

128. R Gurley & JF Dice: Degradation of endocytosed proteins is unaltered in senescent human fibroblasts. Cell Biol Int Rep 12, 885-894, (1988)

129. GE Mortimore, G Miotto, R Venerando & M Kadowaki: Autophagy. Biochemistry 27, 93-135, (1996)

130. B Grinde: Autophagy and lysosomal proteolysis in the liver. Experientia 41, 1089-1095, (1985)

131. E Bergamini, M Bombara, A Del Roso, Z Gori, P Masiello, M Masini, M Pollera & S Vittorini: The regulation of liver protein degradation by amino acids in vivo. Effect of glutamine and leucine Arch Physiol Biochem 103, 512-515, (1995)

132. G Rez, E Fellinger, O Oliva, Z Palfia, J Csak, L Laszlo, AL Kovacs, J Kovacs & AP Karpati: Mechanism and dynamics of macroautophagy in murine exocrine pancreatic cells. A review of vinblastine-induced changes. Acta Biol Hungarica 42, 57-86, (1991)

133. EF Blommaart, JJ Luiken, PJ Blommaart, GM van Woerkom & AJ Meijer: Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270, 2320-2326, (1995)

134. DL Tuttle, AS Lewin & WA Dunn Jr: Selective autophagy of peroxisomes in methylotrophic yeasts. Eur J Cell Biol 60, 283-290, (1993)

135. VI Titorenko, I Keizer, W Harder & M Veenhuis: Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha. J Bacteriol 177, 357-363, (1995)

136. HL Chiang, R Schekman & S Hamamoto: Selective uptake of cytosolic, peroxisomal and plasma membrane proteins into the yeast lysosome for degradation. J Biol Chem 271, 9934-9941, (1996)

137. W Liou, HJ Geuze, MJ Geelen & JW Slot: The autophagic and endocytic pathways converge at the nascent

autophagic vacuoles. J Cell Biol 136, 61-70, (1997)

138. AS Stupina, AK Terman, TI Kvitnitskaia-Ryzhova, NA Mezhiborskaia & VA Zherebitskii: The age-related characteristics of autophagocytosis in different tissues of laboratory animals. Tsitologiia Genetika 28, 15-20, (1994)

139. A Terman: The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocyte. Gerontology 41, 319-325, (1995)

140. J Ahlberg & H Glaumann: Uptake--microautophagy--and degradation of exogenous proteins by isolated rat liver lysosomes. Effects of pH, ATP, and inhibitors of proteolysis. Exp Mol Pathol 42, 78-88, (1985)

141. GE Mortimore, BR Lardeux & CE Adams: Regulation of microautophagy and basal protein turnover in rat liver. Effects of short-term starvation. J Biol Chem 263, 2506-2512, (1988)

142. G Schatz & B Dobberstein: Common principles of protein translocation across membranes. Science 271, 1519-1526, (1996)

143. HL Chiang & JF Dice: Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem 263, 6797-6803, (1988)

144. JF Dice: Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 15, 305-309, (1990)

145. HL Chiang, SR Terlecky, CP Plant & JF Dice: A role for a 70 kDa heat shock protein in lysosomal degradation of intracellular protein. Science 246, 382-385, (1989)

146. AM Cuervo & JF Dice: A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273, 501-503, (1996)

147. FA Agarraberes, SR Terlecky & JF Dice: An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol 137, 825-834, (1997)

148. AM Cuervo, JF Dice & E Knecht: A lysosomal population responsible for the hsc73-mediated degradation of cytosolic proteins in lysosomes. J Biol Chem 272, 5606-5615, (1997)

149. NT Neff, L Bourret, P Miao & JF Dice: Degradation of proteins microinjected into IMR-90 human diploid fibroblasts. J Cell Biol 91, 184-194, (1981)

150. JM Backer, L Bourret & JF Dice: Regulation of catabolism of microinjected ribonuclease A requires the amino-terminal 20 amino acids. Proc Natl Acad Sci USA 80, 2166-2170, (1983)

151. AM Cuervo, SR Terlecky, JF Dice & E Knecht: Selective binding and uptake of ribonuclease A and glyceraldehyde-3-phosphate dehydrogenase by isolated rat liver lysosomes. J Biol Chem 269, 26374-26380, (1994)

152. JF Dice & SA Goff: Error catastrophe theory. In: Modern Biological Theories of Aging. Eds: Warner R, Butler RN, Sprott RL, Schneider EL. Raven Press, NY, 155-168, (1987)

153. SS Wing, HL Chiang, AL Goldberg & JF Dice: Proteins containing peptide sequences related to KFERQ are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J 275, 165-169, (1991)

154. AM Cuervo, A Palmer, AJ Rivett & E Knecht: Degradation of proteasomes by lysosomes in rat liver. Eur J Biochem 227: 792-800, (1995)

155. F Aniento, AG Papavassiliou, E Knecht & E Roche: Selective uptake and degradation of c-fos and v-fos by rat liver lysosomes. FEBS Lett 390, 47-49, (1996)

156. K Kuki, K Maeda, S Takauchi, T Kakigi, S Maeda & C Tanaka: Neurochemical and pathological alterations following infusion of leupeptin, a protease inhibitor, into the rat brain. Dementia 7, 233-238, (1996)

157. E Bednarski, CE Ribak & G Lynch: Suppression of cathepsins B and L causes a proliferation of lysosomes and the formation of meganeurites in hippocampus. J Neurosci 17, 4006-4021, (1997)

158. R Siman, C Gall, LS Perlmutter, C Christian, M Baudry & G Lynch: Distribution of calpain I an enzyme associated with degenerative activity in rat brain. Brain Res 347, 399-403, (1985)

159. K Blomgren & JO Karlsson: Developmental changes of calpain and calpastatin in rabbit brain. Nuerochem Res 14, 1149-1152, (1989)

160. A Kenessey, M Banay-Schwartz, T DeGuzman & A Lajtha: Increase in cathepsin D activity in rat brain in aging. J Nuerosci Res 23, 454-456, (1989)

161. RA Nixon, KI Saito, F Grynspan, WR Griffin, S Katayama, T Honda, PS Mohan, TB Shea & M Beermann: Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease. Ann NY Acad Sci 747, 77-91, (1994)

162. H Nakanishi, K Tominaga, T Amano, I Hirotsu, T Inoue & K Yamamoto: Age-related changes in activities and localization of cathepsins D, E, B, and L in the rat brain tissues. Exp Neurol 126, 119-128, (1994)

163. M Banay-Schwartz, T DeGuzman, M Palkovits & A Lajtha: Calpain activity in adult and aged human brain regions. Neurochem Res 19, 563-567, (1994)

164. A Matus & GD Green: Age-related increase in cathepsin D-like protease that degrades brain microtubule-associated proteins. Biochemistry 26, 8083-8086, (1987)

165. HC Pant: Dephosphorylation of neurofilament proteins enhances their susceptibility to degradation by calpain. Biochem J 256, 665-668, (1988)

166. JA Greenwood, JC Troncoso, AC Costello & GV Johnson: Phosphorylation modulates calpain-mediated proteolysis and calmodulin binding of the 200-kDa and 160-kDa neurofilament proteins. J Neurochem 61, 191-199, (1993)

167. N Ragusa, RF Villa, G Magri, F Ingrao, A Gorini, L Turpeenoja & AM Giuffrida-Stella: Modifications of synaptosomal plasma membrane protein composition in various brain regions during aging. Int J Develop Neurosci 10, 265-273, (1992)

168. ER Bongarzone, EF Soto & JM Pasquini: Increased susceptibility to degradation by trypsin and subtilisin of in vitro peroxidized myelin proteins. Neurochem Res 20, 421-426, (1995)

169. M Benuck, M Banay-Schwartz, T DeGuzman & A Lajtha: Changes in brain protease activity in aging. J Neurochem 67, 2019-2029, (1996)

170. E Porta, S Llesuy, AJ Monserrat, S Benavides & M Travacio: Changes in cathepsin B and lipofuscin during development and aging in rat brain and heart. Gerontology 41, 81-89, (1995)

171. KR Braze, B Kaack & PM Klara: Lipofuscin, intra- and extraneuronal accumulation and regional distribution. In: Advances in Behavioral Biology. Eds: Ordy JM & Brizzee KR, Plenum Press, NY, 463-481, (1975)

172. AN Siakotos & D Armstrong: Age pigment, a biochemical indicator of intracellular aging. In: Advances in Behavioral Biology. Eds: Ordy, JM & Brizzee, KR. Plenum. NY. 369-397, (1975)

173. H Nakanishi, T Amano, DF Sastradipura, Y Yoshimine, T Tsukuba, K Tanabe, I Hirotsu, T Ohono & K Yamamoto: Increased expression of cathepsins E and D in neurons of the aged rat brain and their colocalization with lipofuscin and carboxy-terminal fragments of Alzheimer amyloid precursor protein. J Neurochem 68, 739-749, (1997)

174. A Nunomura & T Miyagishi: Ultrastructural observations on neuronal lipofuscin (age pigment) and dense bodies induced by a proteinase inhibitor, leupeptin, in rat hippocampus Acta Neuropathol 86, 319-328, (1993)

175. M Banay-Schwartz, T DeGuzman, A Kenessey, M Palkovits & A Lajtha: The distribution of cathepsin D activity in adult and aging human brain regions. J Neurochem 50, 2207-2211, (1992)

176. PL Sawant, ID Desai & AL Tappel: Factors affecting the lysosomal membrane and availability of enzymes. Arch Biochem Biophys 105, 247-253, (1964)

177. LI Benowitz,W Rodriguez, P Paskevich, EJ Mufson, D Schenk & RL Neve: The amyloid precursor protein is concentrated in neuronal lysosomes in normal and Alzheimer's disease subjects. Exp Neurol 106, 237-250, (1989)

178. JG Beeson, ER Shelton, HW Chan & FH Gage: Age and damage induced changes in amyloid protein precursor immunohistochemistry in the rat brain. J Com Neurol 342, 69-77, (1994)

179. AM Cataldo, JL Barnett, SA Berman, J Li, S Quarless, S Bursztajn, C Lippa & RA Nixon: Gene expression and cellular content of cathepsin D in human neocortex: evidence for early upregulation of the endosomal-lysosomal system in pyramidal neurons in Alzheimer's disease. Neuron 14, 1-20, (1995)

180. C Haass, EH Koo, A Mellon, AY Hung & DJ Selkoe: Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing to amyloid-bearing fragments. Nature 357, 500-503, (1992)

181. TE Golde, S Estus, LH Younkin, DJ Selkoe & SG Younkin: Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, 728-730, (1992)

182. R Siman, S Mistretta, JT Durkin, MJ Savage, T Loh, S Trusko & RW Scott: Processing of the beta-amyloid precursor; multiple proteases generate and degrade potentially amyloidogenic fragments. J Biol Chem 268, 16602-16609, (1993)

183. BA Bahr, B Abai, CM Gall, PW Vanderklish, KB Hoffman & G Lynch: Induction of beta-amyloid-containing polypeptides in hippocampus: evidence for a concomitant loss of synaptic proteins and interactions with an exocitotoxin. Exp Neurol 129, 81-94, (1994)

184. I Hajimohammadreza, VE Anderson, JB Cavanagh, MP Seville, CC Nolan, BH Anderton & PN Leigh: Amyloid precursor protein fragments and lysosomal dense bodies are found in rat brain neurons after ventricular infusion of leupeptin. Brain Res 640, 25-32, (1994)

185. S Goldstein, D Stotland & RA Cordeiro: Decreased proteolysis and increased amino acid efflux in aging human fibroblasts. Mech Ageing Dev 5, 221-233, (1976)

186. SA Sukharev, OV Pleshakova, AB Moshnikova, VB Sadovnikov & AI Gaziev: Age- and radiation-dependent changes in carbonyl content, susceptibility to proteolysis, and antigenicity of soluble rat liver proteins. Comp Biochem Physiol 116, 333-338, (1997)

187. MO Bradley, JF Dice, L Hayflick & RT Schimke: Protein alterations in aging W138 cells as determined by proteolytic susceptibility. Exp Cell Res 96, 103-112, (1975)

188. RT Dean, S Fu, R Stocker & MJ Davies: Biochemistry and pathology of radical-mediated protein oxidation. Biochem J 324, 1-18, (1997)

189. CN Oliver, BW Ahn, EJ Moerman, S Goldstein & ER Stadtman: Age-related changes in oxidized proteins. J Biol Chem 262, 5488-5491, (1987)

190. BR DiPaolo, RJ Pignolo & VJ Cristofalo: Identification of proteins differentially expressed in quiescent and proliferative senescent fibroblasts cultures. Exp Cell Res 220, 178-185, (1995)

191. RC Costa & U Del Monte: ATP-stimulated proteolysis by soluble extracts of liver of aged rats. In: Modern Aging Research. Protein Metabolism in Aging. Ed: Segal, HL, Rothstein, M and Bergamini, E. Wiley-Liss, NY. 151-158, (1990)

192. H Tauchi, M Hananouchi & T Sato: Accumulation of lipofuscin pigment in human hepatic cells from different races and in different environmental conditions. Mech Ageing Dev 12, 183-195, (1980)

193. G Ferland, A Perea, M Audet & B Tuchweber: Characterization of liver lysosomal enzyme activity in hepatocytes, Kupffer and endothelial cells during aging: effect of dietary restriction. Mech Ageing Dev 56, 143-154 (1990)

194. BR DiPaolo, RJ Pignolo & VJ Cristofalo: Overexpression of the two-chain form of cathepsin B in senescent WI-38 cells. Exp Cell Res 201, 500-505, (1992)

195. A Ishigami & S Goto: Age-related change in the degradation rate of ovalbumin microinjected into mouse liver parenchymal cells. Arch Biochem Biophys 277, 189-195, (1990)

196. J Ahlberg, A Berkenstam, F Henell & H Glaumann: Degradation of short- and long-lived proteins in isolated rat liver lysosomes: effects of pH, temperature, and proteolytic inhibitors. J Biol Chem 260, 5847-5854, (1985)

197. G Mortimore: Mechanism and regulation of induced and basal protein degradation in liver. In: Lysosomes: Their Role in Protein Breakdown. Eds: Glaumann H, Ballard FJ. Academic Press, NY, 415-444, (1987)

198. K Furuno, MN Goodman & AL Goldberg: Role of different proteolytic systems in the degradation of muscle proteins during denervation atrophy. J Biol Chem 265, 8550-8557, (1990)

199. R Medina, SS Wing & AL Goldberg: Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem J 307, 631-637, (1995)

200. H Klitgaard, A Brunet, B Maton, C Lamaziere, C Lesty & H Monod: Morphological and biochemical changes in old rat muscles: effect of increased use. J Appl Physiol 67, 1409-1417, (1989)

201. F Yoshizawa, T Nagasawa, N Nishizawa & R Funabiki: Protein synthesis and degradation change rapidly in response to food intake in muscle of food-deprived mice. J Nutrition 127, 1156-1159, (1997)

202. G Fruhbeck, B Muguerza, I Castilla-Cortazar & S Santidrian: Effect of aging on the rate of muscle protein turnover in rat. Rev Esp Fisiol 52, 207-214, (1996)

203. D Dardevet, C Sornet, D Taillandier, I Savary, D Attaix & J Grizard: Sensitivity and protein turnover response to glucocorticoids are different in skeletal muscle from adult and old rats. J Clin Invest 96, 2113-2119, (1995)

204. D Attaix, D Taillandier, S Temparis, D Larbaud, E Aurousseau, L Combaret & L Voisin: Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting. Reprod Nutr Dev 34, 583-597, (1994)

205 JJ Harding: Changes in lens proteins in cataract. In: Molecular and Cellular Biology of the Eye Lens. Ed: Bloemendal H John Wiley & Sons.,NY, 327-365, (1981)

206. A Taylor, PF Jacques & CK Dorey: Oxidants and aging: impact on vision. In: Antioxidants: Chemical, Physiological, Nutritional and Toxicological Aspects. Ed: Williams GM. Princeton Science Publishing Co., Princeton, NJ, 349-371, (1993)

207. J Blondin & A Taylor: Measures of leucine aminopeptidase can be used to anticipate UV-induced age-related damage to lens proteins L ascorbate can delay this damage. Mech Age Dev 41, 39-46, (1987)

208. A Taylor, JJ Berger, J Reddan & A Zuliani: Effects of aging in vitro on intracellular proteolysis in cultured rabbit lens epithelial cells in the presence and absence of serum. In vitro Cell Develop Biol 27A, 287-292, (1991)

209. J Farber: Endogenous defenses against the cytotoxicity of hydrogen peroxide in cultured rat hepatocytes. J Biol Chem 260, 86-92, (1985)

210. DX Yin & RT Schimke: Tetracycline-controlled gene expression system achieves high-level and quantitative control of gene expression. Anal Biochem 235, 195-201, (1996)