Is Impaired Proteodynamics a Key to Understand the Biomarkers of Human Cellular Aging?

  • Jacek M. WitkowskiEmail author
  • Ewa Bryl
  • Tamas Fulop
Part of the Healthy Ageing and Longevity book series (HAL, volume 10)


Current understanding of the fates of cellular proteins during aging is fragmentary and far from complete. The attention of researchers in the field is on the process of proteostasis, aiming at detection and elimination of misfolded and aggregated proteins. In this chapter we discuss other aspects of the protein behavior during cellular aging, from translation to various posttranslational modifications to limited degradation, together defined as proteodynamics. We argue here that the quantitative and qualitative effects of changed proteodynamics in the aging cells may be at least the biomarkers of aging and the aging-related diseases including but not limited to chronic inflammation, cardiovascular, neurodegenerative, chronic kidney disease, type 2 diabetes mellitus and sarcopenia, or even constitute causative factors in both cellular aging and these ARDs. As an illustration we describe in detail the properties and roles of ubiquitous neutral cytoplasmic proteases—calpains, performing the limited proteolytic modification of multiple substrates and involved in the above mentioned pathologies and in cellular aging.


Cellular aging Proteostasis Proteodynamics Posttranslational modification Calpain-calpastatin system Lymphocytes Aging-related diseases 



This work was supported by the Polish Ministry of Science and Higher Education statutory grant 02-0058/07/262 to JMW.


  1. Abou-Abbass H, Abou-El-Hassan H, Bahmad H, Zibara K, Zebian A, Youssef R et al (2016) Glycosylation and other PTMs alterations in neurodegenerative diseases: Current status and future role in neurotrauma. Electrophoresis 37(11):1549–1561. Scholar
  2. Akasaka-Manya K, Manya H, Endo T (2016) Function and change with aging of alpha-klotho in the kidney. Vitam Horm 101:239–256. Scholar
  3. Alafuzoff I (2018) Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain and in neurodegenerative disorders. Handb Clin Neurol 150:131–141. Scholar
  4. Alafuzoff I, Pikkarainen M, Arzberger T, Thal DR, Al-Sarraj S, Bell J et al (2008) Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein: a study of the BrainNet Europe consortium. Acta Neuropathol 115(5):533–546. Scholar
  5. Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I et al (2009a) Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 117(6):635–652. Scholar
  6. Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I et al (2009b) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117(3):309–320. Scholar
  7. Alafuzoff I, Pikkarainen M, Neumann M, Arzberger T, Al-Sarraj S, Bodi I et al (2015) Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium. J Neural Transm (Vienna) 122(7):957–972. Scholar
  8. Brandman O, Hegde RS (2016) Ribosome-associated protein quality control. Nat Struct Mol Biol 23(1):7–15. Scholar
  9. Brule C, Dargelos E, Diallo R, Listrat A, Bechet D, Cottin P et al (2010) Proteomic study of calpain interacting proteins during skeletal muscle aging. Biochimie 92(12):1923–1933. Scholar
  10. Cardoso AL, Fernandes A, Aguilar-Pimentel JA, de Angelis MH, Guedes JR, Brito MA et al (2018) Towards frailty biomarkers: candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res Rev 47:214–277. Scholar
  11. Chaillou T, Kirby TJ, McCarthy JJ (2014) Ribosome biogenesis: emerging evidence for a central role in the regulation of skeletal muscle mass. J Cell Physiol 229(11):1584–1594. Scholar
  12. Covington MD, Arrington DD, Schnellmann RG (2008) Calpain 10 is required for cell viability and is decreased in the aging kidney. Am J Physiol Renal Physiol 296(3):F478–86. Scholar
  13. Cuervo AM, Dice JF (1998) How do intracellular proteolytic systems change with age? Front Biosci 3:d25–d43CrossRefGoogle Scholar
  14. Cuervo AM, Dice JF (2000) When lysosomes get old. Exp Gerontol 35(2):119–131CrossRefGoogle Scholar
  15. Dargelos E, Brule C, Combaret L, Hadj-Sassi A, Dulong S, Poussard S et al (2007) Involvement of the calcium-dependent proteolytic system in skeletal muscle aging. Exp Gerontol 42(11):1088–1098. Scholar
  16. Dargelos E, Poussard S, Brule C, Daury L, Cottin P (2008) Calcium-dependent proteolytic system and muscle dysfunctions: a possible role of calpains in sarcopenia. Biochimie 90(2):359–368. Scholar
  17. Dermaku-Sopjani M, Kolgeci S, Abazi S, Sopjani M (2013) Significance of the anti-aging protein Klotho. Mol Membr Biol 30(8):369–385. Scholar
  18. Di Bona D, Accardi G, Virruso C, Candore G, Caruso C (2014) Association of Klotho polymorphisms with healthy aging: a systematic review and meta-analysis. Rejuvenation Res 17(2):212–216. Scholar
  19. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 69(Suppl 1):S4–S9. Scholar
  20. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105CrossRefGoogle Scholar
  21. Franceschi C, Zaikin A, Gordleeva S, Ivanchenko M, Bonifazi F, Storci G et al (2018) Inflammaging 2018: an update and a model. Semin Immunol 40:1–5. Scholar
  22. Fulop T, Dupuis G, Baehl S, Le Page A, Bourgade K, Frost E et al (2016a) From inflammaging to immune-paralysis: a slippery slope during aging for immune-adaptation. Biogerontology 17(1):147–157. Scholar
  23. Fulop T, Dupuis G, Witkowski JM, Larbi A (2016b) The role of immunosenescence in the development of age-related diseases. Rev Invest Clin 68(2):84–91PubMedGoogle Scholar
  24. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA et al (2017) Immunosenescence and Inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 8:1960. Scholar
  25. Fulop T, Witkowski JM, Olivieri F, Larbi A (2018) The integration of inflammaging in age-related diseases. Semin Immunol 40:17–35. Scholar
  26. Hamilton KL, Miller BF (2017) Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation. J Physiol 595(20):6401–6407. Scholar
  27. Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ et al (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 17(9):1205–1217. Scholar
  28. Huang J, Zhu X (2016) The molecular mechanisms of calpains action on skeletal muscle atrophy. Physiol Res 65(4):547–560PubMedGoogle Scholar
  29. Iguchi-Hashimoto M, Usui T, Yoshifuji H, Shimizu M, Kobayashi S, Ito Y et al (2011) Overexpression of a minimal domain of calpastatin suppresses IL-6 production and Th17 development via reduced NF-kappaB and increased STAT5 signals. PLoS ONE 6(10):e27020. Scholar
  30. Ji J, Su L, Liu Z (2016) Critical role of calpain in inflammation. Biomed Rep 5(6):647–652. Scholar
  31. Kirby TJ, Lee JD, England JH, Chaillou T, Esser KA, McCarthy JJ (2015) Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis. J Appl Physiol 119(4):321–327. Scholar
  32. Kunkel GH, Chaturvedi P, Tyagi SC (2015a) Resuscitation of a dead cardiomyocyte. Heart Fail Rev 20(6):709–719. Scholar
  33. Kunkel GH, Chaturvedi P, Tyagi SC (2015b) Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions. Biomol Concepts 6(4):303–319. Scholar
  34. Leloup L, Mazeres G, Daury L, Cottin P, Brustis JJ (2006) Involvement of calpains in growth factor-mediated migration. Int J Biochem Cell Biol 38(12):2049–2063. Scholar
  35. Lopatniuk P, Witkowski JM (2011) Conventional calpains and programmed cell death. Acta Biochim Pol 58(3):287–296CrossRefGoogle Scholar
  36. Manya H, Inomata M, Fujimori T, Dohmae N, Sato Y, Takio K et al (2002) Klotho protein deficiency leads to overactivation of mu-calpain. J Biol Chem 20;277(38):35503–35508CrossRefGoogle Scholar
  37. Manya H, Akasaka-Manya K, Endo T (2010) Klotho protein deficiency and aging. Geriatr Gerontol Int 10(Suppl 1):S80–S87. Scholar
  38. Margolis LM, Lessard SJ, Ezzyat Y, Fielding RA, Rivas DA (2017) Circulating MicroRNA are predictive of aging and acute adaptive response to resistance exercise in men. J Gerontol A Biol Sci Med Sci 72(10):1319–1326. Scholar
  39. Martinez G, Duran-Aniotz C, Cabral-Miranda F, Vivar JP, Hetz C (2017) Endoplasmic reticulum proteostasis impairment in aging. Aging Cell 16(4):615–623. Scholar
  40. Mencke R, Hillebrands JL, consortium N (2017) The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology. Ageing Res Rev 35:124–146. Scholar
  41. Mikosik A, Zaremba A, Puchalska Z, Daca A, Smolenska Z, Lopatniuk P et al (2007) Ex vivo measurement of calpain activation in human peripheral blood lymphocytes by detection of immunoreactive products of calpastatin degradation. Folia Histochem Cytobiol 45(4):343–347PubMedGoogle Scholar
  42. Mikosik A, Foerster J, Jasiulewicz A, Frackowiak J, Colonna-Romano G, Bulati M et al (2013) Expression of calpain-calpastatin system (CCS) member proteins in human lymphocytes of young and elderly individuals; pilot baseline data for the CALPACENT project. Immun Ageing. 10(1):27. Scholar
  43. Mikosik A, Jasiulewicz A, Daca A, Henc I, Frackowiak JE, Ruckemann-Dziurdzinska K et al (2016) Roles of calpain-calpastatin system (CCS) in human T cell activation. Oncotarget 7(47):76479–76495. Scholar
  44. Miller BF, Hamilton KL (2017) Overview: the modulation of ageing through altered proteostasis. J Physiol 595(20):6381–6382. Scholar
  45. Miller BF, Drake JC, Naylor B, Price JC, Hamilton KL (2014) The measurement of protein synthesis for assessing proteostasis in studies of slowed aging. Ageing Res Rev 18:106–111. Scholar
  46. Miyazaki T, Miyazaki A (2017) Emerging roles of calpain proteolytic systems in macrophage cholesterol handling. Cell Mol Life Sci 74(16):3011–3021. Scholar
  47. Miyazaki T, Miyazaki A (2018) Dysregulation of calpain proteolytic systems underlies degenerative vascular disorders. J Atheroscler Thromb 25(1):1–15. Scholar
  48. Miyazaki T, Koya T, Kigawa Y, Oguchi T, Lei XF, Kim-Kaneyama JR et al (2013) Calpain and atherosclerosis. J Atheroscler Thromb 20(3):228–237CrossRefGoogle Scholar
  49. Mnatsakanyan R, Shema G, Basik M, Batist G, Borchers CH, Sickmann A et al (2018) Detecting post-translational modification signatures as potential biomarkers in clinical mass spectrometry. Expert Rev Proteomics 15(6):515–535. Scholar
  50. Montesanto A, Dato S, Bellizzi D, Rose G, Passarino G (2012) Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity. Immun Ageing 9(1):6. Scholar
  51. Morimoto RI, Cuervo AM (2009) Protein homeostasis and aging: taking care of proteins from the cradle to the grave. J Gerontol A Biol Sci Med Sci 64(2):167–170. Scholar
  52. Morimoto RI, Cuervo AM (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69(Suppl 1):@@S33–8. Scholar
  53. Nishihara H, Nakagawa Y, Ishikawa H, Ohba M, Shimizu K, Nakamura T (2001) Matrix vesicles and media vesicles as nonclassical pathways for the secretion of m-Calpain from MC3T3-E1 cells. Biochem Biophys Res Commun 285(3):845–853. Scholar
  54. Olivieri F, Capri M, Bonafe M, Morsiani C, Jung HJ, Spazzafumo L et al (2017) Circulating miRNAs and miRNA shuttles as biomarkers: perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev 165(Pt B):162–170. Scholar
  55. Panico P, Salazar AM, Burns AL, Ostrosky-Wegman P (2014) Role of calpain-10 in the development of diabetes mellitus and its complications. Arch Med Res 45(2):103–115. Scholar
  56. Park SC, Moon JC, Shin SY, Son H, Jung YJ, Kim NH et al (2016) Functional characterization of alpha-synuclein protein with antimicrobial activity. Biochem Biophys Res Commun 478(2):924–928. Scholar
  57. Pechmann S, Willmund F, Frydman J (2013) The ribosome as a hub for protein quality control. Mol Cell 49(3):411–421. Scholar
  58. Perkey E, Fingar D, Miller RA, Garcia GG (2013) Increased mammalian target of rapamycin complex 2 signaling promotes age-related decline in CD4 T cell signaling and function. J Immunol 191(9):4648–4655. Scholar
  59. Potz BA, Abid MR, Sellke FW (2016) Role of calpain in pathogenesis of human disease processes. J Nat Sci 2(9)Google Scholar
  60. Santulli G, Totary-Jain H (2013) Tailoring mTOR-based therapy: molecular evidence and clinical challenges. Pharmacogenomics 14(12):1517–1526. Scholar
  61. Scicchitano BM, Rizzuto E, Musaro A (2009) Counteracting muscle wasting in aging and neuromuscular diseases: the critical role of IGF-1. Aging (Albany NY) 1(5):451–457. Scholar
  62. Sopjani M, Rinnerthaler M, Kruja J, Dermaku-Sopjani M (2015) Intracellular signaling of the aging suppressor protein Klotho. Curr Mol Med 15(1):27–37CrossRefGoogle Scholar
  63. Soroczynska-Cybula M, Bryl E, Smolenska Z, Witkowski JM (2011) Varying expression of four genes sharing a common regulatory sequence may differentiate rheumatoid arthritis from ageing effects on the CD4(+) lymphocytes. Immunology 132(1):78–86. Scholar
  64. Stec MJ, Mayhew DL, Bamman MM (1985) The effects of age and resistance loading on skeletal muscle ribosome biogenesis. J Appl Physiol 119(8):851–857. Scholar
  65. Szomor Z, Shimizu K, Yamamoto S, Yasuda T, Ishikawa H, Nakamura T (1999) Externalization of calpain (calcium-dependent neutral cysteine proteinase) in human arthritic cartilage. Clin Exp Rheumatol 17(5):569–574PubMedGoogle Scholar
  66. Tan TCJ, Knight J, Sbarrato T, Dudek K, Willis AE, Zamoyska R (2017) Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells. Proc Natl Acad Sci USA 114(30):E6117–E26. Scholar
  67. Taylor J, Bebawy M (2018) Proteins regulating microvesicle biogenesis and multidrug resistance in cancer. Proteomics e1800165. Scholar
  68. Taylor J, Jaiswal R, Bebawy M (2017) Calcium-calpain dependent pathways regulate vesiculation in malignant breast cells. Curr Cancer Drug Targets 17(5):486–494. Scholar
  69. Teixeira Vde O, Filippin LI, Xavier RM (2012) Mechanisms of muscle wasting in sarcopenia. Rev Bras Reumatol 52(2):252–259CrossRefGoogle Scholar
  70. Thygesen C, Boll I, Finsen B, Modzel M, Larsen MR (2018) Characterizing disease-associated changes in post-translational modifications by mass spectrometry. Expert Rev Proteomics 15(3):245–258. Scholar
  71. Timmer LT, Hoogaars WMH, Jaspers RT (2018) The role of IGF-1 signaling in skeletal muscle atrophy. Adv Exp Med Biol 1088:109–137. Scholar
  72. Vinciguerra M, Musaro A, Rosenthal N (2010) Regulation of muscle atrophy in aging and disease. Adv Exp Med Biol 694:211–233CrossRefGoogle Scholar
  73. Wan TT, Li XF, Sun YM, Li YB, Su Y (2015) Role of the calpain on the development of diabetes mellitus and its chronic complications. Biomed Pharmacother 74:187–190. Scholar
  74. Wang W, Nag S, Zhang X, Wang MH, Wang H, Zhou J et al (2015) Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications. Med Res Rev 35(2):225–285. Scholar
  75. Wende AR (2016) Post-translational modifications of the cardiac proteome in diabetes and heart failure. Proteomics Clin Appl 10(1):25–38. Scholar
  76. Wiemer AJ, Lokuta MA, Surfus JC, Wernimont SA, Huttenlocher A (2010) Calpain inhibition impairs TNF-alpha-mediated neutrophil adhesion, arrest and oxidative burst. Mol Immunol 47(4):894–902. Scholar
  77. Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE et al (2012) Rapamycin slows aging in mice. Aging Cell 11(4):675–682. Scholar
  78. Willmund F, del Alamo M, Pechmann S, Chen T, Albanese V, Dammer EB et al (2013) The cotranslational function of ribosome-associated Hsp70 in eukaryotic protein homeostasis. Cell 152(1–2):196–209. Scholar
  79. Witkowski JM, Soroczynska-Cybula M, Bryl E, Smolenska Z, Jozwik A (2007) Klotho—a common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes. J Immunol 178(2):771–777CrossRefGoogle Scholar
  80. Witkowski JM, Mikosik A, Bryl E, Fulop T (2018) Proteodynamics in aging human T cells—the need for its comprehensive study to understand the fine regulation of T lymphocyte functions. Exp Gerontol 107:161–168. Scholar
  81. Zavialova MG, Zgoda VG, Nikolaev EN (2017) Analysis of contribution of protein phosphorylation in the development of the diseases. Biomed Khim. 63(2):101–114. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PathophysiologyMedical University of GdańskGdanskPoland
  2. 2.Department of Pathology and Experimental RheumatologyMedical University of GdańskGdanskPoland
  3. 3.Research Center on AgingUniversity of SherbrookeSherbrookeCanada

Personalised recommendations