Cancer Immunology, Immunotherapy

, Volume 58, Issue 12, pp 1909–1917 | Cite as

Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53

  • Stefano SalvioliEmail author
  • Miriam Capri
  • Laura Bucci
  • Cristina Lanni
  • Marco Racchi
  • Daniela Uberti
  • Maurizio Memo
  • Daniela Mari
  • Stefano Govoni
  • Claudio Franceschi
Symposium in Writing



Centenarians are exceptionally long living individuals who escaped the most common age-related diseases. In particular they appear to be effectively protected from cancers. The mechanisms that underlie this protection are quite complex and still largely unclear.


To critically analyse the literature in order to propose a unifying hypothesis that can account for this cancer protection in centenarians.


Review of the scientific literature regarding three main players in tumourigenesis such as IGF-1, inflammation and p53, and centenarians.


Centenarians appear to be characterised by low IGF-1-mediated responses and high levels of anti-inflammatory cytokines such as IL-10 and TGF-β, a condition that results in protection from cancer. Both inflammation and IGF-1 pathway converge on the tumour suppressor p53. Accordingly, some studies indicate that genetic variants of p53 are associated with human longevity by providing protection from cancer mortality.


The available data let us to hypothesise that among other possible mechanisms, well-preserved p53-mediated responses are likely a key factor contributing to protection from cancer in centenarians.


Centenarians Cancer p53 IGF-1 Inflammation 



This work was supported by: EU (European Union) Grant “PROTEOMAGE” Contract n. FP6-518230; the PRRIITT program of the Emilia-Romagna Region (and Fondi Strutturali Obiettivo 2); Italian Ministry of Health Grant “Progetto Finalizzato «Studio delle differenze uomo-donna nei meccanismi patogenetici delle malattie cardiovascolari»” to C. Franceschi; Italian Ministry of University and Research (MiUR) PRIN 2006 Project to C. Franceschi (no. 2006061707), and S. Salvioli (no. 2006063387); University of Bologna Grant “Ricerca Fondamentale Orientata (RFO ex 60%) 2005”; Roberto and Cornelia Pallotti Legacy for Cancer Research Grants to C. Franceschi and S. Salvioli. University of Bologna “Progetti Strategici” 2006 grant (“p53 e patologie non neoplastiche nell’anziano: uno studio multidisciplinare sul ruolo del polimorfismo al codone 72 del gene TP53”) to S. Salvioli.


  1. 1.
    Franceschi C, Motta L, Motta M, Malaguarnera M, Capri M, Vasto S, Candore G, Caruso C, CE IMUS (2008) The extreme longevity: the state of the art in Italy. Exp Gerontol 43:45–52PubMedCrossRefGoogle Scholar
  2. 2.
    Caruso C, Lio D, Cavallone L, Franceschi C (2004) Aging, longevity, inflammation, and cancer. Ann N Y Acad Sci 1028:1–13PubMedCrossRefGoogle Scholar
  3. 3.
    Piantanelli L (1988) Cancer and aging: from the kinetics of biological parameters to the kinetics of cancer incidence and mortality. Ann N Y Acad Sci 521:99–109PubMedCrossRefGoogle Scholar
  4. 4.
    Bonafè M, Barbi C, Storci G, Salvioli S, Capri M, Olivieri F, Valensin S, Monti D, Gonos ES, De Benedictis G, Franceschi C (2002) What studies on human longevity tell us about the risk for cancer in the oldest old: data and hypotheses on the genetics and immunology of centenarians. Exp Gerontol 37:1263–1271PubMedCrossRefGoogle Scholar
  5. 5.
    Donehower LA (2005) p53: Guardian AND suppressor of longevity? Exp Gerontol 40:7–9PubMedCrossRefGoogle Scholar
  6. 6.
    Lanni C, Racchi M, Mazzini G, Ranzenigo A, Polotti R, Sinforiani E, Olivari L, Barcikowska M, Styczynska M, Kuznicki J, Szybinska A, Govoni S, Memo M, Uberti D (2008) Conformationally altered p53: a novel Alzheimer’s disease marker? Mol Psychiatry 13:641–647PubMedCrossRefGoogle Scholar
  7. 7.
    Lund PK (1994) Insulin-like growth factor I: molecular biology and relevance to tissue-specific expression and action. Recent Prog Horm Res 49:125–148PubMedGoogle Scholar
  8. 8.
    Longo VD, Fabrizio P (2002) Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans? Cell Mol Life Sci 59:903–908PubMedCrossRefGoogle Scholar
  9. 9.
    Longo V, Finch CE (2003) Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299:1342–1346PubMedCrossRefGoogle Scholar
  10. 10.
    Kenyon C (2001) A conserved regulatory system for aging. Cell 105:165–168PubMedCrossRefGoogle Scholar
  11. 11.
    Dozmorov I, Bartke A, Miller RA (2001) Array-based expression analysis of mouse liver genes: effect of age and of the longevity mutant Prop1df. J Gerontol A Biol Sci Med Sci 56:B72–B80PubMedGoogle Scholar
  12. 12.
    Paolisso G, Gambardella A, Ammendola S, D’Amore A, Balbi V, Varricchio M, D’Onofrio F (1996) Glucose tolerance and insulin action in healthy centenarians. Am J Physiol 270:E890–E894PubMedGoogle Scholar
  13. 13.
    Paolisso G, Barbieri M, Rizzo MR, Cartella C, Rotondi M, Bonafè M, Franceschi C, Rose G, De Benedictis G (2001) Low insulin resistance and preserved beta-cell function contribute to human longevity but are not associated with TH-INS genes. Exp Gerontol 37:149–156PubMedCrossRefGoogle Scholar
  14. 14.
    Barbieri M, Ferrucci L, Ragno E, Corsi A, Bandinelli S, Bonafè M, Olivieri F, Giovagnetti S, Franceschi C, Guralnik JM, Paolisso G (2003) Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons. Am J Physiol Endocrinol Metab 284:E481–E487PubMedGoogle Scholar
  15. 15.
    Bonafè M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G (2003) Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. J Clin Endocrinol Metab 88:3299–3304PubMedCrossRefGoogle Scholar
  16. 16.
    Van Heemst D, Beekman M, Mooijaart SP, Heijmans BT, Brandt BW, Zwaan BJ, Slagboom PE, Westendorp RG (2005) Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4:79–85PubMedCrossRefGoogle Scholar
  17. 17.
    Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA 105:3438–3442PubMedCrossRefGoogle Scholar
  18. 18.
    Cappola AR, Xuem QL, Ferrucci L, Guralnik JM, Volpato S, Fried LP (2003) Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J Clin Endocrinol Metab 88:2019–2025PubMedCrossRefGoogle Scholar
  19. 19.
    Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353PubMedCrossRefGoogle Scholar
  20. 20.
    Baserga R, Peruzzi F, Reiss K (2003) The IGF-1 receptor in cancer biology. Int J Cancer 107:873–877PubMedCrossRefGoogle Scholar
  21. 21.
    Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, van Leeuwen W, Theil AF, Vermeulen W, van der Horst GT, Meinecke P, Kleijer WJ, Vijg J, Jaspers NG, Hoeijmakers JH (2006) A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444:1038–1043PubMedCrossRefGoogle Scholar
  22. 22.
    Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T, Robinson AR, Suh Y, Breit TM, van Steeg H, Niedernhofer LJ, van Ijcken W, Bartke A, Spindler SR, Hoeijmakers JH, van der Horst GT, Garinis GA (2008) Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet 4:e1000161PubMedCrossRefGoogle Scholar
  23. 23.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444PubMedCrossRefGoogle Scholar
  24. 24.
    Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254Google Scholar
  25. 25.
    Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevità emerged from studies in humans. Mech Ageing Dev 128:92–105PubMedCrossRefGoogle Scholar
  26. 26.
    Lio D, Scola L, Crivello A, Colonna-Romano G, Candore G, Bonafé M, Cavallone L, Marchegiani F, Olivieri F, Franceschi C, Caruso C (2003) Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10–1082 promoter SNP and its interaction with TNF-alpha -308 promoter SNP. J Med Genet 40:296–299PubMedCrossRefGoogle Scholar
  27. 27.
    Cavallone L, Bonafè M, Olivieri F, Cardelli M, Marchegiani F, Giovagnetti S, Di Stasio G, Giampieri C, Mugianesi E, Stecconi R, Sciacca F, Grimaldi LM, De Benedictis G, Lio D, Caruso C, Franceschi C (2003) The role of IL-1 gene cluster in longevity: a study in Italian population. Mech Ageing Dev 124:533–538PubMedCrossRefGoogle Scholar
  28. 28.
    Carrieri G, Marzi E, Olivieri F, Marchegiani F, Cavallone L, Cardelli M, Giovagnetti S, Stecconi R, Molendini C, Trapassi C, De Benedictis G, Kletsas D, Franceschi C (2004) The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians. Aging Cell 3:443–448PubMedCrossRefGoogle Scholar
  29. 29.
    Mannucci PM, Mari D, Merati G, Peyvandi F, Tagliabue L, Sacchi E, Taioli E, Sansoni P, Bertolini S, Franceschi C (1997) Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins. A study in centenarians. Arterioscler Thromb Vasc Biol 17:755–759PubMedGoogle Scholar
  30. 30.
    Kortlever RM, Higgins PJ, Bernards R (2006) Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol 8:877–884PubMedCrossRefGoogle Scholar
  31. 31.
    Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D (2005) Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev 126:351–361PubMedCrossRefGoogle Scholar
  32. 32.
    Bonafè M, Olivieri F, Cavallone L, Giovagnetti S, Mayegiani F, Cardelli M, Pieri C, Marra M, Antonicelli R, Lisa R, Rizzo MR, Paolisso G, Monti D, Franceschi C (2001) A gender—dependent genetic predisposition to produce high levels of IL–6 is detrimental for longevity. Eur J Immunol 31:2357–2361PubMedCrossRefGoogle Scholar
  33. 33.
    Cardelli M, Cavallone L, Marchegiani F, Oliveri F, Dato S, Montesanto A, Lescai F, Lisa R, De Benedictis G, Franceschi C (2008) A genetic-demographic approach reveals male-specific association between survival and tumor necrosis factor (A/G)-308 polymorphism. J Gerontol A Biol Sci Med Sci 63:454–460PubMedGoogle Scholar
  34. 34.
    Belluco C, Olivieri F, Bonafè M, Giovagnetti S, Mammano E, Scalerta R, Ambrosi A, Franceschi C, Nitti D, Lise M (2003) 174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res 9:2173–2176PubMedGoogle Scholar
  35. 35.
    Ancrile B, Lim KH, Counter CM (2007) Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev 21:1714–1719PubMedCrossRefGoogle Scholar
  36. 36.
    Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, Chieco P, Bonafè M (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117:3988–4002PubMedCrossRefGoogle Scholar
  37. 37.
    Hodge DR, Peng B, Cherry JC, Hurt EM, Fox SD, Kelley JA, Munroe DJ, Farrar WL (2005) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65:4673–4682PubMedCrossRefGoogle Scholar
  38. 38.
    Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031PubMedCrossRefGoogle Scholar
  39. 39.
    Dijsselbloem N, Goriely S, Albarani V, Gerlo S, Francoz S, Marine JC, Goldman M, Haegeman G, Vanden Berghe W (2007) A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4-stimulated dendritic cells exposed to Genistein. J Immunol 178:5048–5057PubMedGoogle Scholar
  40. 40.
    Ko LJ, Prives C (1996) p53: Puzzle and paradigm. Genes Dev 10:1054–1072PubMedCrossRefGoogle Scholar
  41. 41.
    Levine AJ (1997) p53, The cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRefGoogle Scholar
  42. 42.
    Attardi LD, Donehower LA (2005) Probing p53 biological functions through the use of genetically engineered mouse models. Mutat Res 576:4–21PubMedGoogle Scholar
  43. 43.
    Scrable H, Medrano S, Ungewitter E (2008) Running on empty: how p53 controls INS/IGF signaling and affects lifespan. Exp Gerontol [Epub ahead of print]Google Scholar
  44. 44.
    Staib F, Robles AI, Varticovski L, Wang XW, Zeeberg BR, Sirotin M, Zhurkin VB, Hofseth LJ, Hussain SP, Weinstein JN, Galle PR, Harris CC (2005) The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res 65:10255–10264PubMedCrossRefGoogle Scholar
  45. 45.
    Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH, Levine AJ (2000) Analysis of p53- regulated gene expression patterns using oligonucleotide arrays. Genes Dev 14:981–993PubMedCrossRefGoogle Scholar
  47. 47.
    Wang L, Wu Q, Qiu P, Mirza A, McGuirk M, Kirschmeier P, Greene JR, Wang Y, Pickett CB, Liu S (2001) Analyses of p53 target genes in the human genome by bioinformatic and microarray approaches. J Biol Chem 276:43604–43610PubMedCrossRefGoogle Scholar
  48. 48.
    Leech M, Xue JR, Dacumos A, Hall P, Santos L, Yang Y, Li M, Kitching AR, Morand EF (2008) The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response. Clin Exp Immunol 152:345–353PubMedCrossRefGoogle Scholar
  49. 49.
    Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221PubMedCrossRefGoogle Scholar
  50. 50.
    Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA (2002) p53 Mutant mice that display early ageing-associated phenotypes. Nature 415:45–53PubMedCrossRefGoogle Scholar
  51. 51.
    Donehower LA (2002) Does p53 affect organismal aging? J Cell Physiol 192:23–33PubMedCrossRefGoogle Scholar
  52. 52.
    Moore L, Lu X, Ghebranious N, Tyner S, Donehower LA (2007) Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity. Mech Ageing Dev 128:717–730PubMedCrossRefGoogle Scholar
  53. 53.
    García-Cao I, García-Cao M, Martín-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M (2002) “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21:6225–6235PubMedCrossRefGoogle Scholar
  54. 54.
    Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Viña J, Blasco MA, Serrano M (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:375–379PubMedCrossRefGoogle Scholar
  55. 55.
    Feng Z, Hu W, Teresky AK, Hernando E, Cordon-Cardo C, Levine AJ (2007) Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci USA 104:16633–16638PubMedCrossRefGoogle Scholar
  56. 56.
    Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D (1999) Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 96:14973–14977PubMedCrossRefGoogle Scholar
  57. 57.
    Méplan C, Richard MJ, Hainaut P (2000) Redox signalling and transition metals in the control of the p53 pathway. Biochem Pharmacol 59:25–33PubMedCrossRefGoogle Scholar
  58. 58.
    Uberti D, Lanni C, Carsana T, Francisconi S, Missale C, Racchi M, Govoni S, Memo M (2006) Identification of a mutant-like conformation of p53 in fibroblasts from sporadic Alzheimer’s disease patients. Neurobiol Aging 27:1193–1201PubMedCrossRefGoogle Scholar
  59. 59.
    Uberti D, Carsana T, Bernardi E, Rodella L, Grigolato P, Lanni C, Racchi M, Govoni S, Memo M (2002) Selective impairment of p53-mediated cell death in fibroblasts from sporadic Alzheimer’s disease patients. J Cell Sci 115:3131–3138PubMedGoogle Scholar
  60. 60.
    Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC (2005) Alzheimer disease and cancer. Neurology 64:895–898PubMedGoogle Scholar
  61. 61.
    Lanni C, Uberti D, Racchi M, Govoni S, Memo M (2007) Unfolded p53: a potential biomarker for Alzheimer’s disease. J Alzheimers Dis 12:93–99PubMedGoogle Scholar
  62. 62.
    Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev 18:306–319PubMedCrossRefGoogle Scholar
  63. 63.
    Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP, Saville MK, Lane DP (2005) p53 Isoforms can regulate p53 transcriptional activity. Genes Dev 19:2122–2137PubMedCrossRefGoogle Scholar
  64. 64.
    Bourdon JC (2007) p53 Family isoforms. Curr Pharm Biotechnol 8:332–336PubMedCrossRefGoogle Scholar
  65. 65.
    Van Heemst D, Mooijaart SP, Beekman M, Schreuder J, de Craen AJ, Brandt BW, Slagboom PE, Westendorp RG, Group LongLifeStudy (2005) Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol 40:11–15PubMedCrossRefGoogle Scholar
  66. 66.
    Mammano E, Belluco C, Bonafé M, Olivieri F, Mugianesi E, Barbi C, Mishto M, Cosci M, Franceschi C, Lise M, Nitti D (2008) Association of p53 polymorphisms and colorectal cancer: modulation of risk and progression. Eur J Surg Oncol (Epub ahead of print)Google Scholar
  67. 67.
    Ørsted DD, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG (2007) Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population. J Exp Med 204:1295–1301PubMedCrossRefGoogle Scholar
  68. 68.
    Regula KM, Kirshenbaum LA (2001) p53 Activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcription. J Mol Cell Cardiol 33:1435–1445PubMedCrossRefGoogle Scholar
  69. 69.
    Bonafé M, Salvioli S, Barbi C, Trapassi C, Tocco F, Storci G, Invidia L, Vannini I, Rossi M, Marzi E, Mishto M, Capri M, Olivieri F, Antonicelli R, Memo M, Uberti D, Nacmias B, Sorbi S, Monti D, Franceschi C (2004) The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death. Cell Death Differ 11:962–973PubMedCrossRefGoogle Scholar
  70. 70.
    Salvioli S, Bonafé M, Barbi C, Storci G, Trapassi C, Tocco F, Gravina S, Rossi M, Tiberi L, Mondello C, Monti D, Franceschi C (2005) p53 Codon 72 alleles influence the response to anticancer drugs in cells from aged people by regulating the cell cycle inhibitor p21WAF1. Cell Cycle 4:1264–1271PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Stefano Salvioli
    • 1
    • 2
    • 3
    Email author
  • Miriam Capri
    • 1
    • 2
  • Laura Bucci
    • 1
  • Cristina Lanni
    • 4
  • Marco Racchi
    • 4
  • Daniela Uberti
    • 5
  • Maurizio Memo
    • 5
  • Daniela Mari
    • 6
  • Stefano Govoni
    • 4
  • Claudio Franceschi
    • 1
    • 2
    • 3
  1. 1.Department of Experimental PathologyUniversity of BolognaBolognaItaly
  2. 2.Interdepartmental Centre “L. Galvani” (C.I.G.)BolognaItaly
  3. 3.ER-GenTech LaboratoryFerraraItaly
  4. 4.Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied BiologyUniversity of PaviaPaviaItaly
  5. 5.Department of Biomedical Sciences and BiotechnologiesUniversity of BresciaBresciaItaly
  6. 6.Department of Medical Sciences, Geriatrics UnitUniversity of Milan and IRCCS Istituto Auxologico ItalianoMilanItaly

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