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Strategies for Engineered Negligible Senescence (SENS), Second Conference

Strategies for Engineered Negligible Senescence (SENS), Second Conference Queens' College, Cambridge, England 7-11 September 2005. Zinc homeostasis in aging: two elusive faces of the same “metal”. Dr. Eugenio Mocchegiani.

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Strategies for Engineered Negligible Senescence (SENS), Second Conference

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  1. Strategies for Engineered Negligible Senescence (SENS), Second Conference Queens' College, Cambridge, England 7-11 September 2005 Zinc homeostasis in aging: two elusive faces of the same “metal” Dr. Eugenio Mocchegiani Immunology Centre (Section: Nutrition, Immunity and Aging) Res. Department Italian National Research Centres on Aging (INRCA), Ancona Italy I.N.R.C.A. “N. Masera” Gerontol. Res. Dept.

  2. B) DIRECT Immunoresistance by zinc involving cell-mediated immune responses A) INDIRECT Immunoresistance to infections by zinc involving MTs, iNOS, PARP homeostasis ZINC ZnFTS IL-12 Balance M f NK Th2 Th1 Host defence Th1/Th2/Th3 paradigm Th3 IL-2, IFN g IL- 1, IL-6 rIL-1, rIL-6 PKC (cGMP) (cAMP) iNOS MTmRNA Immune cell NO DNA strand breakage Sequester of intracellular zinc by MTs for their biological functions. ZnMTs PARP Zinc release of MTs by NO to antioxidant enzyme NAD+ Nucleus Antioxidant enzyme activation (SOD) DNA- repair Protection of MTs by oxidative damage Mocchegiani E. et al., TiPS, 2000

  3. Intracellular zinc signals (response to stress) Metallothioneins (MT) are proteins constituted by two sub-units, alpha and beta domains, which can bind 4 and 3 zinc ions into clusters involving 20 cysteine residues which bind zinc through sulfur ligands. Protein and DNA repairing enzymes DNA and protein damage Stressor agent Stress induced response MT Sulfur ligand Zinc Zinc dependent Antioxidant enzymes Zinc dependent Transcription factors

  4. Mocchegiani E. et al., MAD, 1998

  5. * *p<0.01 when compared to adults and nonagenarians Mocchegiani E. et al., MAD, 2003

  6. 4,5 4 Oldest (nonagenary) Old infected 3,5 Young 3 Old Mt2A/bactin 2,5 MT-II A-mRNA 200 bp 2 1,5 245 bp ß-actin 1 0,5 0 35 30 25 20 Plasma IL-6 (pg/ml) young 15 old 10 centenarians 5 old infected 0 MT-IIA-mRNA (RT-PCR) in human lymphocytes * Plasma IL-6 (pg/ml) * * Mocchegiani E. et al.,MAD, 2003

  7. YOUNG (Zn binding with MT) OLD (Zn binding with MT) OLD (Cu binding with MT) YOUNG (Cu binding with MT) Zinc binding with MT in the liver from young and old mice HP 1 0.9 0.8 0.7 0.6 MT Metal (µg/ml) 0.5 0.4 0.3 0.2 0.1 0 1 3 5 7 9 11 13 15 17 19 21 23 25 Fractions Mocchegiani E. et al., MAD, 2002 I.N.R.C.A. “N. Masera” Gerontol. Res. Dept.

  8. Zinc homeostasis in neuronal cells • The release of Zn++ from “zinc enriched neurons” seems to exert a protective action against excessive release and extracellular accumulation of glutamate • Zinc binding is required for NGF activity and for the zinc-fingers mediated transcription of other growth factors • Zinc is required for the regulation of of many relevant enzymes involved in neuronal function • (E. Mocchegiani et al., Progress in Neurobiology, 75, 367, 2005)

  9. Consequences of a possible zinc deficiency in the aged brain ? Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M. Brain, aging and neurodegeneration: role of zinc ion availability. Prog Neurobiol. 2005;75(6):367-90.

  10. Neurotoxicity of zinc for the brain - Excessive increase of intracellular zinc have been reported in degenerating neurons in the hippocampal hilus and CA1, as well as in the cerebral cortex, thalamus, striatum, and amygdala after transient forebrain ischemia in rats (Koh et al., 1996). - Evidences indicate that zinc also enters into postsynaptic neurons in toxic excess during seizures and traumatic brain injury (Frederickson et al., 2005). Vescicular zinc Mithocondrial Zn pool MT-Zn Excessive release of zinc neurotrophin receptor p75NTR p75NTR-associated death executor (NADE) PARP-1 overactivation Mithocondrial release of cytochrome c and AIF drastic depletion of NAD+ and ATP Caspases Apoptosis Necrosis

  11. Accelerated switching on = death of aged Delayed switching on = increased longevity IL-6 Free zinc ions Genetic background ? Stress MTmRNA gp130 MTmRNA (lamp) SUCCESSFUL AGING free zinc ions IL-6 (hand to press switch) gp 130 (switch) Immune plasticity (spring)= normal immune response Absence of immune plasticity = immune decrement Maintenance of immune plasticity = satisfactory immune plasticity 0 2 15 24 Young-adult age Ageing Very old age Age (months) of mice Mocchegiani E. et al., Exp. Gerontol, 2002

  12. General conclusions From the data reported may be stressed the following points: 1) The zinc ion bioavailability, via MT homeostasis, is crucial for the entire efficiency of many body homeostatic mechanisms, including immune and brain functions, with however different effects strictly dependent by the inflammatory status mediated by IL-6 and gp130 2) Zinc transporters are involved in zinc ion bioavailability. Their determination is crucial in order to clarify the zinc homeostasis in ageing 3) An excessive release of zinc can lead to zinc toxicosis in the brain with subsequent neuronal death and beta-amyloid accumulation and formation of senile plaques 4) The genetic polymorphisms of IL-6 may be the background for a correct zinc ion bioavailability and the subsequent successful ageing All these points are the main tasks of Zincage project, in which zinc supplementation is foreseen following the genetic background from each old recruited subject in order to discriminate the real zinc deficiency and to clarify old people who need zinc supply for healthy ageing. I.N.R.C.A. “N. Masera” Gerontol. Res. Dept.

  13. SIXTH FRAMEWORK PROGRAMME PRIORITY 5 FOOD QUALITY AND SAFETY Contract for: SPECIFIC TARGETED RESEARCH PROJECT Annex 1 - “Description of Work” Project acronym: ZINCAGE Project full title: NUTRITIONAL ZINC, OXIDATIVE STRESS AND IMMUNOSENESCENCE: BIOCHEMICAL, GENETIC AND LIFESTYLE IMPLICATIONS FOR HEALTHY AGEING. Contract no.: FOOD-CT-2004-506850. Total contribution 3.000.000 Euro Scientific Coordinator: Dr. Eugenio Mocchegiani Immunology Ctr. Res. Dept. INRCA, Ancona, Italy (e.mocchegiani@inrca.it) Date of preparation of Annex 1: 25/8/2003 Operative start date of the contract: 1 February 2004 Duration of the project : 3 years www.zincage.org I.N.R.C.A. “N. Masera” Gerontol. Res. Dept.

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