strategies for engineered negligible senescence (sens), second conference queens' college,...
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Strategies for Engineered Negligible Senescence (SENS), Second Conference
Queens' College, Cambridge, England7-11 September 2005
Zinc homeostasis in aging: two elusive faces of the same “metal”
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.
Dr. Eugenio Mocchegiani
A) INDIRECTImmunoresistance to infections by zinc
involving MTs, iNOS, PARP homeostasis
B) DIRECTImmunoresistance by zinc involving
cell-mediated immune responses
ZINC
IL-12ZnFTS
Balance
M NK
Host defence
Th3 IL-2, IFN
IL- 1, IL-6 rIL-1, rIL-6
PKC
iNOS
Immune cell
NO
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
DNA strand breakage
MTmRNA
(cGMP)
(cAMP)
Th2 Th1/Th2/Th3paradigm
Th1
Mocchegiani E. et al., TiPS, 2000
Stressor agent
Zinc dependentAntioxidant enzymes
Zinc dependentTranscription factors
Stress induced response
Protein and DNA repairing enzymes
DNA and protein damage
MT
Intracellular zinc signals (response to stress)
Sulfur ligand
Zinc
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.
NK ACTIVITY IN HUMANS
0
10
20
30
40
50
60
70
80
90
NK
(L
.U. 2
0/1
07)
young adult adult infected old old infected nonagen. nonagen. inf.
*
*p<0.01 when compared to adults and nonagenarians Mocchegiani E. et al., MAD, 2003
MT-IIA-mRNA (RT-PCR) in human MT-IIA-mRNA (RT-PCR) in human lymphocyteslymphocytes
You
ng
Old
Old
est
(non
ag
en
ary
)
Old
in
fecte
d
200 bp
245 bp
MT-II A-mRNA
ß-actin
youngold
centenarians
old infected
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
Mt2
A/
acti
n
Plasma IL-6 Plasma IL-6 (pg/ml)(pg/ml)
0
5
10
15
20
25
30
35
Pla
sm
a I
L-6
(p
g/m
l)
*
* * Mocchegiani E. et al.,MAD, 2003
Zinc binding with MT in the liver from young and old miceZinc binding with MT in the liver from young and old mice
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1 3 5 7 9 11 13 15 17 19 21 23 25
Fractions
Meta
l (µ
g/m
l)
YOUNG (Zn binding with MT)
OLD (Zn binding with MT)
OLD (Cu binding with MT)
YOUNG (Cu binding with MT)
HP
MT
I.N.R.C.A.“N. Masera” Gerontol. Res. Dept.
Mocchegiani E. et al., MAD, 2002
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)
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.
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).
MT-Zn Mithocondrial Zn pool
Vescicular zinc
Excessive release of zinc
neurotrophin receptor p75NTR
p75NTR-associated death executor (NADE)
Mithocondrial release of cytochrome c and AIF
Caspases
PARP-1 overactivation
drastic depletion of NAD+ and ATP
Apoptosis Necrosis
Age (months) of mice
Young-adult age Ageing Very old age0 2 15 24
Accelerated switching on =death of aged
Delayed switching on =increased longevity
IL-6Free zinc ions
Genetic background ?
Stress
MTmRNA
gp130
MTmRNA(lamp)
SUCCESSFUL AGING
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
free zinc ions
Mocchegiani E. et al., Exp. Gerontol, 2002
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.
SIXTH FRAMEWORK PROGRAMMESIXTH FRAMEWORK PROGRAMMEPRIORITY 5PRIORITY 5
FOOD QUALITY AND SAFETYFOOD QUALITY AND SAFETY
Contract for:
SPECIFIC TARGETED RESEARCH PROJECTSPECIFIC 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 ([email protected])
Date of preparation of Annex 1: 25/8/2003Operative 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.