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					                                                                      I.N.R.C.A.
                                                            “N. Masera” Gerontol. Res. Dept




         MICRONUTRIENTI E INVECCHIAMENTO DI SUCCESSO:
                  IL PARADIGMA DELLO ZINCO
                      Eugenio Mocchegiani

Immunology Ctr. (Section: Nutrition and Immunosenescence) Res. Dept. INRCA,
                                  Ancona, Italy
                        Email : e.mocchegiani@inrca.it


        Workshop di Medicina Anti-Ageing:from bench to bedside
                     Taormina 6-7 Dicembre 2007
                      Fattori nutrizionali


Fattori Genetici                               Patogeni




                   Omeostasi zincale e
                   di altri “trace elements”
Cambiamenti correlati all’età di alcuni “trace elements”
Cambiamento correlati all’età del rapporto rame/zinco plasmatico
                            Risk of mortality after 3 years
(Classification tree created including gender and all trace elements in the analysis)




             Alive
             Dead
                               Fattori genetici

Assenza/Mutazioni di uno specifico trasportatore
di zinco (Zip4) sembrano essere la causa
dell’acrodermatite enteroepatica caratterizzata
da una grave zinco deficienza (Wang et al., Am.
J. Hum. Genet., 2002; Kury et al.,Nat. Genet.,
2002)



Una mutazione nel trasportatore Znt2 causa una
temporanea deficienza di zinco neonatale
dovuta ad una bassa concentrazione nel latte
materno (Chowanadisai et al., J. Biol. Chem.,
2006)

Varianti genetiche di uno specifico trasportatore
di zinco delle cellule insulino-secernenti
pancreatiche (Znt8) risultano associate al
diabete di tipo II (Scott et al., Science, 2007;
Zeggini et al., Science, 2007)
                                                    Tre dimeri di insulina Asssemblati attorno
                                                    a 2 atomi di zinco (Monomers, Dimers
                                                    and Hexamers." The Principles of Protein
                                                    Structure, 1997)
                           Fattori Nutrizionali




                                                           ZINC IN SOILS
                                                           AND CROP NUTRITION
                                                           Brian J. Alloway


Alcuni sintomi della zinco deficienza: Ridotto sviluppo (neonati, bambini)
                     Ridotta resistenza alle infezioni
                Riduzione e/o danni all’epitelio intestinale
               Perdita di liquidi (diarrea, malassorbimento)
                             Problemi alla pelle
             The Zinc homeostatic-regulatory machinery




The complexity and importance of zinc homeostasis is reflected by the large
number of proteins that are potentially dedicated to Zn2+ transport and buffering.


- 10 members of the ZnT (Zn2+ Transporter) family (Znt1-10).


- 15 members of the ZIP family - i.e., Zn2+-regulated metal transporter (Zip1-14)
and Iron-regulated metal transporter-like protein


- zinc sensors, such as metal response element (MRE)-binding transcription
factor-1 (MTF-1) and 14 Metallothionein isoforms (with at least 10 functional
isoforms)
                             Effect of zinc on immune system
                                    A) INDIRECT                                                               B) DIRECT
                    Immunoresistance to infections by zinc                                    Immunoresistance by zinc involving
                   involving MTs, iNOS, PARP homeostasis                                       cell-mediated immune responses

                                                                                 ZINC

                                                                                                              ZnFTS
                                                                     IL-12

                                                                     Balance
                                M   f                Th2                                Th1              NK
                                                                Th1/Th2/Th3                                             Host defence
                                                                 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
                                                                     ZnMTs                       MTs for their biological functions.

                                 PARP                                                      Zinc release of MTs by NO
                                                                                             to antioxidant enzyme


                                                   NAD+
                 Nucleus

                                                     Antioxidant enzyme activation (SOD)
          I.N.R.C.A.
                                                                                                               Mocchegiani et al., TIPS. 2000
                            DNA- repair
“N. Masera” Gerontol. Res. Dept.
                                                    Protection of MTs by oxidative damage
        Intracellular zinc signals (response to stress)



                                DNA and protein                  Protein and
                                   damage                    DNA repairing enzymes
Stressor agent


                  MT                       Sulfur ligand               Stress induced response




           Zinc




            Zinc dependent
          Antioxidant enzymes
                                                 Zinc dependent
                                               Transcription factors
                                                 Recruited subjects


                                    INRCA          UNIFI        HU         RWTA          UFC         MUL
   Recruited subjects               Ancona        Firenze     Athens      Aachen       Besançon      Lodz
                                     Italy          Italy     Greece      Germany       France      Poland
                                       235           27          193          148          179         143
            Old                    (129F-107M)   (17F-10M)   (128F-65M)   (44F-103M)   (103F-76M)   (91F-52M)
                                        83           25          23           2            13          21
   Nona- Centenarian                (59F-24M)     (8M-17F)   (10F-13M)     (1F-1M)      (6F-7M)     (13F-8M)
                                        38                                                 4
   Old with infection               (14F-24M)                                           (3F-1M)
                                        2                         3                        5
     Old with cancer                  (2F)                      (3F)                    (2F-3M)
                                        38                       30                        76          36
Old with atherosclerosis            (18F-20M)                (19F-12M)                              (28F-8M)
                                                                                       (41F-35M)

       Total (1337)                   408           52          249          150          277         200




          I.N.R.C.A.
“N. Masera” Gerontol. Res. Dept.
     Plasma IL-6, active thymulin, total thymulin and zinc
     from human donors
                                    Young   old        Nonagenarians/ Old infected      Old infected
                                                        centenarians (acute phase) (remission phase)
IL-6 (pg/ml)                 1.7 ± 0.6 3.7 ± 1.0*         5.1 ± 0.9*   23.4 ± 2.0**     21.4 ± 1.8**
Zinc (mg/dl)               120.3 ± 7.3 83.2 ± 5.9*       87.5 ± 4.7*    69.8 ± 5.7*      70.1 ± 5.6*
Active thymulin (log-2)(AT) 5.0 ± 0.3 1.5 ± 0.2*          2.0 ± 0.3*     1.0 ± 0.3*      1.3 ± 0.2*
Total thymulin (log-2)(TT) 5.3 ± 0.2      4.1 ± 0.3       3.5 ± 0.2      4.0 ± 0.2        4.5 ± 0.3
Ratio TT/AT (log-2)         1.04 ± 0.1 2.9 ± 0.3*         1.7 ± 0.3     4.1 ± 0.4**      3.6 ± 0.4**
MT/beta actina mRNA         0.92 ± 0.3 3.0 ± 0.5*         1.5 ± 0.3     4.0 ± 0.3**
gp130/beta actina mRNA 0,29 ± 0,31 0,45 ± 0,28*           0,31 ± 0,33
*p<0.01 and **p<0.001 when compared to young subjects.     Mocchegiani et al., Exp Gerontol. 2004


 TT/AT = zinc ion bioavailability


           I.N.R.C.A.
 “N. Masera” Gerontol. Res. Dept.
Immune plasticity, zinc ion availabiity and inflammation in ageing/succesful ageing

                                                       Accelerated switching on =    Delayed switching on =
                                                             death of aged            increased longevity
                                                                                                                     IL-6
        zinc availability


                                             Genetic background ?


      Stress
                                                                                                                 MTmRNA

                                                                                                                      gp130
           MTmRNA                                                                                           SUCCESSFUL AGING
            (lamp)
                                                                                                              Zinc ion avalability

             IL-6
    (hand to press switch)


               gp 130
               (switch)          Immune plasticity        Absence of immune plasticity =   Maintenance of immune plasticity =
                             (spring)= normal immune           immune decrement              satisfactory immune plasticity
                                     response


  0                 2                                  15                                  24
                             Young-adult age                        Ageing                          Very old age

               I.N.R.C.A.                     Age (months) of mice                     Mocchegiani et al.,
  “N. Masera” Gerontol. Res. Dept.
                                                                                       Exp. Gerontol. 2004
Immune and nutritional parameters in C- and C+ (IL-6 gene promoter -174 G/C
     polymorphism) infected patients, in old and nonagenarian subjects
                         HEALTH YOUNG-ADULT                   OLD            NONAGENARIANS OLD INFECTED PATIENTS
                            (Men) Age-range             (Men) Age-range       (Men) Age-range   (Men) Age-range
                            (30-40 yrs, n=30)           (65-85 yrs, n=30)     (90-97 yrs, n=20) (65-83 yrs, n=20)

                         C+ (n=16)       C- (n=14)    C+(n=14) C-(n=16) C+(n=12)         C-(n=8)    C+(n=13)     C-(n=7)
     IL-6 (pg/ml)         0.70.03       1.000.2*    0.880.3   1.210.4*   0.770.5   1.430.7*   3.500.7    5.720.9*

   NK cell activity
                  7
                          78.18.7       68.77.3*    62.36.7   50.25.5*   73.45.7   58.16.5*   46.37.3    15.25.4*
    (L.U. 20/10 )

    IL-10 (pg/ml)         1.550.37     0.930.23*    1.500.25 0.611.84* 1.700.23 1.300.15*     1.600.26   1.400.12*

                           0.950.21* 0.960.18 to increased IL-6 and
  “C- carriers” were associated 1.440.11* 0.580.15 1.320.14 2.500.12 to 3.670.16*
 TNF-alpha (pg/ml)
                 0.650.14

  impaired peripheral immune efficiency, as well 3.370.08 altered
    MTmRNA
                 0.850.05 1.230.07*  2.120.7 3.130.8* 1.000.03 3.700.5*
                                                                              as, to 4.230.03*
  zinc status
   MT-IIA/actin

     Zinc (g/dl)          13527       128.328.1*   82.27.7   77.56.4    80.48.7   72.27.4*   70.26.7    69.48.2*

       Zinc ion
   bioavailability
(ratio Total thymulin/    1.000.02     2.000.03*    2.330.02 3.530.05* 1.330.02 2.030.05*     3.330.02   4.030.05*
  active thymulin)
p<0.01 as compared to C+ (paired Student’s t-test)                                      Giacconi et al., Exp. Gerontol., 2004

             I.N.R.C.A.
 “N. Masera” Gerontol. Res. Dept.
                                                                          Plasma zinc, labile zinc, MT and Zinc
                                                                          release (by NO donor) In human PBMC
                                                                          from Zincage sample
                                                                                                                                                  1.8

                              14




                                                                                                                           Labile Zinc (Fn ZP1)
Plasma Zinc (uM)




                                                                              France
                              13                                                                                                                  1.6

                                                                              Greece
                              12
                                                                              Germany                                                             1.4
                              11
                                                                               Poland
                              10                                                                                                                  1.2
                                                                               Italy
                              9
                                         60 70 80 90 100 110                                                                                      1.0
                                               age (y)                                                                                                       60   70     80    90   100

                                                                                                                      .6                                               age (y)




                                                                                          NO-induced Release of Zn
                                   100                                                                                .5


                                                                                                                      .4
                   MT (MFI)




                                                                                                                      .3
                                    50
                                                                                                                      .2


                                                                                                                      .1

                                     0                                                                               0.0
                                          60     70      80    90   100
                                                                                                                     -.1
                                                         age (y)                                                                                        60        70      80        90    100
                                         I.N.R.C.A.
         “N. Masera” Gerontol. Res. Dept.                                                                                                                          age (y)
                                                              Mocchegiani et al., AJCN, 2007, submitted
Correlation between MT and NO-induced release of zinc (ZnR) in old
subjects (Zincage population).

                  160

                  140

                  120

                  100                                       Y = 30.3386x + 75.1495
                                                            R2 = 0.119; p = 0.048
                   80

                   60

                   40

                   20                                         Observed

                   0                                          Linear
                    -.1 0.0   .1   .2   .3   .4   .5   .6

                                   ZnR
Effect of zinc supplementation on zinc status, immune and psychological parameters in
old subjects with plasma zinc ≤ 10.5 M in dependence of IL-6 -174 polymorphism



                                                C-                                           C+
                                  (BS)                     (PS)                (BS)                    (PS)
                            Mean         SD          Mean         SD     Mean         SD          Mean        SD
             Age (y)         74           7            -           -      71           7           -           -
        Dietary intake of
                            7.74         3.68          -           -     8.56         2.51         -           -
         zinc (mg/day)
        Plasma Zn (µM)      9.0           1.4         10.2*        1.8    8.7          1.5     10.5*          1.9
             Zn/Alb         .34           .06          .38*        .07    .32          .05     .39*           .06
         RBC Zn (µM)        104           45            98          42   114            39      113            34
           MT (MFI)         80.1         28.2        112.6*       53.7   78.3         22.8    105.1*          33.5
              iZnL          1.25          .10         1.31*        .11   1.27          .07     1.34*          .13
              iZnR          .18           .08          .23*        .10    .18          .05     .22*           .09
           MT/iZnR          583          361          398*        159    541          221       485           303
          NK activity       17.7          6.5         24.9*        4.5    9.8          7.9     15.0*          8.8
              GDS           2.8           2.8           2.5        2.5    3.7          3.2      2.7           2.3
               PSS          17.5          7.5          14.8        7.8   14.1          6.1     13.0           6.7
             MMSE           25.4          2.4          26.4        2.3   23.8          4.6     24.8           3.7




 BS= before supplementation; PS= after supplementation; Zinc dose=10 mg/day for 48 days
Influence of in vivo Zinc on Spontaneous and Induced IL-6 and IFNgamma Production
                                 1000                                                                                                                           120
                                                                                                                                                                                                              *
                                                                                                                                                                100

                                       100
                                               A Basal IL-6 release
                                               Basal IL-6 release                                                                                                C IL-6 release upon LPS stimulation
                                                                                                                                                                IL-6 release upon LPS stimulation
                                                                                                    **
       IL-6 (pg/ml)
                                                                                                                                                                80




                                                                                                                                       IL-6 (ng/ml)
                                           1000                                                                                                                  120
                                               10
                                                                                                                                                                60                                                *
                                                                                                                                                                 100




                                                                                                                                    IL-6 pg/ml
                                                                                                                                                                40
       IL-6 pg/ml

                                               100
                                                                                                        **
                 IL-6 (pg/ml)




                                               1                                                                                                                  80




                                                                                                                                                 IL-6 (ng/ml)
                                                                                                                                                                20

                                                                                                                                                                   60
                                                10                                                                                                                0
                                                 0                      1                           2               3

                                                                                                                                                                  40
                                                                     before                          after                                                                         before                     after
                                                    1                             supplementation                                                                                           supplementation
                                                                                                                                                                  20


                                                                                                                                                                      0
                                                        0                   1                           2               3

                                                                   Before
                                                                     before                      After
                                                                                                    after                                                                        Before
                                                                                                                                                                                  before                 After
                                                                                                                                                                                                           after
                                                                                      supplementation                                                                                        supplementation



                                                    B Basal IFNg release release
                                                    Basal IFNgamma                                                                                              IFNgamma release upon SPEA*
                                                                                                                                                                D IFNg release upon SPEA stimulation
                                                                                                                                                                stimulation
                                               250

                                                                                                                                                                                                              **
       IFNg pg/ml




                                                                                                                                                                300
                                               200
                                                        B       Basal IFNg release                                                                               D        IFNg release upon SPEA stimulation
                                                                                                                                    IFNg pg/ml
                      IFNg (pg/ml)




                                                                                                                                     IFNg ng/ml)

                                               150
                                                 250                                                                                                            200


                                                                                                                                                                 300
                                                                                                                                                                                                               **
                                               100
                                                 200

                                                                                                                                                                100
                                IFNg (pg/ml)




                                                50
                                                                                                                                             IFNg ng/ml)




                                                 150
                                                                                                                                                                 200


                                                    0
                                                    100                                                                                                          0
                                                      0                       1                             2               3



                                                    50
                                                                   Before
                                                                     before                       After
                                                                                                    after                                                        100
                                                                                                                                                                                Before
                                                                                                                                                                                  before                After
                                                                                                                                                                                                          after
                                                                                                                                                                                                                      *streptococcal erythrogenic
                                                                                      supplementation                                                                                       supplementation
                                                                                                                                                                                                                      toxins type A

Data from Rink et al. 2007 (Final report of Zincage)    0
                                                            0                     1                             2               3
                                                                                                                                                                      0
Effect of in vivo zinc supplementation on zinc status and stress response in elderly from Zincage Project
                                                                                                         Effect of
                                                                                                           zinc
                                                    Parameter                                        supplementation*
                                                      Plasma Zinc                                           
                                                 Plasma Zinc/Albumin                                        
   Zinc Status




                                                Labile intracellular zinc                                  

                                                   Metallothioneins                                         
                                              NO-induced release of zinc                                   
                                                   Granulocyte Zinc                                        
                                           poly(ADP-ribosyl)ation capacity                                  
                                                   ROS production                                           
                                                     ApoJ plasma                                            -
   Stress-response




                      Genes involved in Nitrosative stress (ATF2, CSF2, FOS, ICAM1, JUN, LTA,
                                                                                                            
                                     CCL2, SELE, VCAM1, iNOS, TNF, NFKB1)
                                           Total intracellular carbonyl levels                              
                                         MsR activity and protein expression                               
                     Chymotrypsin-like peptidase activity of proteasome and 20S protein expression          
                                           Chaperone (Hsp72) protein levels                                 -

                                            Chaperone (Hsp72) inducibility                                 


* = strongly increased,  = increased,  = decreased - = slightly increased at least in some sub-groups
Effect of zinc supplementation in vitro administered to PBMC in autologous
plasma from a healthy donor on DNA strand break repair




PBMC from a 59 year old donor were resuspended in the plasma of the same donor and supplemented or not with 25 µM zinc for 5 min
at 37°C. The cells were irradiated with 2.5 Gy X-rays and allowed to repair DNA strand breaks over the subsequent 40 min. As is evident
from the graph, repair was massively enhanced upon zinc supplementation.


Data from Buerkle et al. 2007 (Final report of Zincage)
                     Effect of zinc supplementation in vivo administered to healthy subjects on
                     PARP-1 activity and DNA repair capacity (Comet assay).


                                                                                                                                     120




                                                                                                                        %
                                                                                                                                     100

                                                                                                                                         80
                                      All probands                                                                                       60




                                                                                                                        Percentage
                                                           y = 1.5272x - 52.523
                                                                R2 = 0.1779                                                              40                                                                 DNA repair
                     600                                                                                                                                                                                    B
                                                                                                                                         20
                                                                                                                                                                                                            DNA repair
PARP activity in %




                                                                                                                                                                                                            Z
                     500                                                                                                                  0
                                                                                                                                               1   2   3   4   5   6    7    8      9   10   11   12   13
                                                                                                                                         -20
                     400
                                                                                                                                         -40                                            men
                     300                                                                                                                 -60


                     200                                                           % 150
                                                                                     100
                     100
                                                                                      50

                                                                                       0
                      0
                                                                                            1   2   3   4   5   6   7   8            9    10 11 12 13 14 15 16
                           50   70   90    110    130     150     170        190      -50

                                                                                     -100                                                                              DNA repair
                                     Zinc concentration in %                         -150
                                                                                                                                                                       B
                                                                                                                                                                       DNA repair
                                                                                                                                                                       Z
                                                                                     -200


Changes in PARP-1 activity (in %) upon               women                           -250

                                                                                     -300

7-week zinc supplementation plotted as a                                             -350

                                                                                     -400
function of changes in plasma zinc
concentration (in %).                    Mean increase: 75% men and 70% women

       Data from Buerkle et al. 2007                                                        Data from Jajte et al. 2007 (Final
       (Final report of Zincage)                                                            report of Zincage)
                                                                                                                                                        a




                   Effect of zinc supplementation
                   on stress response (Clu/ApoJ,
                   HSP70, MT) and ROS
                   production
                                                                                                            aData     from Soti et al. 2007 (Final report of Zincage)


                                                                                                                     ROS production in lymphocytes of healthy
          Percent increment of Clu/ApoJ and MT in                                                                       elderly subjects, before and after
          supplemented subjectsb                                                                                                 supplementation



                                                                                Increment Zn Granulocytes and MT %
                   20
                                                                         250

                   15
                              *                  *                   *
Increment APOJ %




                                                                         200

                                                                         150
                   10

                                                                         100
                   5
                                                                          50

                   0                                                       0
                        APOJ             Granulocytes Zn
                                                               MT
                                                                          -50
                   -5
                                                                         -100


               bMocchegiani   and Gonos, Ann NY Acad Sci USA, 2007
                                                                                                                                              c
                                                                                                                                              Data from Jajte et al. 2007
                                                                                                                                              (Final report of Zincage)
Effect of zinc supplementation on oxidized protein accumulation, proteasome and
methionine sulfoxide reductase activity per gender.




Data from Friguet et al. 2007 (Final report of Zincage)
Differential regulation of PPAR signalling pathway transcripts (RT-PCR) in vitro
zinc-treated PBMC from young and elderly (confirmed from microarray analysis).




Data from Mazzatti et al. Rej. Res. 2007
Maret and Krezel, Mol Med, 2007
Genes differently regulated between subjects with low grade carotid atherosclerosis
under treatment with HMG-CoA reductase inhibitors and healthy elderly controls age
and sex-matched.

     Gene Symbol                         Gene Name                                             Total Fold Change
                                                                                Up-regulated    P Value Dow regulated   P Value
      MUTYH                          MutY homolog (E. coli)                         7,81          0,01
       MT1F                      Metallothionein 1F (functional)                    4,29          0,01
                   Matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase,
       MMP2                                                                         3,43         0,02
                                   72kDa type IV collagenase)
       PPARA            Peroxisome proliferative activated receptor, alpha          3,12         0,03
       NR1H3            Nuclear receptor subfamily 1, group H, member 3             3,06         0,04
                        Excision repair cross-complementing rodent repair
       ERCC1       deficiency, complementation group 1 (includes overlapping        3,01         0,03
                                        antisense sequence)
        MT2A                            Metallothionein 2A                          2,90         0,01
       PTGES2                       Prostaglandin E synthase 2                      2,73         0,01
        VWF                           Von Willebrand factor                         2,59         0,02
                     Cyclin-dependent kinase inhibitor 2A (melanoma, p16,
      CDKN2A                                                                        2,41         0,01
                                          inhibits CDK4)
      SLC39A4         Solute carrier family 39 (zinc transporter), member 4         2,35         0,03
       PPARD            Peroxisome proliferative activated receptor, delta          2,30         0,03
      MMS19L              MMS19-like (MET18 homolog, S. cerevisiae)                 2,27         0,01
      SLC30A6         Solute carrier family 30 (zinc transporter), member 6         2,10         0,05
        KLF4                        Kruppel-like factor 4 (gut)                                              0,47        0,05
       IFNGR2                      Interferon gamma receptor 2                                               0,42        0,04
      PRKCB1                          Protein kinase C, beta 1                                               0,39        0,02
        CTSH                                Cathepsin H                                                      0,32        0,01
      NDUFS4            NADH dehydrogenase (ubiquinone)Fe-S protein 4                                        0,28        0,02
         IL-8                               Interleukin 8                                                    0,18        0,02
        IL1R2                     Interleukin 1 receptor, type II                                            0,07        0,03
A novel Zip2 Gln/Arg/Leu codon 2 polymorphism is associated to carotid
                           artery disease in aging.
 R. Giacconi, E. Muti, M. Malavolta, M. Cardelli, S. Pierpaoli, C. Cipriano, L.
                 Costarelli, S.Tesei, V. Saba, E. Mocchegiani

                        Elderly controls           CS patients
                            (n. 259)                (n. 250)
                  n.             Frequency   n.          Frequency
      Genotypes
      GG          123            47.5%       150         60%
      AT          3              1.2%        4           1.6%
      TG          107            41.3%       81          32.4%
      TT          26             10%         15          6%
      Total       259                        250
      Alleles
      G allele    353            0.681       381         0.762
      A allele    3              0.006       4           0.008
      T allele    162            0.313       115         0.230
      Total       518                        500

                                                                 Rejuvenation Res in press
                                   CONCLUSIONS

It exists a clear age-dependent decline of plasma zinc in all European countries, more
    deep in Greece and Italy, less in France.

Carriers of C- allele for IL-6 (-174) polymorphisms seem the best candidate for zinc
   supplementation being characterized by low plasma zinc and zinc ion availability
   and high MT levels, suggesting the presence of stressing conditions and bad zinc
   status. Also C+ carriers are prone for zinc supplementation in presence of low
   plasma zinc. Whereas, C+ carriers with normal plasma zinc are less prone for zinc
   supplementation. A correct dietary habit may be sufficient.

Old supplemented subjects display an increased immune response and better zinc
   status as well as increased intracellular stress response.
A major evidence on the immune response is however observed in C- supplemented
   subjects.

Zinc affects some genes related to the inflammation (IL-1, IL-6) contributing to reduces
   the inflammation and at the same time to make old subjects more prompt for a
   rapid immune response to external noxae.

The genetic screening for IL-6 is an useful tool to screen old subjects who effectively
   need zinc supplementation in order to achieve health ageing and longevity.
Contract grant sponsors:
European Commission;                                 I.N.R.C.A. GROUP
Contract grant number:               Immunology Ctr. (Section: Nutrition, Immunity, Ageing).
FOOD-CT-2003-506850            Gerontol. Res. Dept. “N. Masera”, Via G. Birarelli 8, 60121, Ancona (Italy).

Acronym: Zincage                                     Dr. Mocchegiani Eugenio (Responsible)
                                                                                    Dr. Cipriano Catia
                                     Dr. Malavolta Marco
                                                                                    Dr. Tesei Silvia
                                     Mr. Pierandrei Romeo
                                                                                    Dr. Costarelli Laura
                                     Dr. Muti Elisa
                                                                                    Mrs. Gasparini Nazzarena
                                     Dr. Francesco Piacenza
                                                                                    Dr. Giacconi Robertina
                                                     Cytofluorimetry Service
                               Gerontol. Res. Dept. “N. Masera”, Via G. Birarelli 8, 60121, Ancona (Italy).
                                                         Mr. Bernardini Gianni

                                                         Veterinary Service
                               Gerontol. Res. Dept. “N. Masera”, Via G. Birarelli 8, 60121, Ancona (Italy).
                                                         Dr. Orlando Fiorenza

                                                Gerontology and Psychology Ctr.
                           Research Department “N. Masera”, Via Santa Margherita 5, 60131, Ancona (Italy).

                                                 Dr. Marcellini Fiorella (Responsible)
                                                           Dr. Giuli Cinzia
                                                          Dr. Papa Roberta

                                                      Computer Service Ctr.
                           Research Department “N-Masera”, Via della Montagnola, 60100 Ancona, Italy
                                                      Dr. Linari Giorgio (Responsible)
                                              Supported by Eu Zincage project
                                              Coordinator Dr. Eugenio Mocchegiani
                                                      Dr. Efstathios Gonos NHRF
Dr. George Dedoussis HU
                                                      National Hellenic Research Foundation,
University of Athens, Greece.
                                                      Greece
Prof. Alexander Büerkle UKON
                                                      Prof. Marco Colasanti UNIROMA3
Univ. of Konstanz, Germany
                                                      Univ. of Rome “ROMA TRE” , Italy
Dr. Jolanta Jajte MUL
                                                      Prof. Bertrand Friguet UP7DD
Medical University of Łódź, Poland
                                                      Université Paris 7 - France
Dr. Richard Aspinall ICL
Imperial College London, UK                           Dr. Csaba Soti SE
                                                      Semmelweis University, Budapest, Hungary
Dr. Erminia Mariani IOR
Istituti Ortopedici Rizzoli, Bologna, Italy           Prof. Patrizia Mecocci UNIPG
                                                      Univ. of Perugia, Italy
Prof. Lothar Rink RWTA
University of Aachen, Germany                         Dr. Maria Blasco CNIO
                                                      Nacional de Investigaciones Oncológicas,
Prof. Graham Pawelec UNI-TU                         Madrid, Spain
Zentrum fur Medizinische Forschung
Tübingen, Germany                                     Dr. Dawn Mazzatti URC
                                                      Unilever Research Colworth, UK
Prof. Tamas Fulop and Prof. George
Herbein UFC                                         Prof. Daniela Monti UNIFI
Univ. de Besançon,, France                            Univ. of Florence, Italy