oesity oN Oemight reside in oethose polymorphisms for  “yee oeimmune s : system | 1 genes 1 s that 1 me pee geest regulate i Ne> immune | > responses DELLE DIDI III ES YON(Franceschi « et i — oNcal., ,;;=0 _—— ooo-Pawelec « et i cal., ,;;;0 —————e——e—eeCaruso eset : al., .///(cid:30) .//,:5 AeConversely, | the | eee AA AAOdysregulation | of both immune | ii Aeand Fe IEEE TOinflammatory ee FOESresponses © ~occurring with i | increasing « rage i is | ; believed t “dy”| to : ESy substantially « EE OD- contri- bute { to 1 EE EEE OES) morbidity ;  rand 1 | mortality in| 1 humans, « meedue 1 to t » the greater | NN OE JSincidence | of | EDinfections ; Joo **and « “nee NOON| cancer, ; _as” | well ; | as ON ENEinflammatory < ‘age-related « | diseases, : , such ¢ “eo1 as ae GRE; osteoporo- sis, ELLE III” J OEAlzheimer SY eeedisease, type . wee oandiabetes, eee eeeParkinson MeN A REEdisease and ee MIEN INE EEO DONT ™atherosclerosis (Pawelec rereet al., ,;;;0 Franceschi et al., .///(cid:24)0 eee MeBruunsgaard et al., .//,:5 Thus, taking into9 4 NNaccount the “oerole of “ee ancytokines ianin =e er’immune 1 mee Oe> YESpONnses ¢ sand i Lin 1 protection | 1 from ¢   | suscept- ibility | to: a pee &variety | of | ~~ ee eeediseases, | cytokines | _ should | ~PS| play an i ng oe NRE| important 1 oe‘role | in: | successful ; Ieeeageing | and | ENE EET| survival.

within EEE NF ODpromoter ei Ee”regions, wo peey”mostly ae peesingle nucleotide DD IEEpolymorphisms 8 9>(cid:11):(cid:30) or EEEmicrosatellites, have rey’been Ne OO I| described. | Many « ~ PDof 1 the 1 : reported | | polymorphisms within « 1 cytokine | edgenes | > OCCUT ' ~ ASP- within | mo peed| known ¢ ee1 OF | eer putative ELE YOregulatory = oesregions (Bidwell et al., ,;;;:5 These ‘oemchanges 1 ey EN; may | oehave ;  eon| significant ¢ “eeet effect « ton t PR NON| transcription, er —)since ~~they “Jy oemay “oOalter oethe structure of NEE OIDtranscription factor BON YF OOSbinding Loesites within gene promoters or the structure of ME ahem.enhancers and om FEMsilencers within introns Or % at _more | remote 1   ' sites. | Finally, they | may alter | ‘binding : Sites “ioe; within 1 the 1 J vee ee- nuclear 1 DE DOS‘matrix | po Ifor : “J oe- archi- tectural EE OIL EEEtranscription factors | that modulate promoter geometry. It ee ebhas been hypothesized that ve pethese poly- ore DSmorphisms may NNO EYconfer NN LOflexibility in the we peesimmune ONresponse &(cid:21) DEED Neallowing « differential | eM EE MNproduction | of | “cyto- aNepeekines eee(Bidwell et “oO ,;;;:5 — PeCytokine gene wypoly- DRED eemorphisms have 9been “reshown ~dto &(cid:3) i Eeeinvolved in it anthe eee IID IISsusceptibility, : , severity < y and « | clinical « | outcome « > of s f several a peediseases ( cones 3s (see |] J2>vwree* SD> Bidwell « “sylet < tal., ,;;;(cid:30) .//, andt ithe 1 ‘related 7A$ my Lou |tealsite’). In particular pO‘high —r ae eeproducer’ alleles of DEAE ER EEEpro-inflammatory cytokines enhave been shown to &(cid:3) eeassociated me dDwith Fe IIE IIEinflammatory age-related diseases 8$(cid:23)(cid:12)4(cid:24)6 et al., .///0 LLLGrimaldi et >~al., .///0 Hobson and | oat beens| Ralston, .//,0 ND ANOSMcCusker | et 3 cal., ‘ .//,:5

  _ Materials ; ; and | | methods

1!1 Subjects . studied

8(cid:2);; ) years “eee: old, ,(cid:15). } women ; . and ‘ <. /men) | ) from 1 | north- ern | 8’ ow =1:(cid:30) ae A Nacentral | 8’  11: ) and NO NDEE FDIS| southern | 8’   =.: RAE NANItaly. In MTDour NE EENsample, erwomen ON NONI NDI EDoutnumbered » \Semen at ar ratio of about (cid:15)5(cid:15)=B,(cid:30) similar to that expected from previous —en eh eeinvestigations (Franceschi et “peeal., .///&:5 PreeReported age uowas ene MAAverified &(cid:21) we nee EN RODresearching NNO Iarchival ———e—eeeeerecords in ‘oN UFthe City Hall MDand/or ON IIISchurch o “ene eeregistries, paying , attention 1 | to { ) the « - concordance | - between 1 oe eee| reported rey”age. “ee SSand | | personal | chronologies (age of | “ee Ee"marriage, | age “o~of ee eemilitary service for Noe *Nmales, wonage of first and last EIDEpregnancy {  r women, ¢ , age ( > of ¢ we SENf children, < , among ¢ , others). revoDNA een PONEsamples from “> SS248 8;/ wanna eSwomen and ,=(cid:13) whee yemen) LID TEE<60-year-old controls eeematched for ee RENOgeographical aorigin je SS| Were | -also | collected. | Written | aM Bs &*informed | See| consent wefor ae ee eeenrolling in the study and for personal data NE IEE ILI IIISmanagement | > eohad | | been | — Oopreliminary | aN peesobtained - | from | all the et — pies- subjects ; according | » beto Italian | mf| laws.

1 1 Molecular « ‘analysis (cid:4)3 alleles « at (cid:1)45% ! nucleotide (cid:4)3 (cid:9)6’/(cid:1) gene

interferon-y 8(cid:27)’9(cid:26)(cid:1):(cid:30) Peweewhich we eSplays Jr ~~ eNeoepivotal role in defence eee Naagainst nanosviruses and reeye Ss permintracellular pathogens and | in | ~ “SPSthe oMees Naeinduction | of immune-mediated rete omeinflamma-

aN Fe eeeamplification 1 refractory | ‘mutational | system | EEE ES OS. methodol- aeogy | described &(cid:21) eee POS-Pravica | et cal. 8.///:5 Briefly, | >!* “oe Nmproducts | , Were ¢ cs eee ae- obtained | | after | ame Le Pee‘amplification | in| “7?a ,/ ) wl eeevolume containing ,  Tereaction buffer, .// (cid:3)#

, http://www.pam.bris.ac.uk./services/GAI/cytokine4.htm.

 - 874T i and - 1 +874A I . IFN-y < / allele   sin] 1 Italian « 1 centenarians ( ; (number « r of § F genes « ; examined { 1 for « reach § | group i ) is 1 s reported i 1 in t 1 brackets)