Tyrosine DFHydroxylase- Insulin—Insulin Growth  i en aehaplotypes  the lipl: ! chromosomal

)!(cid:1)!  .! Deg AVRe SIUCFranceschi°, (cid:26)! $(cid:2) WOALADE 5 VeBenedictis*

“Department ¢ t of ( f Cell | | Biology, | , University « ) of ( f Calabria, ‘ _ 87030 | ) Rende, 1 , Italy BAS POT OEEDepartment ¢ t of | OE NE EE EA ESPESS,f Experimental | | Path hology, | POE A OAS, University « ) of | f Bologna, 1 , Bologna, | een, Italy EACH CAE EINES“Department ¢ t of § BOY AAPA EEEf Statistics, | _ North 6 EI SASS1 Carolina § Se Meee1 State | ERE OEE AE OS™» University, | ENA EEE_ Raleigh h, | #(cid:11) $(cid:23)%&’(cid:17) (cid:18)!(

Received | (cid:31)/ } February (cid:30)00(cid:31)1 ; received i lint 1 revised f *(cid:11)(cid:21)" (cid:30)2 } May ¢ (cid:30)00(cid:31)1 ; accepted ‘ 3 ) July : (cid:30)00(cid:31)



6(cid:20)(cid:22)& e——————~—Lips ! 7 ) gene i > Is < sociated \  1 with | NOON DO1 human | 1 longevity. ° . The ¢ > aim ¢ (cid:11)* f the y > present s “Joest study \ y was t “wrs to ¢ wee Oe) continue A@&assthe « see Ap ae SS!> exploration «  (cid:11)* F the | > 11p15 ! ) chromosomal 1 RN ee SO| region i raed:in| ye aes. human | BARA D MED BRE1 longevity | by ene ON YON‘ analyzing t x two ¢ ) additional ((cid:29)%9 pee eee> markers, 1 which ] “ars| lie i in t | the | - Insulin ( 6(cid:24):(cid:1)7 oN) and | | Insulin ¢ EL IO1 Growth | ey OD| Factor  7“ DOE I ILE) (IGF2) | ‘eo *umes) genes. | _ Both 1 | the genes, | , which < are | localized « | downstream me Mane1 TH, < eye, are i > indeed | good « | candidates i in | <-e =! &| longevity, :     oo”ont \ the | > basis «  (cid:11)* f laboratory :   ine  1 experimental 1 ms Ee| models. | . Neither | INS 1 nor | rotorp IGF2 1 vves J See. markers « s did 1 | reveal association \  . with | NDE OIE JOM1 longevity. ] ND ARE EN IE. Nevertheless, | , linkage « > disequilibrium <     | sex-specific | > long- evity | ociations |  EO NEST *| defined | by | both ’ | TH-INS | and ' NN EE| TH-IGF2 | EEE LEAST OE| haplotypes. | <(cid:12) | the» ees Ps- whole, | the | materesults Nees Sewreinforce 1 > the i - involvement « (cid:11)* aoeF the « > chromosomal 1 | region :  ae OT| spanning { *(cid:21)(cid:11)" peerTH t [to | ) IGF2 | . loci i i in « . controlling the | - longevity | : phenotype i in |     (cid:30)00(cid:31) ee ANEElsevier | Op ee‘Science | offInc. Alls | rights 1 : reserved.

Keywords: (  : Centenarians; “ ; TH | [ gene; | , INS s } gene; | ; IGF2 s » gene; | ; Linkage > disequilibrium

 , Introduction

show t / that t t the ¢ _eee MEE EES”> concerted < Ste eee| action « (cid:11)* NF OIE NTf stress-response | ey ee ES> pathways < s and EEA ADEI INE IIIS EY DLE INA IAEA| energy-producing 1 TE, mechan- isms 1 is | likely | to | ) be : > an ¢ | evolutionarily : ee ee‘successful : ~ pene ey| strategy | yee' for | we EEE TF‘long-term i reese”| individual : | survival

’ Corresponding ; - author. . _ Address: | - Department « (cid:11)* F Cell | | Biology, | , University « (cid:11)* * Calabria, | 2A0/0 ) Rende, | Italy. Tel.: ; (cid:1)/3(cid:4)32D(cid:4)D3(cid:30)3/(cid:31)1 *(cid:17)(cid:3)? (cid:1)/3(cid:4)32D(cid:4)D3(cid:30)3(cid:31)(cid:31)!

0 531-5 @ B0(cid:31)BC  see | > front 1 t matter  (cid:30)00(cid:31) | Elsevier r Science | > Inc. 4 . All | rights 1 s reserved. 9(cid:24)(cid:24)? (cid:1)0 531-5 @ 60(cid:31)700(cid:31)D@(cid:4)(cid:30)

1004 M. De Luca et al. / Experimental Gerontology 30 (2001) 1005-1071TH varR INS IGF2EL/m— 91/2“i { smHUMTHO1 INSFok| \GF2Avall 

Fig. | (cid:31)! . Diagrammatic > representation ¢ (cid:11)* fthe 7 > TH-INS-IGF2 r region ( 6(cid:1)D0 5(cid:19)7 ) onc 1 chromosome | 2 11p15 ! 5 showing t x the “*5: **three | EN I OLIN- polymorphisms | aN phone; studied. ¢ _ Open, _ closed ; | and | | hatched |  ive \| boxes eX oom”; depict i I NE| introns, ¢ | EXONS sand | aap AS oem| untraslated 1 aN NA| regions, wee pee yaarespectively, ¢ me pene, and t | the t > triangle « ae NPN> depicts t the ] (cid:24):(cid:1)(cid:4),:(cid:20)( locus.

wea ae:robust and NA SN ALLL IISAreproducible ee ee eeemeans (cid:11)* LImodulating life-span and the — Nbest easy aeexample (cid:11)* the complex a eee eerelationship between nutritional eebalancing, stress response |and ren eeelongevity eee eee(Masoro, (cid:31)33 1 Lee « et i (cid:17)(cid:10)!& (cid:31)3337! . Consistently, | .( PEED ED OEconfers 1 } tO 1 eeerodents an j . improved ; at — ee| ability Meratos ve eee) survive | ae eee- heat-stress sand | eg RA AA"| promotes sas L series « (cid:11)* DN EE NINE NEEf neuro-endocrine ¢ > changes | “ees leading x to ¢ ed) efficient glucose | - regulation |  ) and | see pee| improved | | insulin-sensitivity | (Leakey | et i (cid:17)(cid:10)!& (cid:31)33D7!