linked to increased survival at oldest ages (Tazearslan SIRT3 et al. 2012). To this respect, deserves attention both for its role in mitochondrial homeostasis, a funda- mental aspect of cell physiology, and for the available SIRT3 data associating to survival in animal models or in the elderly (Benigni et al. 2009; Halaschek-Wiener et al. 2009; Rose et al. 2003; Bellizzi et al. 2005). We have decided to analyze an informative set of SNPs of SIRT3 gene in a prospective study (TRELONG) allowing us to have access to survival data over a 7- year follow-up. This work has been carried out in a unique group of subjects: a community-based popula- tion with the highest longevity rates in Italy (Gallucci et al. 2007). To this respect, our analysis reflects closely SIRT3 the correlation between and longevity in the Italian population in the real world. As in a previous genetic study performed in our laboratory where we had SIRT3 already investigated a panel of SNPs (Polito et al. 2013), we decided to select from this panel those SIRT3 matching or tagging a list of genetic variants whose presence was highlighted in a population of Caucasian elderly, suggesting their involvement in a prosurvival background (Halaschek-Wiener et al. 2009). Thanks to the existence of linkage disequilibrium SIRT3 blocks within , we were able to choose a couple of SNPs from Polito et al. (2012) (rs3825075 and rs4980329) that were linked to the SNPs rs511744 and rs11246020 reported by Halaschek-Wiener et al. (2009; Fig. 1). The third SNP, rs11555236, was linked to longevity in an Italian study and supposed to be in linkage disequilibrium with a putative functional enhanc- er (a variable number of tandem repeat (VNTR) SIRT3 element) located within intron 5 (Bellizzi et al. 2005). The cross-sectional association study was performed by splitting the TRELONG population around 85 years, a critical point discriminating long-living in- dividuals that has allowed us to find other informative genetic variability in the same population (Albani et al. 2009). However, no association was found with this experimental design. To reanalyze data taking into ac- count the real survival curve of each subject, a prospec- tive analysis was conducted by inputting mortality data of the TRELONG study over a 7-year follow-up. The main result was the association between rs11555236 and

ture, we have not performed in the present study the assessment of the putative VNTR enhancer element of SIRT3 gene described by Bellizzi et al. (2005), but taking advantage from its reported linkage disequilib- rium with rs11555236, we decided to further investi- gate the functional action of the VNTR element in a group of TRELONG subjects bearing the rs11555236 variants. We hypothesized that some sequences of the cis SIRT3 VNTR element acted as a -enhancer on gene, leading to an increase of SIRT3 protein level. We verified this by measuring SIRT3 protein expression in PBMCs, as this was the only available tissue spec- imen from the TRELONG study. Our observation that the (T) allele, that correlated with longevity, was also associated to an increased level of SIRT3 protein is intriguing, as it might suggest that increased SIRT3 level is beneficial, as expected from the current knowl- edge on this protein functions, dealing with response to oxidative stress and control of the mitochondrial acetylome (Bause and Haigis 2012; Fritz et al. 2012).

term survival differently in elderly male and female patients. J Intern Med

:

–

Chung WH, Dao RL, Chen LK, Hung SI (

) The role of genetic variants in human lon- gevity. Ageing Res Rev

(Suppl

):S

–S

Eaton NR, Krueger RF, South SC, Gruenewald TL, Seeman TE, Roberts BW (

) Genes, environments, personality, and successful aging: toward a comprehensive developmental model in later life. J Gerontol A Biol Sci Med Sci

:

–

Fritz KS, Galligan JJ, Hirschey MD, Verdin E, Petersen DR (

) Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT

knockout mice. J Proteome Res

:

–

Gallucci M, Ongaro F, Bresolin F, Bernardi U, Salvato C, Minello A, Amici GP, Barasciutti E, Mazzuco S, Gajo GB, De Angeli S, Forloni GL, Albani D, Zanardo A, Regini C (

) The Treviso Longeva (Trelong) study: a biomedical, demograph- ic, economic and social investigation on people

years and over in a typical town of North-East of Italy. Arch Gerontol Geriatr

(Suppl

):

–

Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, Pieczyk M, Sailer C, Kollar A, Thomas R, Agalaridis G, Yamada S, Oliveira L,Collin

A, Meneilly G, Marra MA,Madden KM, Le ND, Connors JM, Brooks-Wilson AR (

) Genetic variation in healthy oldest-old. PL

One

(

):e

Hallows WC, Albaugh BN, Denu JM (

) Where in the cell is SIRT

?—functional localization of an NAD+-dependent protein deacetylase. Biochem J

:e

–e

Iwahara T, Bonasio R, Narendra V, Reinberg D (

) SIRT

functions in the nucleus in the control of stress-related gene expression. Mol Cell Biol. doi:

/MCB.

-

Lescai F, Blanché H, Nebel A, Beekman M, Sahbatou M, Flachsbart F, Slagboom E, Schreiber S, Sorbi S, Passarino G, Franceschi C (

) Human longevity and

p

: a study in

centenarians. Eur J Hum Genet

:

–

Murabito JM, Yuan R, Lunetta KL (

) The search for lon- gevity and healthy aging genes: insights from epidemiolog- ical studies and samples of long-lived individuals. J Gerontol A Biol Sci Med Sci

:

–

Napolioni V, Carpi FM, Giannì P, Sacco R, Di Blasio L, Mignini F, Lucarini N, Persico AM (

) Age- and gender-specific epistasis between ADA and TNF-α influences human life- expectancy. Cytokine

:

–

Polito L, Kehoe PG, Davin A, Benussi L, Ghidoni R, Binetti G, Quadri P, Lucca U, Tettamanti M, Clerici F, Bagnoli S, Galimberti D, Nacmias B, Sorbi S, Guaita A, Scarpini E, Mariani C, Forloni G, Albani D (

) The SIRT

polymor- phism rs

and risk of Alzheimer's disease in two Caucasian case–control cohorts. Alzheimers Dement

(

):

–