Modulation of human longevity by single nucleotide “ polymorphisms in the prospective study Treviso Longeva ” (TRELONG)

Diego Albani & Eleonora Ateri & Stefano Mazzuco & Alice Ghilardi & Serena Rodilossi & Gloria Biella & Fausta Ongaro & Piero Antuono & Paolo Boldrini & Enrico Di Giorgi & Andrea Frigato & Elisabetta Durante & Livio Caberlotto & Andrea Zanardo & Marinella Siculi & Maurizio Gallucci & Gianluigi Forloni

Received: 13 December 2012 /Accepted: 24 June 2013 # American Aging Association 2013

SIRT3 investigate whether variants within gene were associated to human longevity. We analyzed 549 geno- mic DNA collected during the prospective study “ ” Treviso Longeva, including elderly over 70 years of

Abstract Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to

Electronic supplementary material The online version of this article (doi:10.1007/s11357-013-9559-2) contains supplementary material, which is available to authorized users.

D. Albani (*) E. Ateri A. Ghilardi S. Rodilossi : G. Biella G. Forloni Department of Neuroscience, IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri”, via La Masa

,

Milan, Italy e-mail: diego.albani@marionegri.it

e-mail: mazzuco@stat.unipd.it

P. Antuono

e-mail: elly.a

@gmail.com A. Ghilardi e-mail: alice.ghilardi@marionegri.it S. Rodilossi e-mail: serena.rodilossi@marionegri.it G. Biella e-mail: gloria.biella@marionegri.it G. Forloni e-mail:

P. Antuono

e-mail: PAntuono@mcw.edu

Department of Statistics, University of Padova, Via Cesare Battisti, 241, 35121 Padova, Italy

e-mail: mgallucci@ulss.tv.it

age from the municipality of Treviso, a small city in the SIRT3 northeast of Italy. We genotyped rs3825075, rs4980329, and rs11555236 single nucleotide polymor- phisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a depen- SIRT3 dent variable, we observed an association of rs11555236 and rs4980329 with longevity in the whole p population ( values corrected for potential con- founders=0.04 and 0.03, respectively). After stratifica- tion according to gender, the same SNPs were associat- p ed to female longevity only ( values corrected for potential confounders=0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer with- SIRT3 in the gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3

protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for SIRT3 the (T) allele. We suggest that genetic variability might be relevant for the modulation of human longev- ity in the Italian population.

Background

proteins sharing NAD+-dependent deacetylase activity that seems involved in several basic physiologic mecha- nisms and relevant for age-linked diseases (Albani et al. 2010; Polito et al. 2010). Among SIRTs, SIRT3 is a mitochondrial protein involved in defensive mechanisms against oxidative stress (Yu et al. 2012; Bause and Haigis 2012; Iwahara et al. 2012). Considering that oxidative stress increase is a basic feature of aging, SIRT3 may have a role in modulating longevity, a hypothesis sup- ported by evidence in an animal model, where the dis- ruption of the gene coding for angiotensin II receptor type 1A resulted in marked prolongation of life span in mice, with an increased number of mitochondria in the kidney SIRT3 and upregulation of prosurvival genes (including ) (Benigni et al. 2009). Moreover, genetic association stud- SIRT3 ies pointed out a role for in human longevity. The SIRT3 single nucleotide polymorphism (SNP) rs11555236 minor allele (T) increased male survival in an Italian cohort from Calabria and was found in linkage disequilibrium with a putative enhancer located within SIRT3 intron 5 (Bellizzi et al. 2005; Rose et al. 2003). In a different multicentre study that recruited centenarians from Italy and Germany (for a total of 1,321 centenarians SIRT3 and 1,140 younger subjects), some SNPs in showed significant association with longevity in the Italian female and in the German male subgroups, al- though this result was not supported by a replication enrolling centenarians of French ancestry (Lescai et al. 2009). Moreover, in a study analyzing genetic variants of the oldest old, a list of SIRT3 SNPs was detailed in long- living individuals of Caucasian ancestry (Halaschek- Wiener et al. 2009). Starting from the evidence SIRT3 supporting an involvement of in longevity, we SIRT3 genotyped three SNPs of in an ongoing prospec- tive study enrolling an elderly population (Treviso Longeva (TRELONG) study; Gallucci et al. 2007).

E. Di Giorgi

Territorial Health Services of Treviso, Via Isola di Mezzo, 37, 31100 Treviso, Italy

e-mail: edigiorgi@ulss.tv.it

Transfusional Department, General Hospital of Treviso, Piazza Ospedale, 1, 31100 Treviso, Italy

A. Frigato e-mail: afrigato@ulss.tv.it

P. Boldrini M. Gallucci Cognitive Impairment Centre, General Hospital of Treviso, Piazza Ospedale, 1, 31100 Treviso, Italy

e-mail: lcaberlotto@ulss.tv.it

e-mail: azanardo@ulss.tv.it

FORGEI, Interdisciplinary Geriatric Research Foundation, Viale Trento Trieste 19, 31100 Treviso, Italy