Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly
Introduction
The human sirtuin 3 (SIRT3) gene codes for a mitochondrial protein (SIRT3) (Schwer et al., 2002, Onyango et al., 2002) which is homologous to the yeast protein Sir2p (silent information regulator 2 protein) the founding member of a large family of NAD+ dependent protein deacetylases named sirtuins (Smith et al., 2000). The SIR2 gene is a key determinant in yeast lifespan: indeed null mutations of SIR2 shorten while an extra-copy of SIR2 extends lifespan, probably through chromatin silencing in the ribosomal DNA repeats (Kaeberlein et al., 1999, Sinclair and Guarente, 1997). Also in C. elegans a SIR2 homologue, sir-2.1, seems to modulate lifespan through a mechanism actually unknown, but probably associated with the insulin signalling pathway (Tissenbaum and Guarente, 2001). The role played by Sir2p as NAD+ dependent protein deacetylase links cellular metabolism, transcriptional silencing and ageing (Guarente, 2000) and it has been proposed that SIR2 genes may regulate ageing in many species, possibly by coordinating the pace of ageing to the metabolic rate (Guarente and Kenyon, 2000, Guarente, 2001).
The SIRT3 gene (www.ncbi.nlm.nih.gov/omim: MIM 604481; contig NT_035113) lies at the telomeric terminal on 11p15.5 chromosome. Allelic association studies carried out in people older than 100 years showed that a relationship exists between longevity and polymorphism of four genes located in this region. In particular, by analysing an STR marker of the Tyrosine Hydroxylase (TH) gene, as well as the haplotypes defined by this marker and RFLPs of Proinsulin (INS) and Insulin-like Growth Factor 2 (IGF2) genes, significant age-related variations of the allelic pool had been observed (De Luca et al., 2001, Tan et al., 2002); similar age-related variations were also found for the 3′VNTR marker of the HRAS1 gene (Bonafè et al., 2002). The HRAS1 gene (contig NT_035113) lies at 0.665 Mb from the telomere, while the genes IGF2, INS and TH lie at 2.112, 2.140, and 2.145 Mb, respectively, from the telomeric terminal and are comprised within the contig NT_028310. Therefore, within a short piece of chromosome, five genes potentially involved in longevity are located.
The effect exerted on yeast and worm lifespan by sirtuin 2 genes, as well as the location of SIRT3 in the 11p15.5 chromosomal region, prompted us to investigate whether variants of this gene were associated with longevity. Since polymorphisms of SIRT3 were not known, we first searched for variability in the SIRT3 region encoding for a core domain that contains short motifs of conserved amino acids (Frye, 1999, Frye, 2000). After the identification of a SNP marker in exon 3, we used this marker in searching for possible modifications of the genetic pool which may occur as the population ages and survival selection operates.
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Population sample
An appropriate campaign of recruitment was launched in Calabria (southern Italy) for genetic studies on ageing in 1999, excepted for centenarians whose recruitment started beginning from 1994. The recruitment campaign was focused on University students and staff for 18–60 years old people, thermal baths and aged people-Academy for 60–80 years old people. As to the centenarians, they were identified through the birth registers of the Municipalities of Calabria and then contacted. Only subjects
Results
By searching for variability in the evolutionary conserved domain of the SIRT3 gene (exon 2–exon 3) we identified a silent G/T transversion at the position 477 of the coding region (G477T corresponding to Ser159Ser; AF083108). We used this marker to investigate possible modifications of the SIRT3 gene pool in people of increasing age, including the oldest old. We found that, in males, the TT genotype increased (p=0.0272) while the GT genotype decreased (p=0.0391) the value of the survival
Discussion
By applying a demographic-genetic approach (Yashin et al., 1999) a significant variation of the survivorship, related to the genotypes defined by the G477T polymorphism of the SIRT3 gene, was found in the elderly. Although the possibility that such association is due to chance cannot be ruled out, the statistical significance of the finding seems to be sound. On the other hand the possibility that the association between SIRT3 variability and survival were due to population stratification is
Supplementary material
The following supplementary material is available on the web site of the Department of Cell Biology of the University of Calabria: http://biologia.unical.it/genetica.
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A graph reporting the survival curve of the general Italian population (year 2000)
- 2.
A map of the chromosome 11p15.5 region, showing the—in scale—position of the genes HRAS1, SIRT3, IGF2, INS and TH
- 3.
The table of allele and genotypic frequencies in the whole sample (Table S1).
Acknowledgements
Work financed by the Italian Ministry of Scientific Research and Technology (PRIN 2000–2002 Genetics Determinant of Human Longevity), by the Italian Ministry of Health (IRCCS project 2000–2002. Marcatori genetici e biologici di invecchiamento normale e patologico) and by the EU project ‘European Challenge for Healthy Ageing’ (ECHA, No. QLRT-2001-00128, Call Identifier: QOL-2001-3).
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These authors contributed equally.