Elsevier

Genomics

Volume 85, Issue 2, February 2005, Pages 258-263
Genomics

A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages

https://doi.org/10.1016/j.ygeno.2004.11.003Get rights and content

Abstract

SIR2 genes control life span in model organisms, playing a central role in evolutionarily conserved pathways of aging and longevity. We wanted to verify whether similar effects may act in humans too. First, we searched for variability in the human sirtuin 3 gene (SIRT3) and discovered a VNTR polymorphism (72-bp repeat core) in intron 5. The alleles differed both for the number of repeats and for presence/absence of potential regulatory sites. Second, by transient transfection experiments, we demonstrated that the VNTR region has an allele-specific enhancer activity. Third, by analyzing allele frequencies as a function of age in a sample of 945 individuals (20–106 years), we found that the allele completely lacking enhancer activity is virtually absent in males older than 90 years. Thus the underexpression of a human sirtuin gene seems to be detrimental for longevity as it occurs in model organisms.

Section snippets

Results

To identify variability in the functional domains of SIRT3, we conducted DNA sequence analyses of PCR fragments around the FGE conserved motif (exon 5) in a panel of 50 unrelated subjects (25 males and 25 females randomly chosen from sample 1). We observed a VNTR polymorphism having a 72-bp core in the fifth intron of the gene (12,343 nt initial position referring to www.ncbi.nlm.nih.gov/omim; MIM 604481; contig NT_035113). After verification of Mendelian inheritance in 30 parent/offspring

Discussion

The aim of this study was to identify a putative functional variant occurring in SIRT3 that could account for the association previously observed between longevity and a silent marker of this gene [15]. Transfection experiments demonstrated that the VNTR we identified in intron 5 of SIRT3 is a functional polymorphism and that different VNTR alleles are able to modulate the expression of a reporter gene in an allele-specific way, according to number of repeats and occurrence of GATA3/DeltaEF1

Population samples

A population sample of 945 subjects was analyzed. All the subjects lived in Calabria (southern Italy) and their origin in the area was ascertained up to the grandparents’ generation (interview). The sample consisted of two subsamples: sample 1 was made up of 20- to 80-year-old subjects (median age 59 years); sample 2 was made up of 90- to 106-year-old subjects (median age 102 years). Sample 1 comprised 703 subjects (312 males and 391 females); sample 2 comprised 242 subjects (86 males and 156

Acknowledgments

The authors thank the Municipalities of Calabria (southern Italy) and all the persons who participated in the study for their precious collaboration. This work was financed by the EU project “European Challenge for Healthy Aging” (No. QLRT-2001-00128, Call Identifier QOL-2001-3) and by the Italian Ministry of Instruction, University, and Research (FIRB/2001; project “Identificazione di profili genomici nucleo-mitocondriali nella patogenesi di malattie comuni età-associate. Implicazioni

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    These authors contributed equally to this work.

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