A Novel VNTR Enhancer Within the SIRT3 Gene, a Human Homologue of SIR2, Is Associated With Survival at Oldest Ages

Genomics. 2005 Feb;85(2):258-63. doi: 10.1016/j.ygeno.2004.11.003.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Enhancer Elements, Genetic / genetics*
  • Female
  • Histone Deacetylases / genetics*
  • Humans
  • Longevity / genetics*
  • Male
  • Middle Aged
  • Minisatellite Repeats*
  • Mitochondrial Proteins / genetics*
  • Molecular Sequence Data
  • Polymorphism, Genetic*
  • Sirtuin 3
  • Sirtuins

Substances

  • Mitochondrial Proteins
  • SIRT3 protein, human
  • Sirtuin 3
  • Sirtuins
  • Histone Deacetylases