Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice

W. H. Boylston, James H. DeFord, John Papaconstantinou

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Recent landmark molecular genetic studies have identified an evolutionarily conserved insulin/IGF-1 signal transduction pathway that regulates lifespan. In C. elegans, Drosophila, and rodents, attenuated insulin/IGF-1 signaling appears to regulate lifespan and enhance resistance to environmental stress. The Ames (Prop1 df/df ) and Snell (Pit1 dw/dw ) hypopituitary dwarf mice with growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin deficiencies live 40-60% longer than control mice. Both mutants are resistant to multiple forms of environmental stress in vitro. Taken collectively, these genetic models indicate that diminished insulin/IGF-l signaling may play a central role in the determination of mammalian lifespan by conferring resistance to exogenous and endogenous stressors. These pleiotropic endocrine pathways control diverse programs of gene expression that appear to orchestrate the development of a biological phenotype that promotes longevity. With the ability to investigate thousands of genes simultaneously, several microarray surveys have identified potential longevity assurance genes and provided information on the mechanism(s) by which the dwarf genotypes (dw/dw) and (df/df), and caloric restriction may lead to longevity. We propose that a comparison of specific changes in gene expression shared between Snell and Ames dwarf mice may provide a deeper understanding of the transcriptional mechanisms of longevity determination. Furthermore, we propose that a comparison of the physiological consequences of the Pit1dw and Prop1df mutations may reveal transcriptional profiles similar to those reported for the C. elegans and Drosophila mutants. In this study we have identified classes of genes whose expression is similarly affected in both Snell and Ames dwarf mice. Our comparative microarray data suggest that specific detoxification enzymes of the P450 (CYP) family as well as oxidative and steroid metabolism may play a key role in longevity assurance of the Snell and Ames dwarf mouse mutants. We propose that the altered expression of these genes defines a biochemical phenotype which may promote longevity in Snell and Ames dwarf mice.

Original languageEnglish (US)
Pages (from-to)125-144
Number of pages20
JournalAge
Volume28
Issue number2
DOIs
StatePublished - Jun 2006

Fingerprint

Genes
Gene Expression
Insulin
Insulin-Like Growth Factor I
Drosophila
Phenotype
Caloric Restriction
Genetic Models
Hypothyroidism
Prolactin
Cytochrome P-450 Enzyme System
Growth Hormone
Molecular Biology
Rodentia
Signal Transduction
Steroids
Genotype
Mutation
Surveys and Questionnaires
In Vitro Techniques

Keywords

  • Aging
  • Ames Dwarf
  • Detoxification
  • Metabolism
  • P450
  • PPAR
  • ROS
  • Snell Dwarf
  • Steriod

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Cite this

Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice. / Boylston, W. H.; DeFord, James H.; Papaconstantinou, John.

In: Age, Vol. 28, No. 2, 06.2006, p. 125-144.

Research output: Contribution to journalArticle

Boylston, W. H. ; DeFord, James H. ; Papaconstantinou, John. / Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice. In: Age. 2006 ; Vol. 28, No. 2. pp. 125-144.
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