Long-lived αMUPA transgenic mice show reduced SOD2 expression, enhanced apoptosis and reduced susceptibility to the carcinogen dimethylhydrazine

Oren Tirosh, Michal Pardo, Betty Schwartz, Ruth Miskin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Calorie restriction (CR) extends the life span of various species through mechanisms that are as yet unclear. Recently, we have reported that mitochondrion-mediated apoptosis was enhanced in αMUPA transgenic mice that spontaneously eat less and live longer compared with their wild-type (WT) control mice. To understand the molecular mechanisms underlying the increased apoptosis, we compared αMUPA and WT mice for parameters associated with SOD2 (MnSOD), a mitochondrial antioxidant enzyme that converts superoxide radicals into H2O2 and is also known to inhibit apoptosis. The SOD2-related parameters included the levels of SOD2 mRNA, immunoreactivity and enzymatic activity in the liver, lipid oxidation and aconitase activity in isolated liver mitochondria, and the sensitivity of the mice to paraquat, an agent that elicits oxidative stress. In addition, we compared the mice for the levels of SOD2 mRNA after treatment with bacterial lipopolysaccharides (LPS), and for the DNA binding activity of NFκB as a marker for the inflammatory state. We extended SOD2 determination to the colon, where we also examined the formation of pre-neoplastic aberrant crypt foci (ACF) following treatment with dimethylhydrazine (DMH), a colonic organotypic carcinogen. Overall, αMUPA mice showed reduced basal levels of SOD2 gene expression and activity concomitantly with reduced lipid oxidation, increased aconitase activity and enhanced paraquat sensitivity, while maintaining the capacity to produce high levels of SOD2 in response to the inflammatory stimulus. αMUPA mice also showed increased resistance to DMH-induced pre-neoplasia. Collectively, these data are consistent with a model, in which an optimal fine-tuning of SOD2 throughout a long-term regimen of reduced eating could contribute to longevity, at least in the αMUPA mice.

Original languageAmerican English
Pages (from-to)1262-1273
Number of pages12
JournalMechanisms of Ageing and Development
Issue number12
StatePublished - Dec 2005

Bibliographical note

Funding Information:
We are grateful to Dr. O. Brenner for histologic examination of the mice, and to Ms. R. Abramovitz for excellent technical assistance. The project was supported, in part, by the Crown Endowment Fund at the Weizmann Institute of Science (to R.M.), and by the Hebrew University internal grants no. 0346436 and 0346456 (to O.T.).


  • ACF
  • Apoptosis
  • Calorie restriction
  • Mitochondria
  • MnSOD
  • SOD2
  • αMUPA transgenic mice


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