Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression

Am J Pathol. 2007 Jun;170(6):1893-902. doi: 10.2353/ajpath.2007.061281.


Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low(AGE) diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66(shc) levels compared with mice pair-fed the regular (Reg(AGE)) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low(AGE) mice, compared with Reg(AGE) mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Aging / physiology*
  • Animals
  • Body Weight
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism
  • Diet*
  • Dinoprost / analogs & derivatives
  • Dinoprost / blood
  • Eating
  • Glucose / metabolism
  • Glutathione / metabolism
  • Glycation End Products, Advanced / administration & dosage
  • Glycation End Products, Advanced / metabolism
  • Glycation End Products, Advanced / toxicity*
  • Insulin / metabolism
  • Kidney / cytology
  • Kidney / metabolism
  • Kidney / pathology
  • Life Expectancy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidants / metabolism*
  • Oxidative Stress*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Collagen Type IV
  • Glycation End Products, Advanced
  • Insulin
  • Oxidants
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transforming Growth Factor beta1
  • 8-epi-prostaglandin F2alpha
  • Dinoprost
  • Glutathione
  • Glucose