Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS

PLoS One. 2010 Feb 24;5(2):e9386. doi: 10.1371/journal.pone.0009386.


Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS--citrate synthase content and activity, cytochrome c oxidase--COX activity and protein content of COX subunit-I and IV and UCP3-uncoupling protein 3), oxidative damage (MDA--malondialdehyde and PC--protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-alpha), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-alpha was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Apoptosis / physiology*
  • Blotting, Western
  • Body Weight / physiology
  • Caloric Restriction / adverse effects*
  • Catalase / metabolism
  • Disease Models, Animal
  • Eating / physiology
  • Electron Transport Complex IV / metabolism
  • Female
  • Humans
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Lipid Peroxidation / physiology*
  • Longevity / physiology*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Motor Activity / physiology
  • Sex Factors
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / metabolism


  • Tumor Necrosis Factor-alpha
  • Catalase
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Electron Transport Complex IV