3. Barja G, Cadenas S, Rojas C, Lopez-Torres M, Perez-Campo R (1994) A decrease of free radical production near critical targets as a cause of maximum longevity in animals. Comp Biochem Physiol Biochem Mol Biol 108: 501–512. 4. Gredilla R, Sanz A, Lopez-Torres M, Barja G (2001) Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. Faseb J 15: 1589–1591. 5. Kalani R, Judge S, Carter C, Pahor M, Leeuwenburgh C (2006) Effects of caloric restriction and exercise on age-related, chronic inflammation assessed by C-reactive protein and interleukin-6. J Gerontol A Biol Sci Med Sci 61: 211–217. 6. Mair W, Goymer P, Pletcher SD, Partridge L (2003) Demography of dietary restriction and death in Drosophila. Science 301: 1731–1733. 7. Ramsey JJ, Harper ME, Weindruch R (2000) Restriction of energy intake, energy expenditure, and aging. Free Radic Biol Med 29: 946–968. 8. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264: 1772–1775. 9. Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA (2005) Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse. Muscle Nerve 31: 214–220. 10. Hamadeh MJ, Tarnopolsky MA (2005) Long-term caloric restriction hastens clinical onset, disease progression and endpoint in the Cu/Zn-SOD mutant G93A mouse, an animal model of ALS. Ann Nutr Metab 49: 164 (abst.). 11. Hamadeh MJ, Tarnopolsky MA (2006) Transient caloric restriction in early adulthood hastens disease endpoint in male, but not female, Cu/Zn-SOD mutant G93A mice. Muscle Nerve 34: 709–719. 12. Sango K, McDonald MP, Crawley JN, Mack ML, Tifft CJ, et al. (1996) Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nat Genet 14: 348–352. 13. Weydt P, Hong SY, Kliot M, Moller T (2003) Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport 14: 1051–1054. 14. Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods En- zymol 186: 407–421. 15. Aebi H (1984) Catalase in vitro. Methods Enzymol 105: 121–126. 16. Parise G, Kaczor J, Mahoney J, Phillips S, Tarnopolsky M (2004) Oxidative stress and the mitochondrial theory of aging in human skeletal muscle. Experimental Gerontology 39: 1391–1400. 17. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, et al. (2004) The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 36: 1043–1057. 18. Seng JE, Agrawal N, Horsley ET, Leakey TI, Scherer EM, et al. (2003) Toxicokinetics of chloral hydrate in ad libitum-fed, dietary-controlled, and calorically restricted male B6C3F1 mice following short-term exposure. Toxicol Appl Pharmacol 193: 281–292. 19. Stein O, Dabach Y, Halperin G, Ben-Naim M, Stein Y (2003) Calorie restriction in mice does not affect LDL reverse cholesterol transport in vivo. Biochem Biophys Res Commun 308: 29–34. 20. Wu A, Sun X, Liu Y (2003) Effects of caloric restriction on cognition and behavior in developing mice. Neurosci Lett 339: 166–168. 21. Andrews ZB, Diano S, Horvath TL (2005) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6: 829–840. 22. Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, et al. (1999) Nutritional status is a prognostic factor for survival in ALS patients. Neurology 53: 1059–1063. 23. Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ (1996) Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr 63: 130–137. 24. Slowie LA, Paige MS, Antel JP (1983) Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS). J Am Diet Assoc 83: 44–47. 25. Mattson MP, Cutler RG, Camandola S (2007) Energy intake and amyotrophic lateral sclerosis. Neuromolecular Med 9: 17–20. 26. Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, et al. (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4: e76. 27. Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, et al. (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 103: 1768–1773. 28. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, et al. (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310: 314–317. 29. Wong LJ (2007) Diagnostic challenges of mitochondrial DNA disorders. Mitochondrion 7: 45–52. 30. Joseph AM, Rungi AA, Robinson BH, Hood DA (2004) Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects. Am J Physiol Cell Physiol 286: C867–875. 31. Heddi A, Stepien G, Benke PJ, Wallace DC (1999) Coordinate induction of energy gene expression in tissues of mitochondrial disease patients. J Biol Chem 274: 22968–22976. Caloric Restriction and ALS 32. Mahoney DJ, Kaczor JJ, Bourgeois J, Yasuda N, Tarnopolsky MA (2006) Oxidative stress and antioxidant enzyme upregulation in SOD1-G93A mouse skeletal muscle. Muscle Nerve 33: 809–816. 33. Andrus PK, Fleck TJ, Gurney ME, Hall ED (1998) Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 71: 2041–2048. 34. Bogdanov MB, Ramos LE, Xu Z, Beal MF (1998) Elevated ‘‘hydroxyl radical’’ generation in vivo in an animal model of amyotrophic lateral sclerosis. J Neurochem 71: 1321–1324. 35. Gruber J, Schaffer S, Halliwell B (2008) The mitochondrial free radical theory of ageing–where do we stand? Front Biosci 13: 6554–6579. 36. Davis LJ, Tadolini B, Biagi PL, Walford R, Licastro F (1993) Effect of age and extent of dietary restriction on hepatic microsomal lipid peroxidation potential in mice. Mech Ageing Dev 72: 155–163. 37. Koizumi A, Weindruch R, Walford RL (1987) Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice. J Nutr 117: 361–367. 38. Judge S, Judge A, Grune T, Leeuwenburgh C (2004) Short-term CR decreases cardiac mitochondrial oxidant production but increases carbonyl content. Am J Physiol Regul Integr Comp Physiol 286: R254–259. 39. Gursoy E, Cardounel A, Hu Y, Kalimi M (2001) Biological effects of long-term caloric restriction: adaptation with simultaneous administration of caloric stress plus repeated immobilization stress in rats. Exp Biol Med (Maywood) 226: 97–102. 40. Gredilla R, Barja G, Lopez-Torres M (2001) Effect of short-term caloric restriction on H2O2 production and oxidative DNA damage in rat liver mitochondria and location of the free radical source. J Bioenerg Biomembr 33: 279–287. 41. Lass A, Sohal BH, Weindruch R, Forster MJ, Sohal RS (1998) Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med 25: 1089–1097. 42. Sato A, Huang MZ, Watanabe S, Okuyama H, Nakamoto H, et al. (1998) Protein carbonyl content roughly reflects the unsaturation of lipids in muscle but not in other tissues of stroke-prone spontaneously hypertensive strain (SHRSP) rats fed different fats and oils. Biol Pharm Bull 21: 1271–1276. 43. Sen CK, Atalay M, Agren J, Laaksonen DE, Roy S, et al. (1997) Fish oil and vitamin E supplementation in oxidative stress at rest and after physical exercise. J Appl Physiol 83: 189–195. 44. Fergani A, Oudart H, De Aguilar JL, Fricker B, Rene F, et al. (2007) Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis. J Lipid Res 48: 1571–1580. 45. Mittendorfer B, Horowitz JF, Klein S (2001) Gender differences in lipid and glucose kinetics during short-term fasting. Am J Physiol Endocrinol Metab 281: E1333–1339. 46. Hill JO, Talano CM, Nickel M, DiGirolamo M (1986) Energy utilization in food-restricted female rats. J Nutr 116: 2000–2012. 47. Borras C, Sastre J, Garcia-Sala D, Lloret A, Pallardo FV, et al. (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34: 546–552. 48. Vina J, Sastre J, Pallardo F, Borras C (2003) Mitochondrial theory of aging: importance to explain why females live longer than males. Antioxid Redox Signal 5: 549–556. 49. Valle A, Guevara R, Garcia-Palmer FJ, Roca P, Oliver J (2007) Sexual dimorphism in liver mitochondrial oxidative capacity is conserved under caloric restriction conditions. Am J Physiol Cell Physiol 293: C1302–1308. 50. Behrens WA, Himms-Hagen J (1977) Alteration in skeletal muscle mitochondria of cold-acclimated rats: association with enhanced metabolic response to noradrenaline. J Bioenerg Biomembr 9: 41–63. 51. Moien-Afshari F, Ghosh S, Khazaei M, Kieffer TJ, Brownsey RW, et al. (2008) Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice. Diabetologia 51: 1327–1337. 52. Kim JD, Yu BP, McCarter RJ, Lee SY, Herlihy JT (1996) Exercise and diet modulate cardiac lipid peroxidation and antioxidant defenses. Free Radic Biol Med 20: 83–88. 53. Minamiyama Y, Bito Y, Takemura S, Takahashi Y, Kodai S, et al. (2007) Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats. J Pharmacol Exp Ther 320: 535–543. 54. Dupuis L, di Scala F, Rene F, de Tapia M, Oudart H, et al. (2003) Up- regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. Faseb J 17: 2091–2093. 55. Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME (2005) Long- term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab 289: E429–438. 56. Higami Y, Pugh TD, Page GP, Allison DB, Prolla TA, et al. (2004) Adipose tissue energy metabolism: altered gene expression profile of mice subjected to long-term caloric restriction. Faseb J 18: 415–417. 57. Barber SC, Mead RJ, Shaw PJ (2006) Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta 1762: 1051–1067. 58. Goodall EF, Morrison KE (2006) Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment. Expert Rev Mol Med 8: 1–22. PLoS ONE | www.plosone.org 16 February 2010 | Volume 5 | Issue 2 | e9386