Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. ; This work was supported by grants from the European Commission [FP7-241622], the Spanish Institute for Health Carlos III [FIS PI11/01043], the Oliver’s Army Foundation, the Government of Catalonia [2009SGR85 to AP], the Spanish Institute for Health Carlos III [Miguel Servet program CP11/00080 to S.F.], the European Leukodystrophy Association (ELA) [ELA 2010-020F1 to SF, ELA 2013-003F1 to LM], the Spanish Ministry of Education [FPU program AP2008-03728 to LM]. JG held an IDIBELL PhD fellowship. The studies conducted at the Experimental Medicine Department were supported in part by R+D grants from the Spanish Ministry of Science and Innovation [BFU2009-11879/BFI], the Spanish Ministry of Health [PI081843, PI1300584], the Government of Catalonia [2009SGR735], the 'La Caixa' Foundation and COST B35 Action of the European Union. CIBERER and CIBERNED are initiatives of the Spanish Institute for Health Carlos III.