title: Neurons from senescence-accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol.
abstract: The senescence-accelerated prone 8 (SAMP8) mouse strain shows early cognitive loss that mimics the deterioration of learning and memory in the elderly and is widely used as an animal model of aging. SAMP8 mouse brain suffers oxidative stress, as well as tau- and amyloid-related pathology. Mitochondrial dysfunction and the subsequent increase in cellular oxidative stress are central to the aging processes of the organism. Here, we examined the mitochondrial status of neocortical neurons cultured from SAMP8 and senescence-accelerated-resistant (SAMR1) mice. SAMP8 mouse mitochondria showed a reduced membrane potential and higher vulnerability to inhibitors and uncouplers than SAMR1 mitochondria. DL-buthionine-[S,R]-sulfoximine (BSO) caused greater oxidative damage in neurons from SAMP8 mice than in those from SAMR1 mice. This increased vulnerability, indicative of frailty-associated senescence, was protected by the anti-aging agents melatonin and resveratrol. The sirtuin 1 inhibitor, sirtinol, demonstrated that the neuroprotection against BSO was partially mediated by increased sirtuin 1 expression. Melatonin, like resveratrol, enhanced sirtuin 1 expression in neuron cultures of SAMR1 and SAMP8 mice. Therefore, a deficiency in the neuroprotection and longevity of the sirtuin 1 pathway in SAMP8 neurons may contribute to the early age-related brain damage in these mice. This supports the therapeutic use of sirtuin 1-enhancing agents against age-related nerve cell dysfunction and brain frailty.
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Cristòfol
authors.forename: David
authors.initials: D
authors.lastname: Porquet
authors.forename: Rubén
authors.initials: R
authors.lastname: Corpas
authors.forename: Ana
authors.initials: A
authors.lastname: Coto-Montes
authors.forename: Jofre
authors.initials: J
authors.lastname: Serret
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.forename: Coral
authors.initials: C
authors.lastname: Sanfeliu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D008550:Melatonin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D013267:Stilbenes; D056564:Sirtuin 1; D008550:Melatonin; D000077185:Resveratrol