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 frailtyassociated 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.3

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

“…This supports the therapeutic use of sirtuin 1-enhancing agents against age-related nerve cell dysfunction and brain frailty [20].…”

“…The hydroxyl radical is the principal ROS implicated in biologically relevant oxidative stress and is responsible, either directly or indirectly, for most of the free radical damage seen in AD [12][13][14][15][16]. In mice with accelerated senescence, several of the processes associated with mitochondrial dysfunction have been shown to lead [35] to a vicious circle with the formation of more free radicals resulting in neuronal disturbances [17][18][19][20], as shown in Table 1. The higher oxidative stress status observed in SAMP mice is partly due to mitochondrial dysfunction and may be a cause of the senescence acceleration and age-dependent alterations in cell structure and function [21].…”

“…In addition, significant age-dependent mitochondrial dysfunction with diminished efficiency of the electron transport chain and reduced ATP production has been found, accompanied by increased oxidative/nitrosative stress [123,124]. Primary cultured neurons from SAMP8 showed reduced mitochondrial membrane potential and mitochondrial alterations in complexes II and IV [20]. For disturbances at a glance, see Table 3.…”

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…Accordingly, Hemiki et al (2011) proposed that the Q3 level of ROS generation increases gradually with chronological age until it reaches a level at which the toxicity of ROS now participates in creating the damage that it was meant to help alleviate. Thus, ROS-mediated low-dose signaling events, including caloric restriction and the more recently-discovered sirtuins, may converge to improve cell physiology and homeostatic control (Cristòfol et al, 2012;Ristow and Schmeisser, 2014).…”

Environmental Enrichment Improves Behavior, Cognition, and Brain Functional Markers in Young Senescence-Accelerated Prone Mice (SAMP8)

“…These mice present signs of accelerated aging in several organic systems, such as the skin, skeletal muscle, eyes, vessels, and brain [20,22,23]. Brain-related disturbances include cognitive and behavioral alterations, which are accompanied by molecular features typical of Alzheimer disease (AD), such as increased oxidative stress (OS), increased tau phosphorylation, and overproduction of amyloid-beta protein [23][24][25][26][27]. Consequently, under these adverse genetic and developmental conditions, we tested the influence of EE on the early life stage of these mice.…”