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Senescence represents a stage in life associated with elevated incidence of morbidity and increased risk of mortality due to the accumulation of molecular alterations and tissue dysfunction, promoting a decrease in the organism's protective systems. Thus, aging presents molecular and biological hallmarks, which include chronic inflammation, epigenetic alterations, neuronal dysfunction, and worsening of physical status. In this context, we explored the AAV9‐mediated expression of the two main isoforms of the aging‐protective factor Klotho (KL) as a strategy to prevent these general age‐related features using the senescence‐accelerated mouse prone 8 (SAMP8) model. Both secreted and transmembrane KL isoforms improved cognitive performance, physical state parameters, and different molecular variables associated with aging. Epigenetic landscape was recovered for the analyzed global markers DNA methylation (5‐mC), hydroxymethylation (5‐hmC), and restoration occurred in the acetylation levels of H3 and H4. Gene expression of pro‐ and anti‐inflammatory mediators in central nervous system such as TNF‐α and IL‐10, respectively, had improved levels, which were comparable to the senescence‐accelerated‐mouse resistant 1 (SAMR1) healthy control. Additionally, this improvement in neuroinflammation was supported by changes in the histological markers Iba1, GFAP, and SA β‐gal. Furthermore, bone tissue structural variables, especially altered during senescence, recovered in SAMP8 mice to SAMR1 control values after treatment with both KL isoforms. This work presents evidence of the beneficial pleiotropic role of Klotho as an anti‐aging therapy as well as new specific functions of the KL isoforms for the epigenetic regulation and aged bone structure alteration in an aging mouse model. [ABSTRACT FROM AUTHOR]

With upcoming age, the capability to fight against harmful stimuli decreases and the organism becomes more susceptible to infections and diseases. Here, the objective was to demonstrate the effect of dietary resveratrol in aged mice in potentiating brain defenses against LipoPolySaccharide (LPS). Acute LPS injection induced a strong proinflammatory effect in 24-months-old C57/BL6 mice hippocampi, increasing InterLeukin (Il)-6 , Tumor Necrosis Factor-alpha ( Tnf-α ), Il-1β , and C-X-C motif chemokine ( Cxcl10 ) gene expression levels. Resveratrol induced higher expression in those cytokines regarding to LPS. Oxidative Stress (OS) markers showed not significant changes after LPS or resveratrol, although for resveratrol treated groups a slight increment in most of the parameters studies was observed, reaching signification for NF-kB protein levels and i NOS expression. However, Endoplasmic Reticulum (ER) stress markers demonstrated significant changes in resveratrol-treated mice after LPS treatment, specifically in eIF2α, BIP, and ATF4. Moreover, as described, resveratrol is able to inhibit the mechanistic Target of Rapamycin (mTOR) pathway and this effect could be linked to (eIF2α) phosphorylation and the increase in the expression of the previously mentioned proinflammatory genes as a response to LPS treatment in aged animals. In conclusion, resveratrol treatment induced a different cellular response in aged animals when they encountered acute inflammatory stimuli. [ABSTRACT FROM AUTHOR]

Abstract: Dietary interventions have been proposed as a way to increase lifespan and improve health. The senescence-accelerated prone 8 (SAMP8) mice have a shorter lifespan and show alterations in the central nervous system. Moreover, this mouse strain shows decreased sirtuin 1 protein expression and elevated expression of the acetylated targets NFκB and FoxO1, which are implicated in transcriptional control of key genes in cell proliferation and cell survival, in reference to control strain, SAMR1. After eight weeks of intermittent fasting, sirtuin 1 protein expression was recovered in SAMP8. This recovery was accompanied by a reduction in the two acetylated targets. Furthermore, SAMP8 showed a lower protein expression of BDNF and HSP70 while intermittent fasting re-established normal values. The activation of JNK and FoxO1 was also reduced in SAMP8 mice subjected to an IF regimen, compared with control SAMP8. Our findings provide new insights into the participation of sirtuin 1 in ageing and point to a potential novel application of this enzyme to prevent frailty due to ageing processes in the brain. [ABSTRACT FROM AUTHOR]

Abstract: Senescence-accelerated mice (SAM) are used as a model of aging and age-associated diseases. SAMP8 are prone strains that show shortened life span and deficits in learning and memory processes, while SAMR1 are strains of accelerated senescence-resistant, long-lived mice. Due to their abnormal APP (amyloid precursor protein) metabolism in brain, SAMP8 may be an Alzheimer-type model. Adenosine receptors are G-protein coupled receptors which are altered in brain from Alzheimer disease (AD) cases. The analysis of adenosine receptors in brain from young (21days old) and middle-aged (180days old) SAMP8 as compared with SAMR1 mice revealed differences between these strains associated with age. The age-related increase in mRNA coding A1 and A2B receptors observed in SAMR1 was absent in SAMP8. A1 receptors were significantly decreased with age in SAMR1, while no differences were observed in SAMP8. However, the levels of A1 receptors in young SAMP8 were even lower than those obtained in middle-aged SAMR1. In addition, A2A receptors were significantly increased only in aged SAMR1. A similar age-related decrease in A1 receptors level was also observed in brain from male Wistar rats. These results suggest different age-related effects on adenosine receptors in SAMR1 and SAMP8 strains. Since A1 receptors are mainly neuroprotective, their important loss in very young SAMP8 strain suggests the involvement of these receptors in the pathogenesis of neurodegenerative diseases associated with aging. [Copyright &y& Elsevier]