11 research outputs found
Efectes de l'exercici fĂsic en l'envelliment: ImplicaciĂł de la via de sirtuĂŻna 1, el procĂ©s d'autofĂ gia i la via WNT en rata
Un estil de vida saludable, on la prĂ ctica d’exercici fĂsic hi Ă©s present, millora diferents aspectes relacionats amb el deteriorament cognitiu i fisiològic associat a l’envelliment. Malgrat que els estudis en rosegadors confirmen aquests beneficis, els mecanismes moleculars implicats tant a nivell cerebral com a nivell perifèric no estan del tot ben establerts. Per aquest motiu en aquesta tesi doctoral s’ha volgut avaluar tant a nivell cerebral (hipocamp i còrtex cerebral) com a nivell perifèric (mĂşscul esquelètic, fetge i cor) en rates mascle Sprague-Dawley als 10 mesos de vida (rates adultes) el procĂ©s d’envelliment sobre algunes de les vies moleculars que s’han relacionat i resulten alterades amb l’edat, com sĂłn la via de sirtuĂŻna 1, el procĂ©s d’autofĂ gia i la via Wnt (via canònica). D’altra banda, s’ha volgut determinar la possible modulaciĂł de les anteriors vies amb la realitzaciĂł d’exercici fĂsic moderat de llarg termini (dut a terme durant 36 setmanes des de les 5 setmanes de vida, 4-5 dies a la setmana, durant 30 minuts al dia).
Els resultats obtinguts a nivell cerebral mostren com l’exercici fĂsic Ă©s capaç d’activar la via de sirtuĂŻna 1 (via de supervivència cel•lular) i la biogènesi mitocondrial, el que contribuiria tot plegat al manteniment de la supervivència, la funcionalitat i l’estructura neuronal. TambĂ© l’exercici, al disminuir els nivells de tau fosforilada a mĂ©s d’augmentar els nivells de sinaptofisina, estaria implicat en el manteniment de la transmissiĂł sinĂ ptica. D’altra banda, l’activaciĂł tant del procĂ©s d’autofĂ gia a nivell del còrtex cerebral com de la via de la Wnt a nivell de l’hipocamp, contribuiria al manteniment de l’homeòstasi i supervivència neuronal. Cal destacar la implicaciĂł de sirtuĂŻna 1 en l’activaciĂł tant del procĂ©s d’autofĂ gia com de la via Wnt. AixĂ, amb els nostres resultats podem considerar a sirtuĂŻna 1 com un dels elements clau en la regulaciĂł de les diferents vies moleculars i processos estudiats en aquesta tesi doctoral, i que la prĂ ctica d’exercici moderat de llarg termini Ă©s capaç de modular.
Pel que fa als resultats obtinguts a nivell perifèric (mĂşscul esquelètic, fetge i cor), tambĂ© es va determinar una activaciĂł de la via de sirtuĂŻna 1 amb l’exercici en tots els teixits. En canvi, l’estimulaciĂł de la biogènesi mitocondrial tan sols es va produir a nivell muscular. TambĂ© l’exercici va augmentar els nivells proteics dels enzims SOD i CAT en el mĂşscul, revertint aixĂ l’augment del dany oxidatiu de proteĂŻnes i lĂpids amb l’edat a nivell muscular (tambĂ© en el fetge l’exercici va disminuir el dany oxidatiu de proteĂŻnes), contribuint aixĂ tot plegat a la millora funcional a nivell perifèric. L’exercici fĂsic tambĂ© va incrementar els nivells de VEGF en fetge i cor, fet que podria estimular l’angiogènesi en aquests òrgans. I pel que fa al mecanisme d’autofĂ gia, solament es van observar alguns canvis destacats a nivell hepĂ tic, els quals podrien estar relacionats amb la disminuciĂł del contingut lipĂdic en aquest òrgan.
Com a conclusiĂł que se’n deriva d’aquesta tesi doctoral Ă©s que la realitzaciĂł d’exercici fĂsic des que un Ă©s jove, sinònim d’un estil de vida saludable, podria ser una bona estratègia terapèutica amb l’objectiu de prevenir i/o retardar el deteriorament cognitiu i fisiològic que es produeix amb l’envelliment, el qual conduiria al desenvolupament de les malalties neurodegeneratives i metabòliques, ambdues molt presents actualment en la societat actual dels paĂŻsos desenvolupats.Exercise is known to have beneficial effects on the organism and is increasingly recognized as determinant of successful aging. However, the molecular and cellular mechanisms underlying these effects remain to be elucidated. For this reason, we studied the effects of the aging process on the sirtuin 1 pathway, the autophagy (macroautophagy) and the canonical Wnt pathway, all of which related with the aging process, in adult male Sprague-Dawley rats (10 months), both in the brain (hippocampus and cortex) and peripheral tissues (skeletal muscle, liver and heart). Moreover, we examined the effects of long-term moderate treadmill exercise (30 min, 4-5 days per week for 36 weeks from 5 weeks) on the above pathways.
At cerebral level, our results showed a sirtuin 1 pathway activation and an increase in mitochondrial biogenesis induced by exercise. In addition, exercise increased synaptophysin levels and reduced both levels of phospho-tau and GSK3β activation. On the other hand, exercise induced the macroautophagy in the cortex and Wnt signaling pathway in the hippocampus. Thus, in our rodent model, long-term moderate exercise leads to neuroprotection trough the upregulation of several pathways related with homeostasis and neuronal survival, and also the prevention of signs of neurodegeneration. It is noteworthy to consider the important role of sirtuin 1 modulating the different pathways studied.
In peripheral tissues, long-term moderate exercise induced the sirtuin 1 pathway activation in all rat tissues studied, but only increased mitochondrial biogenesis in the muscle. On the other hand, SOD and CAT protein levels were increased by exercise in the muscle, together with a reduction of oxidative damage of lipids and proteins (the latter also reduced in liver with exercise). Increased VEGF protein levels were found in the liver and the heart, which could induce the angiogenic process in these organs. As for macroautophagic process, only important changes were observed in liver, which could be related with metabolic effects, reducing lipid content. Therefore, these results support that exercise also contributes to functional improvement in peripheral tissues.
To conclude, our results show several benefits related to long-term moderate exercise from young ages on different pathways and parameters related with aging, which reinforce the beneficial role of exercise to prevent or delay the age-related cognitive and physiological impairments
Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise
The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging
Macroautophagic process was differentially modulated by long-term moderate exercise in rat brain and peripheral tissues
The autophagic process is a lysosomal degradation pathway, which is activated during stress conditions, such as starvation or exercise. Regular exercise has beneficial effects on human health, including neuroprotection. However, the cellular mechanisms underlying these effects are incompletely understood. Endurance and a single bout of exercise induce autophagy not only in brain but also in peripheral tissues. However, little is known whether autophagy could be modulated in brain and peripheral tissues by long-term moderate exercise. Here, we examined the effects on macroautophagy process of long-term moderate treadmill training (36 weeks) in adult rats both in brain (hippocampus and cerebral cortex) and peripheral tissues (skeletal muscle, liver and heart). We assessed mTOR activation and the autophagic proteins Beclin 1, p62, LC3B (LC3B-II/LC3B-I ratio) and the lysosomal protein LAMP1, as well as the ubiquitinated proteins. Our results showed in the cortex of exercised rats an inactivation of mTOR, greater autophagy flux (increased LC3-II/LC3-I ratio and reduced p62) besides increased LAMP1. Related with these effects a reduction in the ubiquitinated proteins was observed. No significant changes in the autophagic pathway were found either in hippocampus or in skeletal and cardiac muscle by exercise. Only in the liver of exercised rats mTOR phosphorylation and p62 levels increased, which could be related with beneficial metabolic effects in this organ induced by exercise. Thus, our findings suggest that long-term moderate exercise induces autophagy specifically in the corte
Dendritic Spine Abnormalities in Hippocampal CA1 Pyramidal Neurons Underlying Memory Deficits in the SAMP8 Mouse Model of Alzheimer's Disease
SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer"s disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD
Macroautophagic process was differentially modulated by long-term moderate exercise in rat brain and peripheral tissues
The autophagic process is a lysosomal degradation pathway, which is activated during stress conditions, such as starvation or exercise. Regular exercise has beneficial effects on human health, including neuroprotection. However, the cellular mechanisms underlying these effects are incompletely understood. Endurance and a single bout of exercise induce autophagy not only in brain but also in peripheral tissues. However, little is known whether autophagy could be modulated in brain and peripheral tissues by long-term moderate exercise. Here, we examined the effects on macroautophagy process of long-term moderate treadmill training (36 weeks) in adult rats both in brain (hippocampus and cerebral cortex) and peripheral tissues (skeletal muscle, liver and heart). We assessed mTOR activation and the autophagic proteins Beclin 1, p62, LC3B (LC3B-II/LC3B-I ratio) and the lysosomal protein LAMP1, as well as the ubiquitinated proteins. Our results showed in the cortex of exercised rats an inactivation of mTOR, greater autophagy flux (increased LC3-II/LC3-I ratio and reduced p62) besides increased LAMP1. Related with these effects a reduction in the ubiquitinated proteins was observed. No significant changes in the autophagic pathway were found either in hippocampus or in skeletal and cardiac muscle by exercise. Only in the liver of exercised rats mTOR phosphorylation and p62 levels increased, which could be related with beneficial metabolic effects in this organ induced by exercise. Thus, our findings suggest that long-term moderate exercise induces autophagy specifically in the corte
Dendritic Spine Abnormalities in Hippocampal CA1 Pyramidal Neurons Underlying Memory Deficits in the SAMP8 Mouse Model of Alzheimer's Disease
SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer"s disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD
Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise
The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging
Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise
The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging
Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8
Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation
Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8
Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation