RESUMO
Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.
Assuntos
Envelhecimento/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Transformação Celular Neoplásica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Granuloma/prevenção & controle , Imunoglobulinas/sangue , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fenótipo , Contagem de Plaquetas , Desempenho Psicomotor/efeitos dos fármacos , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologiaRESUMO
Vascular cognitive impairment has been related to dysfunction of the central cholinergic system. Studies exploring the putative relationship between vascular cognitive impairment and cholinergic dysfunction have largely been aimed at symptomatic cholinergic treatment rather than focusing on etiological and pathological factors. The present study characterizes chronic responses of the cholinergic system to focal cerebral infarction. Two separate experiments investigated changes in receptor responsiveness versus changes in cell number after photothrombotic infarction of the frontal cortex in rat brain. First, we conducted pharmacological magnetic resonance imaging (phMRI) together with pilocarpine injection to assess relative cerebral blood volume (CBV) responses related to cholinergic muscarinic receptor activation. PhMRI was conducted at 1 and 3 weeks after photothrombotic infarction of either the left or right frontal cortex. Second, stereological assessment was performed on choline acetyltransferase (ChAT)-immunostained sections to determine cholinergic cell body count in several basal forebrain nuclei at 4 weeks after infarction. Significant reductions in relative CBV responses were observed both inside the ischemic area at 1 and 3 weeks, and in areas distant from the lesion at 3 weeks after right-sided frontal cortical infarction. In contrast, cholinergic cell number remained unchanged. These results demonstrate that cholinergic receptor responsiveness may be significantly altered following cerebral infarction, while projecting cholinergic cells are preserved.
Assuntos
Acetilcolina/metabolismo , Infarto Cerebral/patologia , Lobo Frontal/patologia , Imageamento por Ressonância Magnética/métodos , Neurônios/patologia , Receptores Muscarínicos/metabolismo , Animais , Contagem de Células/métodos , Infarto Cerebral/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Colina O-Acetiltransferase/metabolismo , Lobo Frontal/metabolismo , Masculino , Agonistas Muscarínicos/farmacologia , Neurônios/fisiologia , Pilocarpina/farmacologia , Ratos , Ratos Endogâmicos Lew , Receptores Muscarínicos/fisiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-gamma, TNF-alpha and IL-6 cytokines following mitogen stimulation (p<0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan (p<0.005) and kynurenic acid (p<0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.