Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by cognitive decline and pathological brain changes.While aging is the primary risk factor,circadian rhythm disruption(CRD)is increasin...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by cognitive decline and pathological brain changes.While aging is the primary risk factor,circadian rhythm disruption(CRD)is increasingly recognized as a central driver of AD pathology.CRD exacerbates oxidative stress,systemic inflammation,and gut microbiome dysbiosis,impairing sleep-wake cycles,disrupting metabolic homeostasis,and promoting neuroinflammation,ultimately accelerating disease progression.Oxidative stress,a key factor in neuronal damage,is both a cause and consequence of circadian misalignment,while mitochondrial dysfunction further amplifies oxidative damage,impairing synaptic function and cognitive stability.Additionally,gut microbiome dysbiosis contributes to neuroinflammatory processes,worsening neurodegeneration.Given these complex interactions,this review aims to elucidate the role of CRD in AD pathology and explore potential therapeutic interventions targeting circadian dysfunction.Specifically,it examines the efficacy of time-restricted feeding(TRF),a dietary strategy that aligns food intake with circadian rhythms.TRF has shown promise in restoring circadian function,reducing oxidative stress,improving mitochondrial health,and promoting gut microbiome diversity.By addressing CRD,TRF may offer a novel approach to mitigating AD pathologies.This review also identifies current research gaps and future directions for developing circadian-based interventions in AD prevention and treatment.展开更多
Humans have coevolved with their microbes over thousands of years,but this relationship,is now being dramatically affected by shifts in the collective human microbiome resulting from changes in the environment and soc...Humans have coevolved with their microbes over thousands of years,but this relationship,is now being dramatically affected by shifts in the collective human microbiome resulting from changes in the environment and societal norms.Resulting perturbations of intestinal host-microbe interactions can lead to miscues and altered host responses that increase the risk of pathogenic processes and promote“western”disorders such as inflammatory bowel diseases,cancers,obesity,diabetes,autism,and asthma.Given the current challenges and limitations in gene therapy,approaches that can reshape the gut microbiome represent a reasonable strategy for restoring the balance between host and microbes.In this review and commentary,we highlight recent progress in our understanding of the intestinal microbiome in the context of health and diseases,focusing on mechanistic concepts that underlie the complex relationships between host and microbes.Despite these gains,many challenges lie ahead that make it difficult to close the gap between the basic sciences and clinical application.We will discuss the potential therapeutic strategies that can be used to manipulate the gut microbiota,recognizing that the promise of pharmabiotics(“bugs to drugs”)is unlikely to be completely fulfilled without a greater understanding of enteric microbiota and its impact on mammalian physiology.By leveraging the knowledge gained through these studies,we will be prepared to enter the era of personalized medicine where clinical inventions can be custom-tailored to individual patients to achieve better outcomes.展开更多
基金funded by National Institutes of Health(NIH)grants AG065992,AG068550 and NS133378 to Girish C.Melkani(USA)supported in part by UAB Nathan Shock Center P30 AG050886(USA).
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by cognitive decline and pathological brain changes.While aging is the primary risk factor,circadian rhythm disruption(CRD)is increasingly recognized as a central driver of AD pathology.CRD exacerbates oxidative stress,systemic inflammation,and gut microbiome dysbiosis,impairing sleep-wake cycles,disrupting metabolic homeostasis,and promoting neuroinflammation,ultimately accelerating disease progression.Oxidative stress,a key factor in neuronal damage,is both a cause and consequence of circadian misalignment,while mitochondrial dysfunction further amplifies oxidative damage,impairing synaptic function and cognitive stability.Additionally,gut microbiome dysbiosis contributes to neuroinflammatory processes,worsening neurodegeneration.Given these complex interactions,this review aims to elucidate the role of CRD in AD pathology and explore potential therapeutic interventions targeting circadian dysfunction.Specifically,it examines the efficacy of time-restricted feeding(TRF),a dietary strategy that aligns food intake with circadian rhythms.TRF has shown promise in restoring circadian function,reducing oxidative stress,improving mitochondrial health,and promoting gut microbiome diversity.By addressing CRD,TRF may offer a novel approach to mitigating AD pathologies.This review also identifies current research gaps and future directions for developing circadian-based interventions in AD prevention and treatment.
基金supported by the Swim Across America Research Award to Jun Sun and NIDDK DK42086(DDRCC),DK097268,and DK47722 to Eugene B Chang.
文摘Humans have coevolved with their microbes over thousands of years,but this relationship,is now being dramatically affected by shifts in the collective human microbiome resulting from changes in the environment and societal norms.Resulting perturbations of intestinal host-microbe interactions can lead to miscues and altered host responses that increase the risk of pathogenic processes and promote“western”disorders such as inflammatory bowel diseases,cancers,obesity,diabetes,autism,and asthma.Given the current challenges and limitations in gene therapy,approaches that can reshape the gut microbiome represent a reasonable strategy for restoring the balance between host and microbes.In this review and commentary,we highlight recent progress in our understanding of the intestinal microbiome in the context of health and diseases,focusing on mechanistic concepts that underlie the complex relationships between host and microbes.Despite these gains,many challenges lie ahead that make it difficult to close the gap between the basic sciences and clinical application.We will discuss the potential therapeutic strategies that can be used to manipulate the gut microbiota,recognizing that the promise of pharmabiotics(“bugs to drugs”)is unlikely to be completely fulfilled without a greater understanding of enteric microbiota and its impact on mammalian physiology.By leveraging the knowledge gained through these studies,we will be prepared to enter the era of personalized medicine where clinical inventions can be custom-tailored to individual patients to achieve better outcomes.
