Aligning Rhythms, Defying Alzheimer's: Intermittent Fasting's Role in Combating Alzheimer's Disease Neurodegeneration

Thought LeadersDr. Paula DesplatsAssociate Professor of NeurosciencesUniversity of California San Diego

Ahead of World Alzheimers Month, News Medical interviewed Dr Paula Desplats, an Associate Professor of Neurosciences at the University of California San Diego. Recently hitting the headlines, Paula's most recent study with the Desplats Lab explored whether intermittent fasting could tackle neurodegeneration in Alzheimer’s Disease.

The study found that it is possible to correct circadian disruptions seen in Alzheimer’s disease with time-restricted feeding, a type of intermittent fasting focused on limiting the daily eating window without limiting the amount of food consumed.

We spoke with Dr. Desplats to gain further insight into the study's key outcomes and how this research will advance toward the human clinical trial phase.

Please introduce yourself and tell us about your career background?

I am Paula Desplats, Ph.D. I am an Associate Professor of Neurosciences at the University of California San Diego (UCSD) where I investigate how gene expression programs become altered in the brain contributing to neurodegeneration in Parkinson’s and Alzheimer’s diseases.

My studies aim to work on the bench to uncover molecular underpinnings of pathology that can provide therapeutic targets and to identify biomarkers to diagnose these devastating disorders in the clinic better. I received my Ph.D. from the University of Mar del Plata, Argentina, and moved to California to train in neurodegeneration. I became a faculty member at UCSD Neurosciences in 2009.

My pioneer studies in neuroepigenetics unveiled alterations in DNA methylation as novel mechanisms of disease and opened the exploration of epigenetic biomarkers for improved and early diagnosis of Parkinson’s disease. More recently, the Desplats Lab has focused on understanding how alterations in the circadian clock aggravate Alzheimer’s disease pathology and to evaluate interventions that improve circadian function to reduce pathology.

Can you briefly explain the main findings of your recent research regarding the therapeutic potential of circadian-modulating interventions against Alzheimer’s disease progression?

Our new study shows that restricting the amount of time allowed for daily feeding without changing the amount of food consumed can have a disease-modifying effect, correcting disruptions in brain rhythms and significantly ameliorating both brain pathology and cognitive deficits in transgenic mouse models of Alzheimer’s disease.

Your research highlights the potential role of circadian disruptions in Alzheimer's disease pathology. Could you elaborate on how these disruptions might contribute to the development or progression of the disease?

Loss of normal circadian rhythmicity is a major hallmark of neurodegenerative disease and is experienced by more than 80% of Alzheimer’s patients in the form of disrupted sleep patterns, including falling and staying asleep, and reduced cognitive performance at evening (sundowning).

While the field is still not exactly sure how circadian impairment contributes to Alzheimer’s disease, circadian dysfunction disrupts rhythms in gene transcription that have a profound impact on cellular function, behavior, and disease, and emerging evidence suggests that this circadian unraveling contributes to the pathological cascade by accelerating brain neuroinflammation and neurodegeneration.

Image Credit: EdgeCreative/Shutterstock.com

The concept of time-restricted feeding (TRF) seems to have yielded significant improvements in disease components in your study. Could you describe the underlying mechanism by which TRF positively affects behavioral timing, disease pathology, and memory in Alzheimer's disease mouse models?

Our data suggest that TRF is able to normalize the transcriptional patterns of circadian-controlled genes in the brains of transgenic mouse models of Alzheimer’s disease. Importantly, such TRF-responsive transcriptional changes appear mediated by the polycomb complex protein Bmi1, which regulates cellular senescence, controls responses to DNA damage, and is reduced in the brain with age.

Other important effects we observed were improvements in the time it takes to fall asleep and total sleep. These findings are clinically relevant as patients with Alzheimer’s disease experience difficulties in falling and staying asleep, which can dramatically affect memory and other physiological processes. Another compelling set of findings was the evidence of improved cholesterol pathways and vascular and extracellular matrix remodeling in the brains. These results may lead to insights into the positive effects of TRF on pathology, such as the increased clearance of beta-amyloid.

Your study showed that TRF reduced amyloid deposition and increased Aβ42 clearance. Could you discuss the implications of these findings in the context of Alzheimer's disease and its potential therapeutic intervention?

Accumulation of amyloid beta plaques within the brain is one of the best-known features of Alzheimer’s disease. Amyloid plaques induce pathology and inflammation in surrounding brain tissue, mostly consisting of the Aβ42 fragment. Many patients with Alzheimer’s disease show reduced clearance of Aβ42 in the cerebral spinal fluid decades before the clinical onset of the disease.

If TRF is able to help the brain maintain Aβ clearance and other healthy functions for longer, this could represent a powerful complementary early approach to alter the onset and trajectory of disease.

Your research suggests that timed feeding not only impacts metabolism but also has broader effects on neurodegeneration and circadian rhythmicity. Could you elaborate on how this pleiotropic nature of timed feeding is particularly relevant to our understanding of Alzheimer's disease?

Alzheimer’s disease is a complex, multi-factorial neurodegenerative disease that starts several years (if not decades) before the manifestation of clinical symptoms. Thus, it is fitting that Alzheimer’s pathology seems to be ameliorated by the wide-ranging pleiotropic effects induced by circadian modulation via TRF.

With the advent of more sensitive clinical biomarkers for the onset and progression of the disease, increasing numbers of patients will receive early diagnoses of advancing risk Alzheimer’s disease risk. However, there is currently no standard of care for such cases and time-restricted eating may thus represent a therapeutic approach that could be utilized in early stages of the condition.  

Time-restricted feeding appears to have the potential to modify the trajectory of Alzheimer's disease. How do you envision the translational application of TRF as an accessible approach to address the urgent need for interventions that can slow down or halt the progression of the disease?

Time-restricted feeding is a lifestyle change that can be easily and immediately integrated into our daily lives. This dietary approach could be an effective way to markedly improve the lives of people affected by the disease.

Could you discuss any challenges or limitations encountered during your study, and how these findings might pave the way for future research in both the field of circadian rhythms and Alzheimer's disease? More broadly, what are the biggest challenges faced in Alzheimer’s research in general?  

One of the major challenges is the multifactorial nature of Alzheimer’s pathology, where disruptions in many biological systems contribute to neuronal decay. In addition, except for a few mutations associated with the disease, there is yet not a unique causal factor that can trigger the pathology.

It can be challenging to study the effects of a treatment on patients when the brain is the main organ affected, as it is obviously inaccessible, so sensitive biomarkers need to be deployed to monitor the outcomes of interventions. At the same time there are limitations when using mouse models of Alzheimer's, as they do not adequately represent what is seen in humans with the disease.

Given the complexity of Alzheimer's disease and circadian disruptions, what aspects of your research do you believe should be further explored or validated in human clinical studies?

We are interested in deciphering the molecular mechanisms and cell-specific pathways involved in circadian deregulation at early disease stages, as these studies may uncover novel therapeutic targets that may slow disease progression.

The therapeutic potential of circadian-modulating interventions is an exciting area of research. Based on your findings, what would be the next steps in terms of translating this research into potential treatments for Alzheimer's disease patients?

The next step is, of course, to conduct a well-designed pilot clinical study. We are hoping to translate the findings of our study to the clinic to test the feasibility of practicing time-restricted eating for patients with cognitive decline or dementia and to determine if this diet offers similar benefits in humans as what we observed in animal models. A study of this kind requires trust and cooperation between the families, physicians, clinical teams, and the researchers.

How might your research impact the broader understanding of how lifestyle and environmental factors can influence neurodegenerative diseases beyond traditional pharmaceutical approaches?

Our findings concordance with growing evidence indicate that Alzheimer’s disease must be treated to reflect its complex etiology and pathology. Such approaches could include lifestyle and behavioral changes that complement pharmaceutical interventions and could be highly effective in slowing down and preventing disease progression.

Image Credit: OrawanPattarawimonchai/Shutterstock.com

In conclusion, your study sheds light on the connections between circadian disruptions, time-restricted feeding, and Alzheimer's disease. Could you summarize the key takeaways and implications of your findings for both the scientific community and individuals affected by Alzheimer's disease?

The takeaway message that we would like to emphasize is that circadian modulation by time-restricted feeding is effective at modifying multiple pathological and behavioral traits of Alzheimer’s disease in mouse models. Our work emphasizes the importance of future studies to understand better the therapeutic potential of time-restricted eating as a powerful approach that could significantly change the disease trajectory in patients with Alzheimer’s disease.

Where can readers find more information?

About Dr. Paula Desplats 

Paula Desplats, PhD, is an Associate Professor of Neurosciences at the University of California San Diego (UCSD) and investigates how gene expression programs alter in the brain contributing to neurodegeneration in Parkinson’s and Alzheimer’s diseases. Her studies aim to work on the bench to uncover molecular underpinnings of pathology that can provide therapeutic targets and identify biomarkers to better diagnose these devastating disorders in the clinic. Dr. Desplats received her Ph.D. from the University of Mar del Plata, Argentina, and moved to California to train in neurodegeneration. 

She became a faculty member at UCSD Neurosciences in 2009. Her pioneer studies in neuroepigenetics unveiled alterations in DNA methylation as novel mechanisms of disease and opened the exploration of epigenetic biomarkers for improved and early diagnosis of Parkinson’s disease.

More recently, the Desplats Lab has been focused on understanding how alterations in the circadian clock aggravate Alzheimer’s disease pathology and to evaluate interventions that improve circadian function to reduce pathology.

Lily Ramsey

Written by

Lily Ramsey

Lily holds a distinguished academic background, having earned a first-class degree in Microbiology from the University of Nottingham in 2021. Her pursuit of knowledge continued as she completed her LLM in Medical Law and Ethics at the University of Edinburgh. During her master's studies, Lily dedicated her research to the field of public health ethics, with a specific passion for health equity and justice, with a specialized focus on the ethical aspects of antibiotic resistance.

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