Intermittent Fasting Reduces Pathology in a Mouse Model of Alzheimer's Disease
The sizable body of work produced on calorie restriction and fasting over the last twenty years is supportive of the hypothesis that time spent hungry is an important factor determining the scale of benefits to health and longevity. The cellular response to a transient lack of nutrients involves improved cell maintenance, such as upregulation of autophagy to clear out damaged and worn molecular machinery. Looking at a level of organization above the cell, a transient state of hunger likely produces many other benefits to the way in which complex tissues and relationships between tissues function in the body. It dampens inflammatory signaling in the aging immune system, for example.
With this in mind, we expect to see many age-related conditions improved by calorie restriction, intermittent fasting, and similar interventions, such as fasting mimicking diets. In today's open access paper, researchers report that intermittent fasting without reduced calories can reduce pathology in a mouse model of Alzheimer's disease. As the researchers note, trying this out in humans is quite straightforward; it only requires funding. Unfortunately, funding for clinical trials of interventions such as intermittent fasting, in which there no profit to be made at the end of the day, is hard to come by. There is a role for philanthropy here that has yet to be fully realized.
Intermittent Fasting Improves Alzheimer's Pathology
One of the hallmarks of Alzheimer's disease is disruption to the body's circadian rhythm, the internal biological clock that regulates many of our physiological processes. Nearly 80% of people with Alzheimer's experience these issues, including difficulty sleeping and worsening cognitive function at night. However, there are no existing treatments for Alzheimer's that target this aspect of the disease.
Boosting the circadian clock is an emerging approach to improving health outcomes, and one way to accomplish this is by controlling the daily cycle of feeding and fasting. The researchers tested this strategy in a mouse model of Alzheimer's disease, feeding the mice on a time-restricted schedule where they were only allowed to eat within a six-hour window each day. For humans, this would translate to about 14 hours of fasting each day.
Compared to control mice who were provided food at all hours, mice fed on the time-restricted schedule had better memory, were less hyperactive at night, followed a more regular sleep schedule and experienced fewer disruptions during sleep. The test mice also performed better on cognitive assessments than control mice, demonstrating that the time-restricted feeding schedule was able to help mitigate the behavioral symptoms of Alzheimer's disease.
The researchers also observed improvements in the mice on a molecular level. In mice fed on a restricted schedule, the researchers found that multiple genes associated with Alzheimer's and neuroinflammation were expressed differently. They also found that the feeding schedule helped reduce the amount of amyloid protein that accumulated in the brain. Amyloid deposits are one of the most well-known features of Alzheimer's disease.
Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic mouse models of AD.
We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.