Synchronizing an aging brain: can entraining circadian clocks by food slow Alzheimer's disease?

Abstract

Alzheimer's disease (AD) is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus) is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behavior and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.

Keywords: Alzheimer’s disease; aging; circadian rhythms; food-entrainment; ghrelin.

Figure 1

A simplified model of the mammalian circadian system under normal conditions. The light-entrainable oscillator (LEO) is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The LEO is directly entrained by light-dark cycles in the environment through intrinsically photoreceptive retinal ganglion cells, and generates circadian rest-activity rhythms as well as other rhythms that entrain to the environmental light-dark cycles. The LEO-driven activity rhythms then influence the timing of feeding behavior, which entrains the food-entrainable oscillator (FEO). FEO then drives several neuroendocrine, autonomic, and physiological rhythms throughout the brain and peripheral nervous system. The FEO also sends feedback to the LEO to remain coupled. Under certain conditions when the LEO is dysfunctional, or under conditions of constant darkness, the FEO can drive rest-activity rhythms and other rhythms normally entrained by light.

Figure 2

Hypothesized link between ghrelin and symptoms often associated with aging and Alzheimer’s disease. Ghrelin has been shown to directly affect hippocampal plasticity and neurogenesis, hunger-levels, and circadian processes. Both aging and Alzheimer’s disease (AD) are associated with lower levels of circulating ghrelin. Low ghrelin levels may result in reduced hippocampal plasticity and neurogenesis, and contribute to the cognitive deficits associated with old-age and AD. Lower circulating levels of ghrelin may also reduce hunger levels, and may partially underlie the weight loss associated with older age and AD. Finally, if ghrelin acts to enhance feeding-related zeitgebers, then reductions in circulating ghrelin could dampen food-entrained oscillators and disrupt circadian rhythmicity.