Time-restricted feeding and Alzheimer’s Disease: You are when you eat

Abstract

Time-restricted feeding (TRF) has emerged as a means of synchronizing circadian rhythms, which are commonly disrupted in Alzheimer’s Disease. Whittaker and colleagues demonstrate that TRF exerts protective effects in two mouse models of Alzheimer’s Disease. We discuss the effects of TRF on brain health and mechanisms linking TRF to neurodegeneration.

Time-restricted feeding (TRF) or eating (TRE) in humans is a behavioral intervention where food intake is restricted to a consistent time window resulting in a daily fasting period. In recent years, TRF has attracted increasing attention among researchers, as it has been shown to improve metabolism, immune functions, cognition, and longevity in mice. While human studies have shown mixed results, some suggest that TRE is associated with better metabolic outcomes, cardiovascular functions and immunity [1].

The benefits of TRF/TRE are likely pleiotropic. One possible mechanism of TRF is strengthening of circadian rhythms. Food is a strong signal which can entrain the circadian clock in certain organs, particularly the liver. When food is administered at the right time of day, it can synchronize with light-driven signals from the suprachiasmatic nucleus to bolster behavioral rhythms. A recent transcriptomic study shows that TRF not only synchronizes the peak phases of gene expression levels, but also increases the number of rhythmic genes across multiple tissues in a high-fat diet (HFD) mouse model [2]. Moreover, reversing feeding time so that it is out of phase with the circadian activity cycle can be detrimental, further suggesting that TRF acts in part through enhancing the clock [3,4]. However, TRF also likely acts through metabolic pathways. TRF has been extensively studied as a means of preventing obesity in HFD-treated mice and other metabolic disease models [1,2,5]. TRF elicits metabolic benefits through promoting thermogenesis, increasing ketogenesis, and modulating gut microbiota[1]. Mild caloric restriction (CR) can occur in TRF regimens, but is usually transient[1,2]. Furthermore, CR and TRF can synergizes to extend lifespan in mice [3].

While TRF has gained popularity in the field of metabolism, few studies have investigated its effects on the brain. Desynchronizing feeding from the light cycle can impair cognition and disrupt circadian rhythms in the hippocampus [4]. Conversely, TRF synchronized to the light cycle can rescue impairment in hippocampal long-term potentiation caused by HFD [6], or alleviate neuronal damage and improve cognition in a mouse model of vascular dementia [7]. In a mouse obesity model, TRF improved cognition and decreased tau phosphorylation, a marker associated with Alzheimer’s disease (AD) [8]. Circadian dysfunction is common among AD patients, which poses a huge healthcare burden. Circadian disruption may also contribute to AD pathogenesis by accelerating amyloid plaque deposition [9]. Thus, TRF is an appealing potential intervention in AD for both symptomatic therapy and disease prevention.

A recent paper by Whittaker et al has now examined the impact of TRF in a mouse model of AD [10]. Whittaker et al. first characterized the behavioral and transcriptional abnormalities in the APP23 transgenic mouse model of AD, which develop amyloid beta plaques after 6 months. These mice demonstrate evidence of diurnal behavioral disruption at 11 months, including decreased total sleep, nighttime hyperactivity, altered activity periods, and faster entrainment to a six-hour light phase advance. Transcriptomic analysis of hippocampal tissue at 4 times of day showed that the core molecular clock continued to oscillate normally in APP23 mice. However, 121 downstream genes lost transcriptional rhythms, suggesting that amyloid pathology disrupts clock-controlled gene oscillation without disrupting the core clock directly.

As their intervention, the authors employed TRF during the dark (active) phase of the mice, with food available only between ZT15 and ZT21 (7pm-3am) for 3 months starting at 4.5 months of age. TRF reduced nighttime hyperactivity in APP23 mice, and normalized more than a third of APP-dysregulated genes in the hippocampus. This was accompanied by a marked reduction in amyloid plaque deposition in two different AD mouse models (APP23 and APP-KI). Notably, TRF treated APP-KI mice also showed lower phospho-tau deposition, and reversal of some memory-related cognitive deficits. In silico analysis of transcriptomic data implicated the transcription factor Bmi1 as a possible mediator of the protective effects of TRF, as expression of Bmi1 itself, and several of its transcriptional targets, were disrupted in APP23 mice and restored by TRF. Notably, Bmi1 deficiency has previously been shown to recapitulate AD pathology - including amyloid beta and phospho-tau accumulation - in iPSC models[11].

Whittaker et al. clearly demonstrate that TRF has impressive effects on behavior, gene expression, and pathology in AD mouse models with amyloid pathology, opening the door to broader study of TRF in AD. However, many questions remain. It remains unclear how much of the effect of TRF is mediated through circadian versus metabolic mechanisms, as TRF induced ketogenesis and impacted many non-rhythmic transcripts. It would be instructive to see if TRF could exert protective effects in disease models which lack circadian dysfunction. The role of Bmi1 is implied, but manipulation of Bmi1 is needed to prove causality. Future studies may delineate whether Bmi1 acts independently or in concert with the circadian clock and metabolic elements to modulate pathology. Finally, the precise mechanisms by which TRF mitigates amyloid plaque deposition remains unclear. The authors show changes in AD-related gene expression, decreases in amyloid precursor protein expression and cleavage, and increased Aβ in the blood, implying increased clearance from the brain. Thus, TRF could potentially impact multiple aspects of disease pathogenesis, and underscore the potential that TRF could be protective in other neurodegenerative models. The exciting findings of Whittaker et al. will undoubtedly spur interest in TRF as a potentially powerful and readily-translatable intervention for AD.

Figure 1: Night time-restricted feeding has pleiotropic benefits in neurodegenerative models.

In two mouse models of Alzheimer’s Disease, restricting food access to the active (dark) period reduces amyloid beta plaque formation, phosphorylated tau, and associated cognitive deficits. The authors highlight multiple possible mechanisms as the basis for this improvement, including the ketogenic metabolic response to TRF, as well as the normalization of the hyperactivity and sleep-deprivation phenotype found in these mice. Additionally, RNA-seq analysis implicated Bmi1, a chromatin regulator, as a possible mediator of the effects of TRF on AD pathology.