Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease

Abstract

The circadian clock coordinates physiology, metabolism, and behavior with the 24-h cycles of environmental light. Fundamental mechanisms of how the circadian clock regulates organ physiology and metabolism have been elucidated at a rapid speed in the past two decades. Here we review circadian networks in more than six organ systems associated with complex disease, which cluster around metabolic disorders, and seek to propose critical regulatory molecules controlled by the circadian clock (named clock-controlled checkpoints) in the pathogenesis of complex disease. These include clock-controlled checkpoints such as circadian nuclear receptors in liver and muscle tissues, chemokines and adhesion molecules in the vasculature. Although the progress is encouraging, many gaps in the mechanisms remain unaddressed. Future studies should focus on devising time-dependent strategies for drug delivery and engagement in well-characterized organs such as the liver, and elucidating fundamental circadian biology in so far less characterized organ systems, including the heart, blood, peripheral neurons, and reproductive systems.

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis

“…Several lines of evidence support the involvement of circadian rhythm in the pathogenesis of many neurodegenerative diseases, including MS [ 20 , 22 ]. We highlight differential expression in the wall of IJV, which drains blood from the brain, of several circadian entrainment/rhythm components ( Figure 5 ).…”

“…Dysfunction in the circadian clock system might contribute to neurovascular pathological conditions by affecting protein homeostasis, immune, and inflammatory functions [ 17 , 18 , 19 , 20 , 21 , 22 ]. Indeed, recent evidence suggests the role of molecular clocks in regulating blood–brain barrier [ 23 ], in dictating the response of immune pathways, and in modulating innate and adaptive immune crosstalk in autoimmune diseases [ 24 ].…”

Using Microbiome-Based Approaches to Deprogram Chronic Disorders and Extend the Healthspan following Adverse Childhood Experiences

“…Dietert discussed this very issue relative to the microbiome dysbiosis in two recent review articles [3,61]. Additionally, the significance of including the circadian cycle [119,120,129] and the longevity cycle [195] in healthcare/public health plans has been stressed in a number of recent publications. Much as the microbiome has bidirectional communication with the immune system through the microimmunosome [60,61], microbiota and circadian cycles are involved in cross-talk [196].…”

“…Circadian rhythms are recognized as not simply a novel occurrence within the human body but, more significantly, a key cycle that: (1) spans the operation of systems biology units [116,117], (2) connects the microbiome with those units [118], and (3) ultimately can result in healthy metabolism and physiology [119] or disease [120][121][122].…”

Using Microbiome-Based Approaches to Deprogram Chronic Disorders and Extend the Healthspan Following Adverse Childhood Experiences

“…Dietert discussed this very issue relative to the microbiome dysbiosis in two recent review articles [3,61]. Additionally, the significance of including the circadian cycle [119,120,129] and the longevity cycle [195] in healthcare/public health plans has been stressed in a number of recent publications. Much as the microbiome has bidirectional communication with the immune system through the microimmunosome [Dietert et al, 2017; Dietert 2021a 60,61], microbiota and circadian cycles are involved in cross talk [196].…”