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Review
. 2021 Feb 11;384(6):550-561.
doi: 10.1056/NEJMra1802337.

Circadian Mechanisms in Medicine

Ravi Allada  1 , Joseph Bass  1
Affiliations
Review

Circadian Mechanisms in Medicine

Ravi Allada et al. N Engl J Med. .
No abstract available

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. Circadian Networks and Geophysical Time.
The molecular circuitry of circadian clocks is encoded by an autoregulatory 24-hour transcription loop in the brain, where the clocks align sleep–wake and feeding cycles with the rotation of Earth on its axis. Clocks are also present in nearly all tissues of the body, composing a network of timekeepers that anticipate varying environmental conditions each day. Having evolved across all kingdoms of life, the molecular circuitry provides photosensitive species with a mechanism to enhance bioenergetic cycles and ensure escape from DNA-damaging effects of sunlight. BMAL1 denotes brain and muscle Arnt-like protein 1, CLOCK circadian locomotor output cycles kaput, CRY cryptochrome, PER period, RORE retinoic acid–related orphan receptor (ROR) response elements, and SCN suprachiasmatic nucle
Figure 2.
Figure 2.. Circadian Timing of Physiological Processes and Disease.
Molecular clocks are present in most cells in the brain and throughout peripheral tissues of the body. Clocks are entrained by the brain pacemaker neuron to the environmental light–dark cycle and help maintain the constancy of the internal milieu through anticipation of alterations that occur as mammals undergo daily sleep–wake and fasting–feeding cycles. The top panel highlights a subset of 24-hour oscillating physiological processes across diverse tissues, all coordinated with the day–night cycle. The bottom panel shows the clinical correlates in humans that are associated with circadian disruption across the day and night. “Sundowning” refers to confusion or delirium during the evening or night that disappears or abates during daytime.
Figure 3.
Figure 3.. Potential Exploitation of Clock Pathways for Therapeutics.
Molecular clocks in nearly all cell types drive gene transcription in collaboration with tissue-specific factors. Local clocks generate robust oscillation in the expression of distinct rate-limiting factors according to the time of day. Therapies that affect either central clock activity (e.g., light or melatonin, each of which modulates the sleep–wake cycle) or peripheral-acting targets (e.g., modulators of nucleotide levels, cryptochrome [CRY] stability, and nuclear receptor activity) represent potential targets for manipulating circadian pathways in specific tissues. Shown are the pathways regulated in diverse tissues and, in the center, the localization of input signals and downstream therapeutic targets that are circadian outputs. Carbs denotes carbohydrates, cAMP cyclic AMP, CK1 casein kinase 1, ER endoplasmic reticulum, HIF hypoxia-inducible factor, mTOR mammalian target of rapamycin, NAD+ nicotinamide adenine dinucleotide, NF-κB nuclear f actor κB, PKA protein kinase A, SIRT sirtuin, and UCP1 uncoupling protein 1.
See this image and copyright information in PMC

Comment in

  • Circadian Mechanisms in Medicine.
    Lin HY, Yang MY, Lin SF. Lin HY, et al. N Engl J Med. 2021 May 20;384(20):e76. doi: 10.1056/NEJMc2104154. N Engl J Med. 2021. PMID: 34010542 Free PMC article. No abstract available.
  • Circadian Mechanisms in Medicine.
    Ruan W, Yuan X, Eltzschig H. Ruan W, et al. N Engl J Med. 2021 May 20;384(20):e76. doi: 10.1056/NEJMc2104154. N Engl J Med. 2021. PMID: 34010543 No abstract available.

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