Title:Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer
VOLUME: 14 ISSUE: 3
Author(s):Kenneth Maiese
Affiliation:Cellular and Molecular Signaling, Newark, NY
Keywords:Aging, aging-related disorders, Alzheimer's disease, AMP activated protein kinase (AMPK), angiogenesis, apoptosis,
autophagy, BMAL1, cardiovascular disease, β-catenin, circadian rhythm, CLOCK, clock genes, Cryptochrome, diabetes
mellitus, hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2), Huntington’s disease, mechanistic target
of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), metabolism, nerve growth factor,
nicotinamide, nicotinamide adenine dinucleotide (NAD+), Parkinson's disease, period (PER), oxidative stress, programmed cell
death, REV-ERBα, RORα, RORE, shift work, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae)
(SIRT1), sirtuin, space travel, stem cells, suprachiasmatic nucleus, wingless, Wnt.
Abstract:Background: The mammalian circadian clock and its associated clock genes are increasingly
been recognized as critical components for a number of physiological and disease processes
that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence
suggests that clinical behavior disruptions that involve prolonged shift work and even space travel
may negatively impact circadian rhythm and lead to multi-system disease.
Methods: In light of the significant role circadian rhythm can hold over the body’s normal physiology
as well as disease processes, we examined and discussed the impact circadian rhythm and clock
genes hold over lifespan, neurodegenerative disorders, and tumorigenesis.
Results: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic
mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer’s
disease and Parkinson's disease may suffer disease onset or progression as a result of alterations
in the DNA methylation of clock genes as well as prolonged pharmacological treatment
for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also
can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal
carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian
clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target
of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information
regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms
that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury
and block tumor cell growth.
Conclusion: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control
mammalian circadian rhythm may hold the key for the development of novel and effective therapies
against aging- related disorders, neurodegenerative disease, and tumorigenesis.
