Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

Abstract

Background The mammalian circadian clock and its associated clock genes are increasingly be 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. Conclusions 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.

Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss

“…Throughout the world, almost 47 million people suffer from some form of dementia with approximately 60% of these cases resulting from AD (2–5). Unfortunately, the availability of definitive treatments to resolve or prevent the onset of cognitive loss are limited and to the most extent are non-existent (6, 7). For example, alternative treatments provide only some relief to limit the progression of symptoms (8–13).…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…Multiple mechanisms may lead to cognitive impairment and involve cellular injury from β-amyloid (Aβ), tau, excitotoxicity, mitochondrial damage, acetylcholine loss, astrocytic cell injury, oxidative stress, and cellular metabolic dysfunction with DM (14, 51–57). Yet, there is a growing arsenal of novel therapeutic strategies directed against AD and other neurodegenerative disorders that include circadian rhythm clock genes (9), non-coding ribonucleic acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs) (56, 58, 59). These pathways share common signal transduction mechanisms with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae ) (SIRT1) and the mechanistic target of rapamycin (mTOR).…”

“…Circadian rhythm clock genes have a significant role in the nervous system and with programmed cell death (9, 113) (Figure 1). The mammalian circadian clock resides in the suprachiasmatic nucleus (SCN) located above the optic chiasm and receives light input from photosensitive ganglion cells in the retina.…”

“…mTOR also is known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1. mTOR controls multiple functions that determine the transcription of genes, proliferation and senescence of cells, protein formation, cellular metabolism, and cellular longevity (9, 57, 77, 129, 130). Melatonin, a pineal hormone that controls circadian rhythm, relies upon autophagy pathways and mTOR to control processes of aging and neurodegeneration (131).…”

“…Furthermore, approximately fifty million million people suffer from some form of dementia with approximately sixty percent of these cases resulting from AD (4, 12, 48, 194). Unfortunately, the availability of definitive treatments to resolve or prevent the onset of cognitive loss is limited and to the most extent such definitive treatments are non-existent (9, 50). …”