Table 1.

Highlights—Cognitive Impairment and Dementia: Circadian Clock Gene Pathways.

Neurodegenerative disorders include more than 600 disease entities and currently impact almost one billion individuals throughout the globe, but these numbers are expected to increase with improvements in lifespan and healthcare.

Dementia is the seventh leading cause of death and results in a significant financial burden for all countries throughout the world. Treatment of cognitive disorders is challenging since they are multifactorial and current treatments do not significantly alter disease progression.

Circadian clock gene pathways that involve autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and erythropoietin (EPO) offer an exciting prospect to target cognitive loss and dementia.

Alterations in circadian rhythm can lead to reduce lifespan, cognitive impairment, behavior abnormalities, and locomotor deficits. Autophagy pathways that oversee circadian rhythm may limit cognitive loss and protect neurons during toxic insults such as ischemia.

Cognitive decline can be associated with the loss of mTOR activity and altered circadian rhythm. Fluctuations of mTOR activity in conjunction with altered circadian rhythm also may lead to cognitive loss as well as neuronal cell death. In contrast, enhanced mTOR activity with loss of PER2 proteins can alter chemotherapy drug efficacy

SIRT1 control of circadian rhythm and melatonin can affect cellular glucose tolerance, inflammation, and cognitive loss. SIRT1 also can regulate the generation of NAD+ pools that have been linked to aging during circadian rhythmicity. Although an inverse relationship is usually present, SIRT1 can require mTOR and FoxOs for neuroprotection. SIRT1 also relies upon EPO for energy homeostasis and cellular protection that is based upon intact circadian rhythm function.