Novel treatment strategies for neurodegenerative disease with sirtuins

2023

Biomolecules

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

Section: Cellular Metabolism In the Nervous Systemmentioning

confidence: 99%

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

2023

Biomolecules

“…In regard to SIRT1, SIRT1 activity leads to increased survival through inhibition of FoxO activity [5,14,[194][195][196]. Yet, FoxOs also can bind to the SIRT1 promoter region to alter forkhead transcription [206]. This allows FoxOs to function through autofeedback mechanisms to regulate SIRT1 activity.…”

Section: Circadian Clock Genes and The Silent Mating Type Information Regulation 2 Homolog 1 (Saccharomyces Cerevisiae) (Sirt1)mentioning

confidence: 99%

“…It is interesting to note that SIRT1 also has an inverse relationship with mTOR [14, 189,[210][211][212][213]. As previously mentioned, SIRT1 also can significantly affect pathways of autophagy [58,69,161,[189][190][191]206,[214][215][216]. SIRT1 activity can result in neurite outgrowth and increased neuronal survival during nutrient limiting conditions with the inhibition of mTOR [217].…”

Section: Circadian Clock Genes and The Silent Mating Type Information Regulation 2 Homolog 1 (Saccharomyces Cerevisiae) (Sirt1)mentioning

confidence: 99%

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

2021

Biomolecules

Self Cite

Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with 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 the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.

“…SIRT1 maintains an inverse relationship with mTOR [19,[176][177][178][179][180]. SIRT1 can also affect pathways of autophagy [49,65,163,178,[181][182][183][184][185][186]. SIRT1 activity can lead to the expansion of neurites and promote the survival of neurons during conditions that limit nutrients that involves mTOR inhibition [187].…”

Section: The Mechanistic Target Of Rapamycin (Mtor) and Autophagymentioning

confidence: 99%

“…In regard to SIRT1, blockade of the activity of FoxOs by SIRT1 can promote cell survival [19,67,[249][250][251]. However, FoxOs can attach to the SIRT1 promoter region to further change forkhead transcription [181]. This mechanism permits FoxOs to use auto-feedback mechanisms to regulate the activity of SIRT1.…”

Section: Mammalian Forkhead Transcription Factors (Foxos)mentioning

confidence: 99%

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

Front. Biosci. (Landmark Ed)

2021

Introduction 3. Biological clocks and circadian rhythm pathways for dementia treatment 4. Circadian rhythm disruption and the wingless wnt pathway 5. The mechanistic target of rapamycin (mTOR) and autophagy 6. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) 7. Mammalian forkhead transcription factors (FoxOs) 8. Future perspectives 9. Author contributions 10. Ethics approval and consent to participate 11. Acknowledgment 12. Funding 13. Conflict of interest 14. References