SIRT1: new avenues of discovery for disorders of oxidative stress

Abstract

Introduction: The sirtuin SIRT1 is expressed throughout the body, has broad biological effects and can significantly affect both cellular survival and longevity during acute and long-term injuries, which involve both oxidative stress and cell metabolism.

Areas covered: SIRT1 has an intricate role in the pathology, progression, and treatment of several disease entities, including neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, tumorigenesis, cardiovascular disease with myocardial injury and atherosclerosis, metabolic disease, and aging-related disease. New areas of study in these disciplines, with discussion of the cellular biology, are highlighted.

Expert opinion: Novel signaling pathways for SIRT1, which can be targeted to enhance cellular protection and potentially extend lifespan, continue to emerge. Investigations that can further determine the intracellular signaling, trafficking and post-translational modifications that occur with SIRT1 in a variety of cell systems and environments will allow us to further translate this knowledge into effective therapeutic strategies that will be applicable to multiple systems of the body.

Figure 1. Activation of SIRT1 protects against oxidative-stress-associated diseases in multiple systems

Oxidative stress has been linked to the progression of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, acute ischemic stroke), heart failure associated with atherosclerosis, cardiac hypertrophy and ischemic/reperfusion injury, diabetes mellitus as the result of insulin resistance and decreased secretion and aging. SIRT1 functions as an antioxidant to protect cells of these systems and increase insulin sensitivity to benefit the body metabolic homeostasis. Resveratrol can function similarly through activating SIRT1.

Figure 2. SIRT1 cell signaling pathways

AMP activated protein kinase (AMPK) can activate SIRT1 through regulating the NAD⁺:NADH ratio, conversely, SIRT1 activates AMPK by deacetylation of the serine-threonine liver kinase B1 (LKB1), constituting a positive feedback system. Similarly, there is another positive feedback mechanism between SIRT1 and transcriptional factor FoxOs. FoxOs can directly bind to SIRT1 promoter to induce FoxOs-dependent SIRT1 transcription. Other SIRT1 substrates include PPAR-γ coactivator-1α (PGC-1α), protein tyrosine phosphatase 1B (PTP1B), p53, NF-κB and apoptotic transcription regulator E2F1. Interestingly, although SIRT1 inhibit E2F1 transcriptional activity, E2F1 can upregulate SIRT1 expression. In addition, SIRT1 can stimulate glucose-dependent insulin secretion from pancreatic β cells via repressing the uncoupling protein gene UCP2. The RNA binding protein HuR and A nuclear protein active regulator of SIRT1 (AROS) also enhances the SIRT1 activity. In contrast, hypermethylated in cancer 1 (HIC1) and deleted in breast cancer 1 (DBC1) have emerged as negative regulators of SIRT1. Through regulating these cell signals, SIRT1 can increase the resistance to oxidative stress and mediate metabolism.