Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence

Abstract

Sirtuin1 (SIRT1), a type III protein deacetylase, is considered as a novel anti-aging protein involved in regulation of cellular senescence/aging and inflammation. SIRT1 level and activity are decreased during lung inflammaging caused by oxidative stress. The mechanism of SIRT1-mediated protection against inflammaging is associated with the regulation of inflammation, premature senescence, telomere attrition, senescence associated secretory phenotype, and DNA damage response. A variety of dietary polyphenols and pharmacological activators are shown to regulate SIRT1 so as to intervene the progression of type 2 diabetes, cancer, cardiovascular diseases, and chronic obstructive pulmonary disease associated with inflammaging. However, recent studies have shown the non-specific regulation of SIRT1 by the aforementioned pharmacological activators and polyphenols. In this perspective, we have briefly discussed the role of SIRT1 in regulation of cellular senescence and its associated secretory phenotype, DNA damage response, particularly in lung inflammaging and during the development of chronic obstructive pulmonary diseases. We have also discussed the potential directions for future translational therapeutic avenues for SIRT1 in modulating lung inflammaging associated with senescence in chronic lung diseases associated with increased oxidative stress.

Figure 1. SIRT1 regulates protein acetylation and deacetylation in inflammaging

SIRT1 removes the acetyl moieties from the ε-acetamido groups of lysine residues of proteins that include FOXO3, p53, Nrf2, NF-κB, PARP-1, Ku70 and Notch. The acetylation and deacetylation of these proteins alter their transcriptional and enzymatic activities, as well as protein levels, thereby regulating cellular senescence, apoptosis, inflammation, ROS production, DNA damage and repair, and angiogenesis. All these cellular processes are involved in the inflammaging that occurs in aging-associated diseases such as COPD, diabetes, and cancer.