SIRT1 as a therapeutic target in inflammaging of the pulmonary disease

Abstract

Objective: Chronic inflammation and cellular senescence are intertwined in the pathogenesis of premature aging, which is considered as an important contributing factor in driving chronic obstructive pulmonary disease (COPD). Sirtuin1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent protein/histone deacetylase, regulates inflammation, senescence/aging, stress resistance, and deoxyribonucleic acid (DNA) damage repair via deacetylating intracellular signaling molecules and chromatin histones. The present review describes the mechanism and regulation of SIRT1 by environmental agents/oxidants/reactive aldehydes and pro-inflammatory stimuli in lung inflammation and aging. The role of dietary polyphenols in regulation of SIRT1 in inflammaging is also discussed.

Methods: Analysis of current research findings on the mechanism of inflammation and senescence/aging (i.e., inflammaging) and their regulation by SIRT1 in premature aging of the lung.

Results: COPD is a disease of the lung inflammaging, which is associated with the DNA damage response, transcription activation and chromatin modifications. SIRT1 regulates inflammaging via regulating forkhead box class O 3, p53, nuclear factor kappa B, histones and various proteins involved in DNA damage and repair. Polyphenols and its analogs have been shown to activate SIRT1 although they have anti-inflammatory and antioxidant properties.

Conclusions: Targeting lung inflammation and cellular senescence as well as premature lung aging using pharmacological SIRT1 activators or polyphenols would be a promising therapeutic intervention for COPD/emphysema.

Keywords: COPD; DNA damage response; FOXO3; Histone modifications; Inflammaging; NF-κB; Oxidative stress; Polyphenols; SIRT1; Tobacco smoke.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1. Oxidative stress induces persistent DNA damage leading to cellular senescence and inflammation

Sustained or persistent DNA damage from oxidative/carbonyl stress recruits checkpoint kinase ataxia telangiectasia mutated (ATM) leading to cellular senescence and inflammatory response through activation of p53 and NF-κB, respectively. Oxidative/carbonyl stress also damages the DNA repair pathways, such as double-strand break (DBS), base excision repair (BER), and nucleotide excision repair (NER), which further cause DNA damage. The cellular senescence and inflammation will form a positive feedback to compromise normal cellular homeostasis.

Figure 2. SIRT1 reduction caused by cigarette smoke results in deacetylation of proteins in DNA repair, FOXO3, p53 and NF-κB leading to premature lung aging

SIRT1 is subjected to posttranslational modifications in response to oxidative/carbonyl stress, which causes the acetylation of various substrates, including ku70, Werner syndrome protein, FOXO3, p53 and NF-κB. These molecules play an important role in initiating and causing inflammation, cellular senescence and DNA damage, which is a major characteristic of lung premature aging. Activation of SIRT1 by polyphenols and its analogs (pharmacological activators) may attenuate lung inflammaging.