Silent information regulator, Sirtuin 1, and age‐related diseases

Abstract

Sirtuin 1 (SIRT1), a member of the silent information regulator 2 in mammals, has recently been found to be involved in age-related diseases, such as cancer, metabolic diseases, cardiovascular disease, neurodegenerative diseases, osteoporosis and chronic obstructive pulmonary disease (COPD), mainly through deacetylation of substrates such as p53, forkhead box class O, peroxisome proliferator activated receptor g co-activator 1a, and nuclear factor-kB. It is widely reported that SIRT1 can promote not only carcinogenesis but also metastasis and insulin resistance, andhave beneficial effects in metabolic diseases, mediate high-density lipoprotein synthesis and regulate endothelial nitric oxide to protect against cardiovascular disease, have a cardioprotective role in heart failure, protect against neurodegenerative pathological changes, promote osteoblast differentiation, and also play a pivotal role as an anti-inflammatory mediator in COPD. However, there are controversial results suggesting that SIRT1 has an effect in protecting against DNA damage and accumulation of mutations, and preventing tumorigenesis. In addition, a high level of SIRT1 can induce cardiomyopathy and even heart failure. This article reviews recent developments relating to these issues.

SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice

“…SIRT1 deacetylates not only histone proteins but various transcription factors such as p53, the forkhead box class O (FOXO) transcription factor, peroxisome proliferator activated receptors (PPARs) co-activator 1α (PGC-1α) and nuclear factor-κB (10,26). The substrates of SIRT1 are expected to differ from one organ to another (27). Therefore, SIRT1 would play different roles depending on the type of tissue or tumor, although SIRT1 expression is upregulated in a variety of cancer types as mentioned in the Introduction.…”

SIRT1 gene is associated with cardiovascular disease in the Iranian population

“…SIRT1 has protective effects against CVD and through its deacetylase activity plays pivotal roles in regulating numerous biological functions including regulation of energy, detoxification of oxidative stress, promotion of angiogenesis, intracellular Ca 2+ handling, promoting cell survival and longevity and induction of autophagy [7]. SIRT1 exerts its function through deacetylation of important substrates such as p53, Forkhead box class O (FOXO) transcription factors, peroxisome proliferator activated receptor (PPAR)g co-activator 1a (PGC-1a), nuclear factor (NF)-jB and others, which are all closely linked to the age-related diseases including CVD [6]. Cardiac-specific upregulation of SIRT1 has extensively been shown to prevent atherogenesis, premature cardiac hypertrophy, apoptosis, cardiac fibrosis, cardiac dysfunction, and expression of cellular senescence markers, which increases with age [8][9][10].…”

“…As the exciting targets for CVD management, Sirtuins are expressed broadly in the nucleus and cytoplasm of multiple tissues and highly expressed in the heart tissue and the vascular endothelium [5]. SIRT1 is the best-known member of the sirtuin family which belongs to the sirtuin family of nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylases, whose activation appears beneficial for aging associated metabolic, inflammatory, and cardiac diseases, and to increase lifespan in model organisms [6]. SIRT1 has protective effects against CVD and through its deacetylase activity plays pivotal roles in regulating numerous biological functions including regulation of energy, detoxification of oxidative stress, promotion of angiogenesis, intracellular Ca 2+ handling, promoting cell survival and longevity and induction of autophagy [7].…”

Expanding Proteostasis by Membrane Trafficking Networks

“…For example, the APS has been shown to control the function of key proteostasis components (Westerheide et al 2009;Zeng et al 2009;Hutt et al 2010;Bouchareilh et al 2012) such as Hsp90 (Aoyagi and Archer 2005) and the central HSR transcription factor, heat shock factor 1 (HSF1) ( Fig. 1) (Westerheide et al 2009;Zeng et al 2009;Morimoto 2011). The APS also regulates protein degradation through its links to the UPS (Box 2) (Canettieri et al 2010;Du et al 2010;Alamdari et al 2012) as well as autophagy (Yi et al 2012).…”

“…1). For example, the APS has been shown to control the function of key proteostasis components (Westerheide et al 2009;Zeng et al 2009;Hutt et al 2010;Bouchareilh et al 2012) such as Hsp90 (Aoyagi and Archer 2005) and the central HSR transcription factor, heat shock factor 1 (HSF1) ( Fig. 1) (Westerheide et al 2009;Zeng et al 2009;Morimoto 2011).…”