Regulation of SIRT1 in aging: Roles in mitochondrial function and biogenesis

https://doi.org/10.1016/j.mad.2016.02.003Get rights and content

Highlights

  • Descripting the dysregulation of mitochondrial biogenesis in the development of aging and aging-related diseases.

  • Completed description of the transcriptional and post-translational regulation of SIRT1 in aging process.

  • Regulation of mitochondrial biogenesis via SIRT1-PGC1α dependent and independent pathway have been elaborated in this paper.

Abstract

Aging is a degenerative process associated with cumulative damage, which leads to cellular dysfunction, tissue failure, and disorders of body function. Silent information regulator-1, also known as sirtuin 1 (SIRT1), has been reported to be involved in the regulation of various important biological processes, including inflammation, mitochondrial biogenesis, as well as cell senescence and consequent aging. The level of SIRT1 is decreased in both transcriptional and postranscriptional conditions during aging, accompanied by attenuated mitochondrial biogenesis, an important component of aging-related diseases. Over the last decade, extensive studies have demonstrated that SIRT1 can activate several transcriptional factors, such as peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) and hypoxia-inducible factor 1α (HIF-1α) resulting in ameliorated mitochondria biogenesis and extended life span. In this review, we focus on the molecular regulation of SIRT1 and its role in mitochondrial biogenesis during in the context of aging and aging-related diseases.

Introduction

Aging is a degenerative process, manifested by the progressive decline in physiological functions in biological systems. The deleterious changes are believed to be associated with metabolic activities and are controlled by many factors including genetic traits, environmental stimuli and stochastic processes. A well-known theory of aging, presented by Denham Harman is the “free radical theory of aging”. Briefly, the theory is based on the idea that free radicals, in particular reactive oxygen species (ROS) produced from normal metabolism, may be the primary cause of aging and aging-related degenerative diseases. Few years later, professor Harman updated the theory with the “mitochondrial theory of aging” (Lee and Wei, 2012) (Bereiter-Hahn, 2014), claiming that as an organism grows, mitochondria accumulate oxidative damage caused by the toxicity of ROS. Reactive species are associated with detrimental effects on mitochondrial function, leading to abnormal amounts of ROS production, and so further damage.

As an essential intracellular organelle for aerobic metabolism, mitochondria are critically relevant to energy homeostasis, since approximately 90% of cellular ATP production is associated with oxidative phosphorylation in the respiratory chain (RC) complexes located in their inner membrane (Romano et al., 2014). The decline of mitochondrial function has been reported to be important during the process of aging with distinct mitochondrial morphological changes, e.g., abnormal rounded mitochondria (Lin et al., 2015), reduction of mitochondrial DNA but increase of mutation rate (Gaziev et al., 2014, LaRocca et al., 2014), reduction of RC activity (Sudheesh et al., 2009) as well as impaired mitochondrial biogenesis (8). A decrease in mitochondrial biogenesis may reduce the turnover of mitochondrial components resulting in the accumulation of oxidized lipids, proteins and DNA (Ungvari et al., 2010). Thus, it is believed that maintenance of mitochondrial biogenesis capacity during aging is a key factor in preventing the progression of aging-related diseases.

With homology to Saccharomyces cerevisiae silent information regulator 2 (Sir2), the sirtuin family is a highly conserved class of nicotinamide adenine dinucleotide (NAD+) dependent deacetylases and ADP-ribosyltransferase proteins. This family is composed by seven members in both prokaryotes and eukaryotes (Morris, 2013). SIRT1 is the most extensively studied sirtuin protein, probably because of its involvement in the regulations of diverse cellular physiological and pathological processes including gene silencing, stress resistance, apoptosis, inflammation and senescence, as well as its potential for therapeutic approaches (Chung et al., 2010, LaRocca et al., 2014, Revollo and Li, 2013). Interestingly, overexpression of SIRT1 in mice (Sirt1-overexpressing transgenic mice) results in significant life span extension and exhibits phenotypes associated with delayed aging, such as enhancement in physical activity, body temperature, oxygen consumption, and quality of sleep compared to age-matched control mice, whereas inhibition of SIRT1 in these mice abrogates the effect of life span extension (Satoh et al., 2013).

Recent studies demonstrated that SIRT1 promotes mitochondrial biogenesis by deacetylation of target proteins such as peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) (Wenz, 2013) and hypoxia-inducible factor 1α (HIF-1α) (Gomes et al., 2013). These findings suggested potential therapeutic benefits of SIRT1 activation for metabolic and other aging-related diseases. For the better understanding of its molecular and cellular mechanisms, we discussed the role of SIRT1 in aging focusing on the regulation of mitochondrial biogenesis in this review.

Section snippets

Mitochondrial biogenesis

Mitochondria are the most dynamically responsive sensing systems in eukaryotic cells, acting to satisfy metabolic energy demands, supply biosynthetic precursors, and consequently regulate diverse processes, including proliferation (Li et al., 2015a), immune responses (Kim et al., 2015), apoptosis (Kuo et al., 2015), and cell viability (Radogna et al., 2015). Cells can degrade damaged mitochondria (the process of mitophagy) and under appropriate conditions, stimulate functional mitochondria to

SIRT1 and aging

SIRT1 has the capability to extend life span, delay aging and prevent aging-related diseases, mainly by catalyzing the deacetylation of histones, and regulation of transcription factors, or coactivators, such as P53, forkhead box O (FOXO), nuclear factor-κB (NF-κB), PGC-1α, and Ku70 (Table 1) (Ramis et al., 2015, Yao and Rahman, 2012). Activity is augmented by a SIRT1 activator (e.g., SRT1720), leading to attenuation of stress-induced premature cellular senescence and protection against

Role of SIRT1 in mitochondrial biogenesis

Evidence has suggested that increased mitochondrial biogenesis mediated by SIRT1 plays a key role in improving life span and aging-related diseases (Menzies and Hood, 2012). Indeed, some studies have proven that pharmacological treatment targeting for stimulating SIRT1 such as Resveratrol (Sin et al., 2014), Metformin (Qin et al., 2014), and Tetramethylpyrazine (Xu et al., 2014), increase mitochondrial biogenesis, slowing senescence. In respect to the mechanisms involved, both PGC1α-dependent

Conclusion

SIRT1 acts in the complex coordination of nuclear, cytosolic and mitochondrial metabolic and cell stress responses. Beside its role in metabolism, stress resistance, apoptosis, autophagy and inflammation, SIRT1 regulates senescence through deacetylation of target proteins when the NAD+/NADH balance is disturbed by ROS and oxidative stress. Through AMPK, HIF-1α and PGC1α, SIRT1 activates mitochondrial biogenesis promoting an increase in expression of mitochondrial genes critical for

Acknowledgement

This work was supported by the National Natural Science Foundation of China: Grant number: 81370824.

References (140)

  • S. Chung et al.

    Regulation of SIRT1 in cellular functions: role of polyphenols

    Arch. Biochem. Biophys.

    (2010)
  • V. Dehennaut et al.

    DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair

    J. Biol. Chem.

    (2013)
  • S. Deng et al.

    Chronic pancreatitis and pancreatic cancer demonstrate active epithelial-mesenchymal transition profile, regulated by miR-217-SIRT1 pathway

    Cancer Lett.

    (2014)
  • E.F. Fang et al.

    Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction

    Cell

    (2014)
  • R.A. Frye

    Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins

    Biochem. Biophys. Res. Commun.

    (2000)
  • Z.G. Gao et al.

    Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity

    J. Biol. Chem.

    (2011)
  • C.F. García-Prieto et al.

    Vascular AMPK as an attractive target in the treatment of vascular complications of obesity

    Vasc. Pharmacol.

    (2015)
  • A.P. Gomes et al.

    Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging

    Cell

    (2013)
  • A.Z. Herskovits et al.

    SIRT1 in neurodevelopment and brain senescence

    Neuron

    (2014)
  • J.W. Hwang et al.

    Redox regulation of SIRT1 in inflammation and cellular senescence

    Free Radic. Biol. Med.

    (2013)
  • T. Ito et al.

    MicroRNA-34a regulation of endothelial senescence

    Biochem. Biophys. Res. Commun.

    (2010)
  • K. Ji et al.

    Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1alpha pathway

    Free Radic. Biol. Med.

    (2015)
  • S. Kim et al.

    Mitochondrial reactive oxygen species modulate innate immune response to influenza A virus in human nasal epithelium

    Antivir. Res.

    (2015)
  • C.Y. Kuo et al.

    Mitochondrial Lon protease controls ROS-dependent apoptosis in cardiomyocyte under hypoxia

    Mitochondrion

    (2015)
  • T.J. LaRocca et al.

    Mitochondrial quality control and age-associated arterial stiffening

    Exp. Gerontol.

    (2014)
  • N. Li et al.

    Increased expression of miR-34a and miR-93 in rat liver during aging: and their impact on the expression of Mgst1 and Sirt1

    Mech. Ageing Dev.

    (2011)
  • Y. Li et al.

    Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling regulates mitochondrial biogenesis and respiration via estrogen-related receptor alpha (ERRalpha)

    J. Biol. Chem.

    (2013)
  • G. Lopez-Lluch et al.

    Mitochondrial biogenesis and healthy aging

    Exp. Gerontol.

    (2008)
  • K.J. Menzies et al.

    The role of SirT1 in muscle mitochondrial turnover

    Mitochondrion

    (2012)
  • B.J. Morris

    Seven sirtuins for seven deadly diseases of aging

    Free Radic. Biol. Med.

    (2013)
  • K.A. Moynihan et al.

    Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice

    Cell Metab.

    (2005)
  • A. Purushotham et al.

    Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation

    Cell Metab.

    (2009)
  • F. Radogna et al.

    Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid

    Mitochondrion

    (2015)
  • M.R. Ramis et al.

    Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

    Mech. Ageing Dev.

    (2015)
  • J.R. Revollo et al.

    The ways and means that fine tune Sirt1 activity

    Trends Biochem. Sci.

    (2013)
  • J.T. Rodgers et al.

    Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways

    FEBS Lett.

    (2008)
  • R. Amat et al.

    SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma Co-activator-1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha autoregulatory loop and interaction with MyoD

    J. Biol. Chem.

    (2009)
  • K. Aquilano et al.

    Extranuclear localization of SIRT1 and PGC-1: an insight into possible roles in diseases associated with mitochondrial dysfunction

    Curr. Mol. Med.

    (2013)
  • G. Arunachalam et al.

    Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1

    Br. J. Pharmacol.

    (2014)
  • B. Bai et al.

    Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis

    Circulation

    (2012)
  • S. Baldelli et al.

    PGC-1alpha buffers ROS-mediated removal of mitochondria during myogenesis

    Cell Death Dis.

    (2014)
  • E. Bellafante et al.

    PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine

    PNAS

    (2014)
  • J. Bereiter-Hahn

    Do we age because we have mitochondria?

    Protoplasma

    (2014)
  • Vanessa Byles et al.

    Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K IGF-1R signaling in human cancer cells

    Int. J. Biol. Sci.

    (2010)
  • S. Caito et al.

    SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress

    FASEB J.

    (2010)
  • P.C. Calder et al.

    Glucose metabolism in lymphoid and inflammatory cells and tissues

    Curr. Opin. Clin. Nutr. Metab. Care

    (2007)
  • C. Canto et al.

    AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

    Nature

    (2009)
  • J. Carabelli et al.

    High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia

    J. Cell. Mol. Med.

    (2011)
  • S.H. Cho et al.

    SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1 beta

    J. Neurosci.

    (2015)
  • S.E. Choi et al.

    Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT

    Aging Cell

    (2013)
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