Review
Dichotomous Sirtuins: Implications for Drug Discovery in Neurodegenerative and Cardiometabolic Diseases

https://doi.org/10.1016/j.tips.2019.09.003Get rights and content

Highlights

  • Mammalian sirtuins (SIRT1–7) are NAD+-dependent deacylases with essential roles in the regulation of cellular homeostasis and stress responses.

  • Research has shown that sirtuins, and SIRT1 in particular, are promising therapeutic targets for numerous diseases, particularly neurodegenerative and cardiometabolic diseases.

  • Recent research has uncovered divergent findings resulting from the modulation of different sirtuin isoforms, which may stem from methodological differences and/or poorly characterized biological functions.

  • Resolving these discrepancies is likely to expand our knowledge of the relevance of sirtuins in human disease, necessary to make an informed choice of the most appropriate pharmacological strategy for specific therapeutic applications.

Sirtuins (SIRT1–7), a class of NAD+-dependent deacylases, are central regulators of metabolic homeostasis and stress responses. While numerous salutary effects associated with sirtuin activation, especially SIRT1, are well documented, other reports show health benefits resulting from sirtuin inhibition. Furthermore, conflicting findings have been obtained regarding the pathophysiological role of specific sirtuin isoforms, suggesting that sirtuins act as ‘double-edged swords’. Here, we provide an integrated overview of the different findings on the role of mammalian sirtuins in neurodegenerative and cardiometabolic disorders and attempt to dissect the reasons behind these different effects. Finally, we discuss how addressing these obstacles may provide a better understanding of the complex sirtuin biology and improve the likelihood of identifying effective and selective drug targets for a variety of human disorders.

Section snippets

Overview of Sirtuin Research

Sirtuins are highly conserved enzyme homologs of the Saccharomyces cerevisiae silent information regulator 2 (Sir2) gene, initially identified as genetic silencing factors in yeast and later found to extend longevity in several organisms 1, 2. Similar to yeast Sir2 [3], the mammalian sirtuins (SIRT1–7) (Box 1) are a family of conserved enzymes with NAD+-dependent deacylase (see Glossary) activity. Given that sirtuins exhibit ubiquitous tissue distribution and act on many protein substrates in

Sirtuins in Neurodegenerative Diseases

Sirtuins have been implicated in the modulation of age-related neurodegenerative disorders and the toxicity associated with different proteins, namely α-synuclein, huntingtin, tau, or amyloid β (Aβ) peptide [6]. Here, we discuss the most relevant studies that produced contradictory results on the biological and therapeutic roles of sirtuins in major neurodegenerative disorders and frequently associated comorbidities, such as depression, cognitive deficits, stroke, neuropathic pain, and seizures.

Sirtuins in Cardiometabolic Diseases

It is widely accepted that compromised sirtuin activity and/or expression contributes to the pathogenesis of cardiovascular and metabolic diseases [45]. While a significant proportion of these studies have demonstrated that increasing sirtuin activity and/or expression in mice can mitigate disease syndromes, some reports also show the opposite effects in certain diseases and settings. Here, we review these contrasting findings.

Potential Causes for the Observed Dichotomy of Sirtuins

Here, we discuss the putative causes of the observed dichotomy in the activity of sirtuins when modulated pharmacologically and genetically.

Concluding Remarks and Future Perspectives

Owing to their broad spectrum of health-promoting effects, sirtuins have emerged as attractive therapeutic targets for several age-related diseases. However, accumulating evidence demonstrates distinct functions and disease outcomes following genetic and/or pharmacological sirtuin modulation, suggesting that sirtuins are capable of functioning as either positive or negative regulators of disease-associated pathways (Figure 1). Although the mechanisms underlying these apparently contradictory

Acknowledgments

This work was supported by European Regional Development Fund (FEDER), through Programa Operacional Factores de Competitividade COMPETE2020 and National funds via Fundação para a Ciência e a Tecnologia (FCT) under the projects POCI-01-0145-FEDER-007440, UID/NEU/04539/2013, UID/NEU/04539/2019, POCI-01-0145-FEDER-030167, POCI-01-0145-FEDER-031712, PTDC/SAU-NUT/31712/2017, and CENTRO-01-0145-FEDER-000012-HealthyAging. H.L. is supported by a PhD scholarship from FCT (SFRH/BD/121923/2016). We are

Glossary

α-synuclein
aggregation-prone presynaptic neuronal protein that is linked to the pathogenesis of PD.
Amyloid β (Aβ)
peptide derived from the amyloid precursor protein (APP) that forms the amyloid plaques found in the brains of patients with AD.
Demalonylation
removal of a malonyl group from a specific lysine residue of a target protein.
Demyristoylation
removal of a myristoyl group attached covalently by an amide bond to the alpha-amino group of an N-terminal glycine residue.
Desuccinylation
removal of

References (115)

  • L. Liu

    Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson's disease

    Behav. Brain Res.

    (2015)
  • C. Diaz-Canestro

    Sirtuin 5 as a novel target to blunt blood-brain barrier damage induced by cerebral ischemia/reperfusion injury

    Int. J. Cardiol.

    (2018)
  • S. Kaluski

    Neuroprotective functions for the histone deacetylase SIRT6

    Cell Rep.

    (2017)
  • J.M. Andrade

    Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation

    Nutrition

    (2014)
  • C. Sun

    SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B

    Cell Metab.

    (2007)
  • A. Chalkiadaki et al.

    High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction

    Cell Metab.

    (2012)
  • M. Lu

    Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues

    J. Biol. Chem.

    (2013)
  • Y. Li

    SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons

    Cell Metab.

    (2008)
  • M. Pacholec

    SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1

    J. Biol. Chem.

    (2010)
  • E. Jing

    SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation

    Cell Metab.

    (2007)
  • J.P. Belman

    Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment

    J. Biol. Chem.

    (2015)
  • Y. Lu

    SIRT3 in cardiovascular diseases: emerging roles and therapeutic implications

    Int. J. Cardiol.

    (2016)
  • R. Paulin

    Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans

    Cell Metab.

    (2014)
  • C. Canto

    The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity

    Cell Metab.

    (2012)
  • J.G. Anderson

    Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6

    Mol. Metab.

    (2015)
  • J.E. Dominy

    The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis

    Mol. Cell

    (2012)
  • R. Mostoslavsky

    Genomic instability and aging-like phenotype in the absence of mammalian SIRT6

    Cell

    (2006)
  • L. Zhong

    The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha

    Cell

    (2010)
  • N. Nasrin

    SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells

    J. Biol. Chem.

    (2010)
  • K.A. Hershberger

    Sirtuin 5 is required for mouse survival in response to cardiac pressure overload

    J. Biol. Chem.

    (2017)
  • K.A. Hershberger

    Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload

    J. Biol. Chem.

    (2018)
  • D. Ryu

    A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function

    Cell Metab.

    (2014)
  • J. Shin

    SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease

    Cell Rep.

    (2013)
  • T. Yoshizawa

    SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway

    Cell Metab.

    (2014)
  • S.J. Park

    Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

    Cell

    (2012)
  • M.C. Haigis et al.

    Mammalian sirtuins: biological insights and disease relevance

    Annu. Rev. Pathol.

    (2010)
  • S.J. Lin

    Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae

    Science

    (2000)
  • S. Imai

    Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

    Nature

    (2000)
  • P. Bheda

    The substrate specificity of sirtuins

    Annu. Rev. Biochem.

    (2016)
  • J.A. Baur

    Are sirtuins viable targets for improving healthspan and lifespan?

    Nat. Rev. Drug Discov.

    (2012)
  • D. Kim

    SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

    EMBO J.

    (2007)
  • D. Porquet

    Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer's disease

    J. Alzheimers Dis.

    (2014)
  • H. Jeong

    Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway

    Nat. Med.

    (2011)
  • L. Naia

    Comparative mitochondrial-based protective effects of resveratrol and nicotinamide in Huntington’s disease models

    Mol. Neurobiol.

    (2017)
  • J. Cunha-Santos

    Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway

    Nat. Commun.

    (2016)
  • M.R. Smith

    A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease

    Hum. Mol. Genet.

    (2014)
  • K.N. Green

    Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau

    J. Neurosci.

    (2008)
  • T.F. Outeiro

    Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease

    Science

    (2007)
  • G. Biella

    Sirtuin 2 inhibition improves cognitive performance and acts on amyloid-beta protein precursor processing in two Alzheimer's disease mouse models

    J. Alzheimers Dis.

    (2016)
  • R. Luthi-Carter

    SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

    Proc. Natl. Acad. Sci. U S A

    (2010)
  • Cited by (25)

    • The role of microRNA-34 family in Alzheimer's disease: A potential molecular link between neurodegeneration and metabolic disorders

      2021, Pharmacological Research
      Citation Excerpt :

      The important roles of PTP1B related to obesity and diabetes were confirmed by a deletion of PTP1B gene in mice [209,210]. Decreased levels of SIRT1 and its co-substrate (NAD+) can be seen in many age related diseases, including neurodegeneration, diabetes and cancer [211–214]. Interestingly, SIRT1 can be regulated directly by miR-34a and there is evidence showing the connection between low levels of hepatic SIRT1 and high levels of miR-34a in fatty liver disease and obesity [43,215].

    • Common risk factors and therapeutic targets in obstructive sleep apnea and osteoarthritis: An unexpectable link?

      2021, Pharmacological Research
      Citation Excerpt :

      Although this antagonistic crosstalk between NF-κB and SIRT1 is far more complex, its outcome is either the persistence of inflammation associated with glycolytic energy flux, oxidative stress and cellular senescence, if NF-κB predominates, as occurs in OA, OSA and many other conditions associated with aging and metabolic disturbances; or the resolution of inflammation with increased energy production through oxidative phosphorylation and cell survival, when SIRT1 expression and activity are restored [9,10]. In line with this, pre-clinical and clinical studies suggest that resveratrol and other SIRT1 activators have beneficial effects on lipid and glucose metabolism, improving cognitive functions in models of neurodegenerative diseases and causing an overall anti-aging effect [11,226]. In vitro and in vivo studies of OA indicate that inducing SIRT1 expression and/or activity has protective effects, reducing inflammatory and catabolic responses, increasing the production of major cartilage matrix components and promoting chondrocyte survival [50,54,56,227–231].

    • Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT

      2021, Bioorganic and Medicinal Chemistry
      Citation Excerpt :

      Mammalian SIRTs consist of seven isoforms (SIRT1-7), which show different subcellular localizations and enzymatic functions.2 The SIRT enzymes have been engaged in various pathologies such as cancer, neurodegeneration, diabetes, inflammation, cardiovascular diseases and therefore, the modulation of SIRTs is of therapeutic importance.3–12 SIRT1 and SIRT2 are the best studied members of sirtuin family at present, and several SIRT1/2 inhibitors have been described, including nicotinamide, splitomicin and its analogues, sirtinol, tenovin, suramin and its analogues, cambinol, salermide, toxoflavin, thiobarbiturates, and other compounds.1,13–19

    View all citing articles on Scopus
    View full text