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Role of Sirt1 During the Ageing Process: Relevance to Protection of Synapses in the Brain

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Abstract

Ageing is a stochastic process associated with a progressive decline in physiological functions which predispose to the pathogenesis of several neurodegenerative diseases. The intrinsic complexity of ageing remains a significant challenge to understand the cause of this natural phenomenon. At the molecular level, ageing is thought to be characterized by the accumulation of chronic oxidative damage to lipids, proteins and nucleic acids caused by free radicals. Increased oxidative stress and misfolded protein formations, combined with impaired compensatory mechanisms, may promote neurodegenerative disorders with age. Nutritional modulation through calorie restriction has been shown to be effective as an anti-ageing factor, promoting longevity and protecting against neurodegenerative pathology in yeast, nematodes and murine models. Calorie restriction increases the intracellular levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1) activity and a cofactor for oxidative phosphorylation and ATP synthesis. Promotion of intracellular NAD+ anabolism is speculated to induce neuroprotective effects against amyloid-β-peptide (Aβ) toxicity in some models for Alzheimer’s disease (AD). The NAD+-dependent histone deacetylase, Sirt1, has been implicated in the ageing process. Sirt1 serves as a deacetylase for numerous proteins involved in several cellular pathways, including stress response and apoptosis, and plays a protective role in neurodegenerative disorders, such as AD.

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Acknowledgements

This work was supported by grants PFB 12/2007 from the Basal Centre for Excellence in Science and Technology, FONDECYT 1120156 and MIFAB Institute and Fundación Ciencia y Vida to NCI and FONDECYT No. 11130033 to JMZ. NB is a recipient of the Alzheimer’s Australia and NHMRC Early Career Postdoctoral Research Fellowship at the University of New South Wales, Sydney, Australia.

Conflict of Interest

The authors declare that they have no competing interests.

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  1. Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Alameda 340, Santiago, Chile

    Juan A. Godoy & Nibaldo C. Inestrosa

  2. Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica, Chile

    Juan M. Zolezzi

  3. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nady Braidy & Nibaldo C. Inestrosa

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  1. Juan A. Godoy
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  2. Juan M. Zolezzi
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  4. Nibaldo C. Inestrosa
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Correspondence to Nibaldo C. Inestrosa.

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Godoy, J.A., Zolezzi, J.M., Braidy, N. et al. Role of Sirt1 During the Ageing Process: Relevance to Protection of Synapses in the Brain. Mol Neurobiol 50, 744–756 (2014). https://doi.org/10.1007/s12035-014-8645-5

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  • DOI: https://doi.org/10.1007/s12035-014-8645-5

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