Format

Send to

Choose Destination
Cell Metab. 2014 Nov 4;20(5):840-855. doi: 10.1016/j.cmet.2014.10.005. Epub 2014 Nov 4.

A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome.

Author information

1
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
3
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
4
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
5
Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.
6
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
7
The Brain and Muscle Energy Group - Synaptic Neurochemistry Laboratory, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; Danish Center for Healthy Aging, ICMM, University of Copenhagen, Copenhagen, Denmark.
8
Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney, NSW 2139, Australia.
9
Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney, NSW 2139, Australia.
10
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: decabora@grc.nia.nih.gov.
11
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Danish Center for Healthy Aging, ICMM, University of Copenhagen, Copenhagen, Denmark. Electronic address: vbohr@nih.gov.

Abstract

Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csb(m/m) mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/m) mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD(+) supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS.

PMID:
25440059
PMCID:
PMC4261735
DOI:
10.1016/j.cmet.2014.10.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center