A high-fat diet and NAD+ activate sirt1 to rescue premature aging in cockayne syndrome

Morten Scheibye-Knudsen; Sarah J. Mitchell; Evandro F. Fang; Teruaki Iyama; Theresa Ward; James Wang; Christopher A. Dunn; Nagendra Singh; Sebastian Veith; Md Mahdi Hasan-Olive; Aswin Mangerich; Mark A. Wilson; Mark P. Mattson; Linda H. Bergersen; Victoria C. Cogger; Alessandra Warren; David G. Le Couteur; Ruin Moaddel; David M. Wilson; Deborah L. Croteau; Rafael De Cabo; Vilhelm A. Bohr

doi:10.1016/j.cmet.2014.10.005

A high-fat diet and NAD⁺ activate sirt1 to rescue premature aging in cockayne syndrome

Morten Scheibye-Knudsen, Sarah J. Mitchell, Evandro F. Fang, Teruaki Iyama, Theresa Ward, James Wang, Christopher A. Dunn, Nagendra Singh, Sebastian Veith, Md Mahdi Hasan-Olive, Aswin Mangerich, Mark A. Wilson, Mark P. Mattson, Linda H. Bergersen, Victoria C. Cogger, Alessandra Warren, David G. Le Couteur, Ruin Moaddel, David M. Wilson, Deborah L. CroteauRafael De Cabo^*, Vilhelm A. Bohr

^*Corresponding author for this work

177 Citations (Scopus)

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.

Original language	English
Journal	Cell Metabolism
Volume	20
Issue number	5
Pages (from-to)	840-855
Number of pages	16
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2014.10.005
Publication status	Published - 4 Nov 2014

Access to Document

10.1016/j.cmet.2014.10.005

http://www.cell.com/article/S1550413114004525/pdf

Cite this

Scheibye-Knudsen, M., Mitchell, S. J., Fang, E. F., Iyama, T., Ward, T., Wang, J., Dunn, C. A., Singh, N., Veith, S., Hasan-Olive, M. M., Mangerich, A., Wilson, M. A., Mattson, M. P., Bergersen, L. H., Cogger, V. C., Warren, A., Le Couteur, D. G., Moaddel, R., Wilson, D. M., ... Bohr, V. A. (2014). A high-fat diet and NAD⁺ activate sirt1 to rescue premature aging in cockayne syndrome. Cell Metabolism, 20(5), 840-855. https://doi.org/10.1016/j.cmet.2014.10.005

Scheibye-Knudsen, M, Mitchell, SJ, Fang, EF, Iyama, T, Ward, T, Wang, J, Dunn, CA, Singh, N, Veith, S, Hasan-Olive, MM, Mangerich, A, Wilson, MA, Mattson, MP, Bergersen, LH, Cogger, VC, Warren, A, Le Couteur, DG, Moaddel, R, Wilson, DM, Croteau, DL, De Cabo, R & Bohr, VA 2014, 'A high-fat diet and NAD⁺ activate sirt1 to rescue premature aging in cockayne syndrome', Cell Metabolism, vol. 20, no. 5, pp. 840-855. https://doi.org/10.1016/j.cmet.2014.10.005

@article{d61458e6ad5b4baca35ceecb00d0ffb4,

title = "A high-fat diet and NAD+ activate sirt1 to rescue premature aging in cockayne syndrome",

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, Csbm/m mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csbm/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.",

author = "Morten Scheibye-Knudsen and Mitchell, {Sarah J.} and Fang, {Evandro F.} and Teruaki Iyama and Theresa Ward and James Wang and Dunn, {Christopher A.} and Nagendra Singh and Sebastian Veith and Hasan-Olive, {Md Mahdi} and Aswin Mangerich and Wilson, {Mark A.} and Mattson, {Mark P.} and Bergersen, {Linda H.} and Cogger, {Victoria C.} and Alessandra Warren and {Le Couteur}, {David G.} and Ruin Moaddel and Wilson, {David M.} and Croteau, {Deborah L.} and {De Cabo}, Rafael and Bohr, {Vilhelm A.}",

year = "2014",

month = nov,

day = "4",

doi = "10.1016/j.cmet.2014.10.005",

language = "English",

volume = "20",

pages = "840--855",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - A high-fat diet and NAD+ activate sirt1 to rescue premature aging in cockayne syndrome

AU - Scheibye-Knudsen, Morten

AU - Mitchell, Sarah J.

AU - Fang, Evandro F.

AU - Iyama, Teruaki

AU - Ward, Theresa

AU - Wang, James

AU - Dunn, Christopher A.

AU - Singh, Nagendra

AU - Veith, Sebastian

AU - Hasan-Olive, Md Mahdi

AU - Mangerich, Aswin

AU - Wilson, Mark A.

AU - Mattson, Mark P.

AU - Bergersen, Linda H.

AU - Cogger, Victoria C.

AU - Warren, Alessandra

AU - Le Couteur, David G.

AU - Moaddel, Ruin

AU - Wilson, David M.

AU - Croteau, Deborah L.

AU - De Cabo, Rafael

AU - Bohr, Vilhelm A.

PY - 2014/11/4

Y1 - 2014/11/4

N2 - 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, Csbm/m mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csbm/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.

AB - 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, Csbm/m mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csbm/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.

UR - http://www.scopus.com/inward/record.url?scp=84910132320&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2014.10.005

DO - 10.1016/j.cmet.2014.10.005

M3 - Journal article

C2 - 25440059

AN - SCOPUS:84910132320

SN - 1550-4131

VL - 20

SP - 840

EP - 855

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

A high-fat diet and NAD⁺ activate sirt1 to rescue premature aging in cockayne syndrome

Abstract

Access to Document

Other files and links

Fingerprint

Cite this