Reduced expression of MYC increases longevity and enhances healthspan

Jeffrey W. Hofmann; Xiaoai Zhao; Marco De Cecco; Abigail L. Peterson; Luca Pagliaroli; Jayameenakshi Manivannan; Gene B. Hubbard; Yuji Ikeno; Yongqing Zhang; Bin Feng; Xiaxi Li; Thomas Serre; Wenbo Qi; Holly Van Remmen; Richard A. Miller; Kevin G. Bath; Rafael De Cabo; Haiyan Xu; Nicola Neretti; John M. Sedivy

doi:10.1016/j.cell.2014.12.016

Reduced expression of MYC increases longevity and enhances healthspan

Jeffrey W. Hofmann, Xiaoai Zhao, Marco De Cecco, Abigail L. Peterson, Luca Pagliaroli, Jayameenakshi Manivannan, Gene B. Hubbard, Yuji Ikeno, Yongqing Zhang, Bin Feng, Xiaxi Li, Thomas Serre, Wenbo Qi, Holly Van Remmen, Richard A. Miller, Kevin G. Bath, Rafael De Cabo, Haiyan Xu, Nicola Neretti, John M. Sedivy

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Abstract

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc^+/-) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc^+/- mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

Original language	English (US)
Pages (from-to)	477-488
Number of pages	12
Journal	Cell
Volume	160
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2014.12.016
State	Published - Jan 29 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., Hubbard, G. B., Ikeno, Y., Zhang, Y., Feng, B., Li, X., Serre, T., Qi, W., Van Remmen, H., Miller, R. A., Bath, K. G., De Cabo, R., Xu, H., Neretti, N., & Sedivy, J. M. (2015). Reduced expression of MYC increases longevity and enhances healthspan. Cell, 160(3), 477-488. https://doi.org/10.1016/j.cell.2014.12.016

Hofmann, JW, Zhao, X, De Cecco, M, Peterson, AL, Pagliaroli, L, Manivannan, J, Hubbard, GB, Ikeno, Y, Zhang, Y, Feng, B, Li, X, Serre, T, Qi, W, Van Remmen, H, Miller, RA, Bath, KG, De Cabo, R, Xu, H, Neretti, N & Sedivy, JM 2015, 'Reduced expression of MYC increases longevity and enhances healthspan', Cell, vol. 160, no. 3, pp. 477-488. https://doi.org/10.1016/j.cell.2014.12.016

@article{121b7d155de64011aa2d4fb15b0bd15d,

title = "Reduced expression of MYC increases longevity and enhances healthspan",

abstract = "MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/-) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/- mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.",

author = "Hofmann, {Jeffrey W.} and Xiaoai Zhao and {De Cecco}, Marco and Peterson, {Abigail L.} and Luca Pagliaroli and Jayameenakshi Manivannan and Hubbard, {Gene B.} and Yuji Ikeno and Yongqing Zhang and Bin Feng and Xiaxi Li and Thomas Serre and Wenbo Qi and {Van Remmen}, Holly and Miller, {Richard A.} and Bath, {Kevin G.} and {De Cabo}, Rafael and Haiyan Xu and Nicola Neretti and Sedivy, {John M.}",

note = "Funding Information: This work was supported by NIH grant R37 AG016694 to J.M.S. J.W.H. was supported in part by grant F30 AG035592. J.M.S. was a Senior Scholar of the Ellison Medical Foundation and a recipient of the Glenn Award for Research on the Biological Mechanisms of Aging. The Brown Molecular Pathology and Genomics core facilities were supported by NIH grants P42 ES013660 and P30 GM103410. R.dC. is funded by the Intramural Research Program of the National Institute on Aging (NIH). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jan,

day = "29",

doi = "10.1016/j.cell.2014.12.016",

language = "English (US)",

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T1 - Reduced expression of MYC increases longevity and enhances healthspan

AU - Hofmann, Jeffrey W.

AU - Zhao, Xiaoai

AU - De Cecco, Marco

AU - Peterson, Abigail L.

AU - Pagliaroli, Luca

AU - Manivannan, Jayameenakshi

AU - Hubbard, Gene B.

AU - Ikeno, Yuji

AU - Zhang, Yongqing

AU - Feng, Bin

AU - Li, Xiaxi

AU - Serre, Thomas

AU - Qi, Wenbo

AU - Van Remmen, Holly

AU - Miller, Richard A.

AU - Bath, Kevin G.

AU - De Cabo, Rafael

AU - Xu, Haiyan

AU - Neretti, Nicola

AU - Sedivy, John M.

N1 - Funding Information: This work was supported by NIH grant R37 AG016694 to J.M.S. J.W.H. was supported in part by grant F30 AG035592. J.M.S. was a Senior Scholar of the Ellison Medical Foundation and a recipient of the Glenn Award for Research on the Biological Mechanisms of Aging. The Brown Molecular Pathology and Genomics core facilities were supported by NIH grants P42 ES013660 and P30 GM103410. R.dC. is funded by the Intramural Research Program of the National Institute on Aging (NIH). Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/1/29

Y1 - 2015/1/29

N2 - MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/-) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/- mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

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Reduced expression of MYC increases longevity and enhances healthspan

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