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Deletion of microRNA-80 activates dietary restriction to extend C. elegans healthspan and lifespan.

Vora M, Shah M, Ostafi S, Onken B, Xue J, Ni JZ, Gu S, Driscoll M - PLoS Genet. (2013)

Bottom Line: Caloric/dietary restriction (CR/DR) can promote longevity and protect against age-associated disease across species.The molecular mechanisms coordinating food intake with health-promoting metabolism are thus of significant medical interest.Under food limitation, lowered miR-80 levels directly or indirectly increase CBP-1 protein levels to engage metabolic loops that promote DR.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.

ABSTRACT
Caloric/dietary restriction (CR/DR) can promote longevity and protect against age-associated disease across species. The molecular mechanisms coordinating food intake with health-promoting metabolism are thus of significant medical interest. We report that conserved Caenorhabditis elegans microRNA-80 (mir-80) is a major regulator of the DR state. mir-80 deletion confers system-wide healthy aging, including maintained cardiac-like and skeletal muscle-like function at advanced age, reduced accumulation of lipofuscin, and extended lifespan, coincident with induction of physiological features of DR. mir-80 expression is generally high under ad lib feeding and low under food limitation, with most striking food-sensitive expression changes in posterior intestine. The acetyltransferase transcription co-factor cbp-1 and interacting transcription factors daf-16/FOXO and heat shock factor-1 hsf-1 are essential for mir-80(Δ) benefits. Candidate miR-80 target sequences within the cbp-1 transcript may confer food-dependent regulation. Under food limitation, lowered miR-80 levels directly or indirectly increase CBP-1 protein levels to engage metabolic loops that promote DR.

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A model for miR-80 regulation of DR metabolism.In adults, when food is abundant, mir-80 is expressed at a high level, and miR-80 binds to metabolic and signaling targets to down-regulate their expression. The cbp-1 transcript, which includes two potential binding sites for miR-80, one in the 5′ UTR and one in exon 8 (exons thick dark blue lines, promoter lighter blue), and is essential for mir-80(Δ) benefits, is one candidate target (light blue represents relatively low CBP-1 concentration in food). When food is limiting, miR-80 levels drop, and translational repression of cbp-1 could be relieved (dark blue circle represents higher concentration CBP-1). The CBP-1 protein associates with DAF-16 and HSF-1 to promote expression of genes required for DR metabolism and longevity. Note that although cbp-1 is essential for mir-80(Δ) DR benefits, direct targeting remains to be proved and it is likely that additional targets help modulate the DR state. Since we cannot rule out that daf-16, hsf-1, and cbp-1 disruptions make animals too generally sick to gain mir-80(Δ) benefits, alternative models are possible.
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pgen-1003737-g007: A model for miR-80 regulation of DR metabolism.In adults, when food is abundant, mir-80 is expressed at a high level, and miR-80 binds to metabolic and signaling targets to down-regulate their expression. The cbp-1 transcript, which includes two potential binding sites for miR-80, one in the 5′ UTR and one in exon 8 (exons thick dark blue lines, promoter lighter blue), and is essential for mir-80(Δ) benefits, is one candidate target (light blue represents relatively low CBP-1 concentration in food). When food is limiting, miR-80 levels drop, and translational repression of cbp-1 could be relieved (dark blue circle represents higher concentration CBP-1). The CBP-1 protein associates with DAF-16 and HSF-1 to promote expression of genes required for DR metabolism and longevity. Note that although cbp-1 is essential for mir-80(Δ) DR benefits, direct targeting remains to be proved and it is likely that additional targets help modulate the DR state. Since we cannot rule out that daf-16, hsf-1, and cbp-1 disruptions make animals too generally sick to gain mir-80(Δ) benefits, alternative models are possible.

Mentions: Our data are consistent with a model in which in the presence of food, cbp-1 is translationally repressed by binding of miR-80 to target sites within the cbp-1 transcript (Fig. 7). When food is lacking, miR-80 levels drop, translational repression of cbp-1 is relieved, and CBP-1+DAF-16+HSF-1-mediated transcriptional changes induce DR within the animal. Interestingly, the human CREBBP transcript might be targeted by miR-80 family members or another miRNA homologous to the exon 8 site (Fig. S7C), suggesting miRNAs could exert a conserved role in DR metabolic regulation that might be harnessed in the future to promote healthy metabolism with anti-aging applications.


Deletion of microRNA-80 activates dietary restriction to extend C. elegans healthspan and lifespan.

Vora M, Shah M, Ostafi S, Onken B, Xue J, Ni JZ, Gu S, Driscoll M - PLoS Genet. (2013)

A model for miR-80 regulation of DR metabolism.In adults, when food is abundant, mir-80 is expressed at a high level, and miR-80 binds to metabolic and signaling targets to down-regulate their expression. The cbp-1 transcript, which includes two potential binding sites for miR-80, one in the 5′ UTR and one in exon 8 (exons thick dark blue lines, promoter lighter blue), and is essential for mir-80(Δ) benefits, is one candidate target (light blue represents relatively low CBP-1 concentration in food). When food is limiting, miR-80 levels drop, and translational repression of cbp-1 could be relieved (dark blue circle represents higher concentration CBP-1). The CBP-1 protein associates with DAF-16 and HSF-1 to promote expression of genes required for DR metabolism and longevity. Note that although cbp-1 is essential for mir-80(Δ) DR benefits, direct targeting remains to be proved and it is likely that additional targets help modulate the DR state. Since we cannot rule out that daf-16, hsf-1, and cbp-1 disruptions make animals too generally sick to gain mir-80(Δ) benefits, alternative models are possible.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757059&req=5

pgen-1003737-g007: A model for miR-80 regulation of DR metabolism.In adults, when food is abundant, mir-80 is expressed at a high level, and miR-80 binds to metabolic and signaling targets to down-regulate their expression. The cbp-1 transcript, which includes two potential binding sites for miR-80, one in the 5′ UTR and one in exon 8 (exons thick dark blue lines, promoter lighter blue), and is essential for mir-80(Δ) benefits, is one candidate target (light blue represents relatively low CBP-1 concentration in food). When food is limiting, miR-80 levels drop, and translational repression of cbp-1 could be relieved (dark blue circle represents higher concentration CBP-1). The CBP-1 protein associates with DAF-16 and HSF-1 to promote expression of genes required for DR metabolism and longevity. Note that although cbp-1 is essential for mir-80(Δ) DR benefits, direct targeting remains to be proved and it is likely that additional targets help modulate the DR state. Since we cannot rule out that daf-16, hsf-1, and cbp-1 disruptions make animals too generally sick to gain mir-80(Δ) benefits, alternative models are possible.
Mentions: Our data are consistent with a model in which in the presence of food, cbp-1 is translationally repressed by binding of miR-80 to target sites within the cbp-1 transcript (Fig. 7). When food is lacking, miR-80 levels drop, translational repression of cbp-1 is relieved, and CBP-1+DAF-16+HSF-1-mediated transcriptional changes induce DR within the animal. Interestingly, the human CREBBP transcript might be targeted by miR-80 family members or another miRNA homologous to the exon 8 site (Fig. S7C), suggesting miRNAs could exert a conserved role in DR metabolic regulation that might be harnessed in the future to promote healthy metabolism with anti-aging applications.

Bottom Line: Caloric/dietary restriction (CR/DR) can promote longevity and protect against age-associated disease across species.The molecular mechanisms coordinating food intake with health-promoting metabolism are thus of significant medical interest.Under food limitation, lowered miR-80 levels directly or indirectly increase CBP-1 protein levels to engage metabolic loops that promote DR.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.

ABSTRACT
Caloric/dietary restriction (CR/DR) can promote longevity and protect against age-associated disease across species. The molecular mechanisms coordinating food intake with health-promoting metabolism are thus of significant medical interest. We report that conserved Caenorhabditis elegans microRNA-80 (mir-80) is a major regulator of the DR state. mir-80 deletion confers system-wide healthy aging, including maintained cardiac-like and skeletal muscle-like function at advanced age, reduced accumulation of lipofuscin, and extended lifespan, coincident with induction of physiological features of DR. mir-80 expression is generally high under ad lib feeding and low under food limitation, with most striking food-sensitive expression changes in posterior intestine. The acetyltransferase transcription co-factor cbp-1 and interacting transcription factors daf-16/FOXO and heat shock factor-1 hsf-1 are essential for mir-80(Δ) benefits. Candidate miR-80 target sequences within the cbp-1 transcript may confer food-dependent regulation. Under food limitation, lowered miR-80 levels directly or indirectly increase CBP-1 protein levels to engage metabolic loops that promote DR.

Show MeSH
Related in: MedlinePlus