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Autophagy-mediated longevity is modulated by lipoprotein biogenesis.

Seah NE, de Magalhaes Filho CD, Petrashen AP, Henderson HR, Laguer J, Gonzalez J, Dillin A, Hansen M, Lapierre LR - Autophagy (2016)

Bottom Line: Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling.In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism.Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.

View Article: PubMed Central - PubMed

Affiliation: a Department of Molecular Biology , Cell Biology and Biochemistry, Brown University , Providence , RI , USA.

ABSTRACT
Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.

No MeSH data available.


Related in: MedlinePlus

VIT overexpression impairs longevity. Life span analyses of wild-type (WT) (A), germline-less glp-1(e2141) (B), insulin/IGF-1 receptor mutant daf-2(e1370) (C) and their corresponding vit-2-overexpressing transgenic counterparts (green) grown on OP50 E. coli. Details on life span analyses are found in Table S1. Micrographs of Oil-Red-O stained day-20 wild-type (WT) (D), germline-less glp-1(e2141) (E), insulin/IGF-1 receptor mutant daf-2(e1370) (F) and their corresponding vit-2-overexpressing transgenic counterparts. Insets in panels (D to F) are corresponding micrographs for each strain (black border, parent strain; green border, transgenic strain) at d 20, displaying the dark intestine phenotype in the proximal intestine associated with intestinal lipid droplet storage.
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f0001: VIT overexpression impairs longevity. Life span analyses of wild-type (WT) (A), germline-less glp-1(e2141) (B), insulin/IGF-1 receptor mutant daf-2(e1370) (C) and their corresponding vit-2-overexpressing transgenic counterparts (green) grown on OP50 E. coli. Details on life span analyses are found in Table S1. Micrographs of Oil-Red-O stained day-20 wild-type (WT) (D), germline-less glp-1(e2141) (E), insulin/IGF-1 receptor mutant daf-2(e1370) (F) and their corresponding vit-2-overexpressing transgenic counterparts. Insets in panels (D to F) are corresponding micrographs for each strain (black border, parent strain; green border, transgenic strain) at d 20, displaying the dark intestine phenotype in the proximal intestine associated with intestinal lipid droplet storage.

Mentions: To investigate the role of reduced VIT production in the longevity mechanism of autophagy-dependent, long-lived animals, we assessed the effect of increasing vitellogenesis on their life span. A previously constructed strain2 expressing a highly conserved VIT protein, VIT-2, fused to GFP under its endogenous promoter was utilized to generate elevated levels of VIT (Fig. S1A). Expressed in wild-type animals, VIT-2::GFP localized primarily to the oocytes in early adulthood, as previously reported2, and accumulated in the pseudocoelomic fluid and gonads after reproduction ended (d 7). A modest decrease in VIT accumulation was also observed when vit-2::GFP was expressed in glp-1(e2141) animals (Fig. S1A). In long-lived insulin/IGF-1 receptor daf-2(e1370) mutants, we found that vit-2::GFP expression was markedly attenuated (Fig. S1A), consistent with previous work showing that animals in which DAF-16/FOXO is active in the intestine31,32 have reduced VIT gene expression33 and protein accumulation.5 Overexpression of vit-2 had no effect on the life span of wild-type animals (Fig. 1A, Table S1). However, it significantly reduced the long life span of glp-1 and daf-2 mutants (Fig. 1B and 1C, and Table S1). Notably, progeny production and pharyngeal pumping were not affected by increased VIT-2 production in wild-type, glp-1 or daf-2 animals (Fig. S1B), suggesting that increasing VIT-2 biogenesis did not reduce the life span of glp-1 and daf-2 animals through alterations in reproduction or food intake, both physiological aspects linked to life span.Figure 1.


Autophagy-mediated longevity is modulated by lipoprotein biogenesis.

Seah NE, de Magalhaes Filho CD, Petrashen AP, Henderson HR, Laguer J, Gonzalez J, Dillin A, Hansen M, Lapierre LR - Autophagy (2016)

VIT overexpression impairs longevity. Life span analyses of wild-type (WT) (A), germline-less glp-1(e2141) (B), insulin/IGF-1 receptor mutant daf-2(e1370) (C) and their corresponding vit-2-overexpressing transgenic counterparts (green) grown on OP50 E. coli. Details on life span analyses are found in Table S1. Micrographs of Oil-Red-O stained day-20 wild-type (WT) (D), germline-less glp-1(e2141) (E), insulin/IGF-1 receptor mutant daf-2(e1370) (F) and their corresponding vit-2-overexpressing transgenic counterparts. Insets in panels (D to F) are corresponding micrographs for each strain (black border, parent strain; green border, transgenic strain) at d 20, displaying the dark intestine phenotype in the proximal intestine associated with intestinal lipid droplet storage.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836030&req=5

f0001: VIT overexpression impairs longevity. Life span analyses of wild-type (WT) (A), germline-less glp-1(e2141) (B), insulin/IGF-1 receptor mutant daf-2(e1370) (C) and their corresponding vit-2-overexpressing transgenic counterparts (green) grown on OP50 E. coli. Details on life span analyses are found in Table S1. Micrographs of Oil-Red-O stained day-20 wild-type (WT) (D), germline-less glp-1(e2141) (E), insulin/IGF-1 receptor mutant daf-2(e1370) (F) and their corresponding vit-2-overexpressing transgenic counterparts. Insets in panels (D to F) are corresponding micrographs for each strain (black border, parent strain; green border, transgenic strain) at d 20, displaying the dark intestine phenotype in the proximal intestine associated with intestinal lipid droplet storage.
Mentions: To investigate the role of reduced VIT production in the longevity mechanism of autophagy-dependent, long-lived animals, we assessed the effect of increasing vitellogenesis on their life span. A previously constructed strain2 expressing a highly conserved VIT protein, VIT-2, fused to GFP under its endogenous promoter was utilized to generate elevated levels of VIT (Fig. S1A). Expressed in wild-type animals, VIT-2::GFP localized primarily to the oocytes in early adulthood, as previously reported2, and accumulated in the pseudocoelomic fluid and gonads after reproduction ended (d 7). A modest decrease in VIT accumulation was also observed when vit-2::GFP was expressed in glp-1(e2141) animals (Fig. S1A). In long-lived insulin/IGF-1 receptor daf-2(e1370) mutants, we found that vit-2::GFP expression was markedly attenuated (Fig. S1A), consistent with previous work showing that animals in which DAF-16/FOXO is active in the intestine31,32 have reduced VIT gene expression33 and protein accumulation.5 Overexpression of vit-2 had no effect on the life span of wild-type animals (Fig. 1A, Table S1). However, it significantly reduced the long life span of glp-1 and daf-2 mutants (Fig. 1B and 1C, and Table S1). Notably, progeny production and pharyngeal pumping were not affected by increased VIT-2 production in wild-type, glp-1 or daf-2 animals (Fig. S1B), suggesting that increasing VIT-2 biogenesis did not reduce the life span of glp-1 and daf-2 animals through alterations in reproduction or food intake, both physiological aspects linked to life span.Figure 1.

Bottom Line: Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling.In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism.Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.

View Article: PubMed Central - PubMed

Affiliation: a Department of Molecular Biology , Cell Biology and Biochemistry, Brown University , Providence , RI , USA.

ABSTRACT
Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.

No MeSH data available.


Related in: MedlinePlus