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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 reduction increases life span, lipid storage, autophagy and lysosomal lipolysis. (A) QPCR analysis of the expression of vit genes in d-1 animals fed control bacteria or bacteria expressing dsRNA against vit-1 from hatching (N = 3 per condition). (B) Life span analysis of animals fed control bacteria or bacteria expressing dsRNA against vit during adulthood. (C) Oil-Red-O staining of d-20 wild-type fed control bacteria or bacteria against vit during adulthood (insets are corresponding micrographs of each treated group). (D) Quantification of GFP::LGG-1 foci in the proximal intestine of d-1 wild-type animals fed control bacteria or bacteria expressing dsRNA against vit from hatching. *, P < 0.001, N = 28 worms per condition, ±SEM, t test. (E) QPCR analysis of the expression of lysosomal acid lipase (lipl-1 to lipl-8) genes in d-3 animals fed control bacteria or bacteria expressing dsRNA against vit from hatching (N = 3 per condition). ±SD; *, P<0.05; N = 3, t test. (F) Measurement of lysosomal acid lipase activity in wild-type animals and animals with reduced vitellogenesis. Fluorometric values normalized to the wild type. ±SD; *, P < 0.05; N = 3 per condition, t test. Life-span analysis of atg-18(gk378) mutants (G), lipl-3(tm4498) (H) and lipl-4(tm4417) mutants (I), daf-12(rh61rh411) mutants (J), nhr-49(nr2014) mutants (K) and glp-1(e2141);nhr-80(tm1011) mutants (raised at the permissive temperature) (L) fed control bacteria or bacteria expressing dsRNA against vit during adulthood. Details on life span analyses are found in Table S3.
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f0003: VIT reduction increases life span, lipid storage, autophagy and lysosomal lipolysis. (A) QPCR analysis of the expression of vit genes in d-1 animals fed control bacteria or bacteria expressing dsRNA against vit-1 from hatching (N = 3 per condition). (B) Life span analysis of animals fed control bacteria or bacteria expressing dsRNA against vit during adulthood. (C) Oil-Red-O staining of d-20 wild-type fed control bacteria or bacteria against vit during adulthood (insets are corresponding micrographs of each treated group). (D) Quantification of GFP::LGG-1 foci in the proximal intestine of d-1 wild-type animals fed control bacteria or bacteria expressing dsRNA against vit from hatching. *, P < 0.001, N = 28 worms per condition, ±SEM, t test. (E) QPCR analysis of the expression of lysosomal acid lipase (lipl-1 to lipl-8) genes in d-3 animals fed control bacteria or bacteria expressing dsRNA against vit from hatching (N = 3 per condition). ±SD; *, P<0.05; N = 3, t test. (F) Measurement of lysosomal acid lipase activity in wild-type animals and animals with reduced vitellogenesis. Fluorometric values normalized to the wild type. ±SD; *, P < 0.05; N = 3 per condition, t test. Life-span analysis of atg-18(gk378) mutants (G), lipl-3(tm4498) (H) and lipl-4(tm4417) mutants (I), daf-12(rh61rh411) mutants (J), nhr-49(nr2014) mutants (K) and glp-1(e2141);nhr-80(tm1011) mutants (raised at the permissive temperature) (L) fed control bacteria or bacteria expressing dsRNA against vit during adulthood. Details on life span analyses are found in Table S3.

Mentions: To clarify the role of VITs in the life span of C. elegans, we silenced VITs by using E. coli expressing double-stranded RNA (RNAi) against vit genes (vit-1/2, −3, −4 and −5), and studied the effect on life span and lipid accumulation. Vit-1/2 RNAi (hereafter referred as vit RNAi) sufficed in silencing vit-1 to vit-5 (Figs. 3A and S3A and B), largely due to the high level of homology shared by the targeted sequences. The reduction in vit gene expression resulted in a significant (16 to 40%) increase in the life span of wild-type animals (Fig. 3B and Table S3), without affecting progeny production and pumping rates (Fig. S3C). These observations are consistent with a previous report that also demonstrates life span extension when another RNAi, vit-5, was used (Table S3).33 Altogether, these data indicate that reducing the production of VITs has beneficial effects on the life span of C. elegans without relying on a reproductive trade-off.Figure 3.


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 reduction increases life span, lipid storage, autophagy and lysosomal lipolysis. (A) QPCR analysis of the expression of vit genes in d-1 animals fed control bacteria or bacteria expressing dsRNA against vit-1 from hatching (N = 3 per condition). (B) Life span analysis of animals fed control bacteria or bacteria expressing dsRNA against vit during adulthood. (C) Oil-Red-O staining of d-20 wild-type fed control bacteria or bacteria against vit during adulthood (insets are corresponding micrographs of each treated group). (D) Quantification of GFP::LGG-1 foci in the proximal intestine of d-1 wild-type animals fed control bacteria or bacteria expressing dsRNA against vit from hatching. *, P < 0.001, N = 28 worms per condition, ±SEM, t test. (E) QPCR analysis of the expression of lysosomal acid lipase (lipl-1 to lipl-8) genes in d-3 animals fed control bacteria or bacteria expressing dsRNA against vit from hatching (N = 3 per condition). ±SD; *, P<0.05; N = 3, t test. (F) Measurement of lysosomal acid lipase activity in wild-type animals and animals with reduced vitellogenesis. Fluorometric values normalized to the wild type. ±SD; *, P < 0.05; N = 3 per condition, t test. Life-span analysis of atg-18(gk378) mutants (G), lipl-3(tm4498) (H) and lipl-4(tm4417) mutants (I), daf-12(rh61rh411) mutants (J), nhr-49(nr2014) mutants (K) and glp-1(e2141);nhr-80(tm1011) mutants (raised at the permissive temperature) (L) fed control bacteria or bacteria expressing dsRNA against vit during adulthood. Details on life span analyses are found in Table S3.
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f0003: VIT reduction increases life span, lipid storage, autophagy and lysosomal lipolysis. (A) QPCR analysis of the expression of vit genes in d-1 animals fed control bacteria or bacteria expressing dsRNA against vit-1 from hatching (N = 3 per condition). (B) Life span analysis of animals fed control bacteria or bacteria expressing dsRNA against vit during adulthood. (C) Oil-Red-O staining of d-20 wild-type fed control bacteria or bacteria against vit during adulthood (insets are corresponding micrographs of each treated group). (D) Quantification of GFP::LGG-1 foci in the proximal intestine of d-1 wild-type animals fed control bacteria or bacteria expressing dsRNA against vit from hatching. *, P < 0.001, N = 28 worms per condition, ±SEM, t test. (E) QPCR analysis of the expression of lysosomal acid lipase (lipl-1 to lipl-8) genes in d-3 animals fed control bacteria or bacteria expressing dsRNA against vit from hatching (N = 3 per condition). ±SD; *, P<0.05; N = 3, t test. (F) Measurement of lysosomal acid lipase activity in wild-type animals and animals with reduced vitellogenesis. Fluorometric values normalized to the wild type. ±SD; *, P < 0.05; N = 3 per condition, t test. Life-span analysis of atg-18(gk378) mutants (G), lipl-3(tm4498) (H) and lipl-4(tm4417) mutants (I), daf-12(rh61rh411) mutants (J), nhr-49(nr2014) mutants (K) and glp-1(e2141);nhr-80(tm1011) mutants (raised at the permissive temperature) (L) fed control bacteria or bacteria expressing dsRNA against vit during adulthood. Details on life span analyses are found in Table S3.
Mentions: To clarify the role of VITs in the life span of C. elegans, we silenced VITs by using E. coli expressing double-stranded RNA (RNAi) against vit genes (vit-1/2, −3, −4 and −5), and studied the effect on life span and lipid accumulation. Vit-1/2 RNAi (hereafter referred as vit RNAi) sufficed in silencing vit-1 to vit-5 (Figs. 3A and S3A and B), largely due to the high level of homology shared by the targeted sequences. The reduction in vit gene expression resulted in a significant (16 to 40%) increase in the life span of wild-type animals (Fig. 3B and Table S3), without affecting progeny production and pumping rates (Fig. S3C). These observations are consistent with a previous report that also demonstrates life span extension when another RNAi, vit-5, was used (Table S3).33 Altogether, these data indicate that reducing the production of VITs has beneficial effects on the life span of C. elegans without relying on a reproductive trade-off.Figure 3.

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