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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 prevents autophagy-associated gene induction. (A) QPCR analysis of pha-4 and pha-4-regulated autophagy targets lgg-1 and lgg-2, (B) daf-16 and daf-16-regulated targets sod-3 and C08H9.1 as well as (C) members of the lysosomal acid lipase gene family (lipl-1 to lipl-8) in d-1 WT, glp-1, daf-2 animals and their transgenic counterparts. N = 3 per condition. Graphs represent mean±SD; *, P<0.05 vs parent strain using the Student t test.
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f0002: VIT overexpression prevents autophagy-associated gene induction. (A) QPCR analysis of pha-4 and pha-4-regulated autophagy targets lgg-1 and lgg-2, (B) daf-16 and daf-16-regulated targets sod-3 and C08H9.1 as well as (C) members of the lysosomal acid lipase gene family (lipl-1 to lipl-8) in d-1 WT, glp-1, daf-2 animals and their transgenic counterparts. N = 3 per condition. Graphs represent mean±SD; *, P<0.05 vs parent strain using the Student t test.

Mentions: Longevity in nematodes is generally dependent on the activity of transcription factors including but not limited to, PHA-4/FOXA, DAF-16/FOXO and HLH-30/TFEB.11 The expression of these transcription factors is increased in different longevity models and their levels have been shown to correlate with their activity as they can autoregulate their own expression.11 Hence, to determine the role of lipoprotein biogenesis in the mechanisms promoting longevity, we investigated the effect of increasing VIT levels on the expression and activity of these longevity-associated transcription factors. VIT-2 overproduction led to a significant decrease in pha-4 mRNA levels in glp-1 animals (Fig. 2A). The expression of autophagy gene lgg-1 (ortholog of GABARAP35), a PHA-4/FOXA target gene20,36, was decreased in both glp-1 and daf-2 animals, while Igg-2 (ortholog of LC3A and LC3B) was decreased in glp-1 animals (Fig. 2A). Overexpressing vit-2 also resulted in decreased daf-16 levels, as well as the DAF-16/FOXO target gene sod-337, in both glp-1 and daf-2 animals (Fig. 2B). In contrast, expression of the lysosomal serine carboxypeptidase homolog of cathepsin A, C08H9.1, a DAF-16/FOXO target,38 was unaffected, suggesting that the expression of specific subsets of DAF-16/FOXO targets may be differentially altered by increased vitellogenesis.Figure 2.


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 prevents autophagy-associated gene induction. (A) QPCR analysis of pha-4 and pha-4-regulated autophagy targets lgg-1 and lgg-2, (B) daf-16 and daf-16-regulated targets sod-3 and C08H9.1 as well as (C) members of the lysosomal acid lipase gene family (lipl-1 to lipl-8) in d-1 WT, glp-1, daf-2 animals and their transgenic counterparts. N = 3 per condition. Graphs represent mean±SD; *, P<0.05 vs parent strain using the Student t test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0002: VIT overexpression prevents autophagy-associated gene induction. (A) QPCR analysis of pha-4 and pha-4-regulated autophagy targets lgg-1 and lgg-2, (B) daf-16 and daf-16-regulated targets sod-3 and C08H9.1 as well as (C) members of the lysosomal acid lipase gene family (lipl-1 to lipl-8) in d-1 WT, glp-1, daf-2 animals and their transgenic counterparts. N = 3 per condition. Graphs represent mean±SD; *, P<0.05 vs parent strain using the Student t test.
Mentions: Longevity in nematodes is generally dependent on the activity of transcription factors including but not limited to, PHA-4/FOXA, DAF-16/FOXO and HLH-30/TFEB.11 The expression of these transcription factors is increased in different longevity models and their levels have been shown to correlate with their activity as they can autoregulate their own expression.11 Hence, to determine the role of lipoprotein biogenesis in the mechanisms promoting longevity, we investigated the effect of increasing VIT levels on the expression and activity of these longevity-associated transcription factors. VIT-2 overproduction led to a significant decrease in pha-4 mRNA levels in glp-1 animals (Fig. 2A). The expression of autophagy gene lgg-1 (ortholog of GABARAP35), a PHA-4/FOXA target gene20,36, was decreased in both glp-1 and daf-2 animals, while Igg-2 (ortholog of LC3A and LC3B) was decreased in glp-1 animals (Fig. 2A). Overexpressing vit-2 also resulted in decreased daf-16 levels, as well as the DAF-16/FOXO target gene sod-337, in both glp-1 and daf-2 animals (Fig. 2B). In contrast, expression of the lysosomal serine carboxypeptidase homolog of cathepsin A, C08H9.1, a DAF-16/FOXO target,38 was unaffected, suggesting that the expression of specific subsets of DAF-16/FOXO targets may be differentially altered by increased vitellogenesis.Figure 2.

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