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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

Dietary-restricted animals have reduced lipoprotein expression. (A) QPCR analysis of vit genes in d-1 adult wild-type and eat-2(ad1116) animals. ±SD; *, P <0.05, N = 3 per condition, t test. (B) Life-span analysis of eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP. Details on life-span analyses are found in Table S1. (C) Oil-Red-O staining of day-20 eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP (insets are corresponding micrographs of each strain). (D) Life-span analysis of eat-2(ad1116) animals fed control bacteria or bacteria expressing dsRNA against vit. Details on life-span analyses are found in Table S3. (E) QPCR analysis of hepatic Apob expression of mice fed ad libitum or dietary restricted at 3 mo of age for 5.5 wk. ±SEM; *, P<0.05; N = 8 to 10 per condition, t test. (F) Model depicting the connections associated with vitellogenesis, lipophagy and lipid signaling. During vitellogenesis, ER lipids are packaged into secretable yolk lipoproteins. Reduction in vitellogenesis results in the redistribution of lipids into neutral lipid droplets and leads to an increase in the expression of autophagy genes and lipl genes involved in lipophagy. Lipid signaling products of lysosomal lipolysis can serve as activators of nuclear hormone receptors NHR-49 and NHR-80, as well as potential inter-tissue signaling molecules. Their translocation to the nucleus stimulates lipid metabolic gene expression in conjunction with DAF-16 (which is negatively regulated by LET-363/TOR) activating lipl gene expression and repressing vit gene expression, thereby maintaining elevated autophagy and lysosomal lipolysis.
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f0004: Dietary-restricted animals have reduced lipoprotein expression. (A) QPCR analysis of vit genes in d-1 adult wild-type and eat-2(ad1116) animals. ±SD; *, P <0.05, N = 3 per condition, t test. (B) Life-span analysis of eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP. Details on life-span analyses are found in Table S1. (C) Oil-Red-O staining of day-20 eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP (insets are corresponding micrographs of each strain). (D) Life-span analysis of eat-2(ad1116) animals fed control bacteria or bacteria expressing dsRNA against vit. Details on life-span analyses are found in Table S3. (E) QPCR analysis of hepatic Apob expression of mice fed ad libitum or dietary restricted at 3 mo of age for 5.5 wk. ±SEM; *, P<0.05; N = 8 to 10 per condition, t test. (F) Model depicting the connections associated with vitellogenesis, lipophagy and lipid signaling. During vitellogenesis, ER lipids are packaged into secretable yolk lipoproteins. Reduction in vitellogenesis results in the redistribution of lipids into neutral lipid droplets and leads to an increase in the expression of autophagy genes and lipl genes involved in lipophagy. Lipid signaling products of lysosomal lipolysis can serve as activators of nuclear hormone receptors NHR-49 and NHR-80, as well as potential inter-tissue signaling molecules. Their translocation to the nucleus stimulates lipid metabolic gene expression in conjunction with DAF-16 (which is negatively regulated by LET-363/TOR) activating lipl gene expression and repressing vit gene expression, thereby maintaining elevated autophagy and lysosomal lipolysis.

Mentions: Having established the importance of vitellogenesis in autophagy and lysosomal lipolysis, we sought to determine whether VIT production also plays a role in the ability of an animal to survive nutrient stress, especially since enhanced autophagy mediates life-span extension by dietary restriction.53 The expression of vit genes was significantly decreased in pumping-defective, dietary-restricted, eat-2(ad1116) mutants (Fig. 4A), which mirrors the markedly decreased levels of VIT protein observed in glp-1 and daf-2 animals (Fig. S1A).5 This suggests that both animal models may have a similar requirement of reduced vitellogenesis for longevity. Concomitantly, the expression of lysosomal acid lipases (lipl-1, −2, −3, −4 and -5) in eat-2 animals was significantly increased (Fig. S6A). Similarly, silencing the nutrient sensor let-363/tor also led to an increase in lysosomal lipase expression (lipl-1, −2 and −4) (Fig. S6B). These observations demonstrated that multiple, mechanistically distinct longevity models display increased lysosomal lipolysis. As seen in other longevity models (Fig. S1A), we observed that vitellogenesis is suppressed in eat-2 animals (Fig. S6C). Increasing vitellogenesis by expressing vit-2::GFP in eat-2 animals reduced their life span significantly (Fig. 4B, Table S1), in addition to producing animals devoid of neutral lipid stores (Fig. 4C). Silencing let-363/tor in vit-2::GFP-expressing animals failed to extend their life span (Fig. S6D, Table S2), suggesting that the life-span extension associated with reduced nutrient sensing is sensitive to VIT production. Likewise, further reduction of vitellogenesis by subjecting eat-2 animals to vit RNAi did not lead to additional extension in life span, as seen in glp-1 animals (Fig. 4D, Table S3). Altogether, these observations indicate that the reduction in vitellogenesis is an important mechanism in distinct longevity models.Figure 4.


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)

Dietary-restricted animals have reduced lipoprotein expression. (A) QPCR analysis of vit genes in d-1 adult wild-type and eat-2(ad1116) animals. ±SD; *, P <0.05, N = 3 per condition, t test. (B) Life-span analysis of eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP. Details on life-span analyses are found in Table S1. (C) Oil-Red-O staining of day-20 eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP (insets are corresponding micrographs of each strain). (D) Life-span analysis of eat-2(ad1116) animals fed control bacteria or bacteria expressing dsRNA against vit. Details on life-span analyses are found in Table S3. (E) QPCR analysis of hepatic Apob expression of mice fed ad libitum or dietary restricted at 3 mo of age for 5.5 wk. ±SEM; *, P<0.05; N = 8 to 10 per condition, t test. (F) Model depicting the connections associated with vitellogenesis, lipophagy and lipid signaling. During vitellogenesis, ER lipids are packaged into secretable yolk lipoproteins. Reduction in vitellogenesis results in the redistribution of lipids into neutral lipid droplets and leads to an increase in the expression of autophagy genes and lipl genes involved in lipophagy. Lipid signaling products of lysosomal lipolysis can serve as activators of nuclear hormone receptors NHR-49 and NHR-80, as well as potential inter-tissue signaling molecules. Their translocation to the nucleus stimulates lipid metabolic gene expression in conjunction with DAF-16 (which is negatively regulated by LET-363/TOR) activating lipl gene expression and repressing vit gene expression, thereby maintaining elevated autophagy and lysosomal lipolysis.
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Related In: Results  -  Collection

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f0004: Dietary-restricted animals have reduced lipoprotein expression. (A) QPCR analysis of vit genes in d-1 adult wild-type and eat-2(ad1116) animals. ±SD; *, P <0.05, N = 3 per condition, t test. (B) Life-span analysis of eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP. Details on life-span analyses are found in Table S1. (C) Oil-Red-O staining of day-20 eat-2(ad1116) animals and eat-2(ad1116) animals expressing vit-2::GFP (insets are corresponding micrographs of each strain). (D) Life-span analysis of eat-2(ad1116) animals fed control bacteria or bacteria expressing dsRNA against vit. Details on life-span analyses are found in Table S3. (E) QPCR analysis of hepatic Apob expression of mice fed ad libitum or dietary restricted at 3 mo of age for 5.5 wk. ±SEM; *, P<0.05; N = 8 to 10 per condition, t test. (F) Model depicting the connections associated with vitellogenesis, lipophagy and lipid signaling. During vitellogenesis, ER lipids are packaged into secretable yolk lipoproteins. Reduction in vitellogenesis results in the redistribution of lipids into neutral lipid droplets and leads to an increase in the expression of autophagy genes and lipl genes involved in lipophagy. Lipid signaling products of lysosomal lipolysis can serve as activators of nuclear hormone receptors NHR-49 and NHR-80, as well as potential inter-tissue signaling molecules. Their translocation to the nucleus stimulates lipid metabolic gene expression in conjunction with DAF-16 (which is negatively regulated by LET-363/TOR) activating lipl gene expression and repressing vit gene expression, thereby maintaining elevated autophagy and lysosomal lipolysis.
Mentions: Having established the importance of vitellogenesis in autophagy and lysosomal lipolysis, we sought to determine whether VIT production also plays a role in the ability of an animal to survive nutrient stress, especially since enhanced autophagy mediates life-span extension by dietary restriction.53 The expression of vit genes was significantly decreased in pumping-defective, dietary-restricted, eat-2(ad1116) mutants (Fig. 4A), which mirrors the markedly decreased levels of VIT protein observed in glp-1 and daf-2 animals (Fig. S1A).5 This suggests that both animal models may have a similar requirement of reduced vitellogenesis for longevity. Concomitantly, the expression of lysosomal acid lipases (lipl-1, −2, −3, −4 and -5) in eat-2 animals was significantly increased (Fig. S6A). Similarly, silencing the nutrient sensor let-363/tor also led to an increase in lysosomal lipase expression (lipl-1, −2 and −4) (Fig. S6B). These observations demonstrated that multiple, mechanistically distinct longevity models display increased lysosomal lipolysis. As seen in other longevity models (Fig. S1A), we observed that vitellogenesis is suppressed in eat-2 animals (Fig. S6C). Increasing vitellogenesis by expressing vit-2::GFP in eat-2 animals reduced their life span significantly (Fig. 4B, Table S1), in addition to producing animals devoid of neutral lipid stores (Fig. 4C). Silencing let-363/tor in vit-2::GFP-expressing animals failed to extend their life span (Fig. S6D, Table S2), suggesting that the life-span extension associated with reduced nutrient sensing is sensitive to VIT production. Likewise, further reduction of vitellogenesis by subjecting eat-2 animals to vit RNAi did not lead to additional extension in life span, as seen in glp-1 animals (Fig. 4D, Table S3). Altogether, these observations indicate that the reduction in vitellogenesis is an important mechanism in distinct longevity models.Figure 4.

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