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Autophagy. 2016;12(2):261-72. doi: 10.1080/15548627.2015.1127464.

Autophagy-mediated longevity is modulated by lipoprotein biogenesis.

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a Department of Molecular Biology , Cell Biology and Biochemistry, Brown University , Providence , RI , USA.
b The Howard Hughes Medical Institute, The Glenn Center for Aging Research, The Salk Institute for Biological Studies , La Jolla , CA , USA.
c The Howard Hughes Medical Institute, Molecular and Cell Biology Department, Li Ka Shing Center, University of California Berkeley , Berkeley , CA , USA.
d Del E. Webb Neuroscience , Aging and Stem Cell Research Center, Program of Development and Aging, Sanford-Burnham Medical Research Institute , La Jolla , CA , USA.


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.


C. elegans; TOR; apolipoprotein B; autophagy; fat storage; intestine; life span; lipid metabolism; lipoprotein; vitellogenin

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