PT  - JOURNAL ARTICLE
AU  - Daniele, Joseph R.
AU  - Higuchi-Sanabria, Ryo
AU  - Ramachandran, Vidhya
AU  - Sanchez, Melissa
AU  - Durieux, Jenni
AU  - Tronnes, Sarah U.
AU  - Paul, Joseph W.
AU  - Esping, Daniel J.
AU  - Monshietehadi, Samira
AU  - Metcalf, Melissa G.
AU  - Dillin, Andrew
TI  - A non-canonical arm of UPR<sup>ER</sup> mediates longevity through ER remodeling and lipophagy
AID  - 10.1101/471177
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 471177
4099  - http://biorxiv.org/content/early/2018/11/15/471177.short
4100  - http://biorxiv.org/content/early/2018/11/15/471177.full
AB  - Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms implicated in regulating lifespan extension is the ability to induce protein chaperones to promote protein homeostasis. However, it is unclear whether protein chaperones exclusively regulate longevity. Previous work has shown that activating the unfolded protein response of the endoplasmic reticulum (UPRER) in neurons can signal peripheral tissues to promote chaperone expression, thus enhancing organismal stress resistance and extending lifespan. Here, we find that this activation not only promotes chaperones, but facilitates a dramatic restructuring of ER morphology in intestinal cells. This restructuring, which includes depletion of lipid droplets, ER expansion, and ER tubulation, depends of lipophagy. Surprisingly, we find that lipophagy is required for lifespan extension and is completely independent of chaperone function. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the canonical arm through protein chaperones, and a non-canonical mechanism through lipid depletion. In summary, our study identifies lipophagy as an integral component of UPRER-induced longevity.