Lysosome lipid signalling from the periphery to neurons regulates longevity

Abstract

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-γ-linolenic acid, and acts through NHR-49 nuclear receptor and NLP-11 neuropeptide in neurons to extend lifespan. These results reveal lysosomes as a signalling hub to coordinate metabolism and ageing, and lysosomal signalling mediated inter-tissue communication in promoting longevity.

Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity

“…In our previous studies, we found that upon LIPL-4-induced lysosomal lipolysis, a lysosome-to-nucleus retrograde lipid messenger signaling pathway is activated in intestinal cells to promote longevity (Folick et al ., 2015; Ramachandran et al ., 2019; Savini et al ., 2022; Wang et al ., 2008). Interestingly, when analyzing the LMP-1 lysosome-enriched proteome in the lipl-4 Tg worms, we found an enrichment of nucleus-localized proteins (Figure 4A), including two nucleoporin proteins NPP-6/Nup160 and NPP-15/Nup133 in the Nup160 complex that localizes at the basket side of the nuclear pore (Figure 4B) (Vasu et al, 2001).…”

A lysosomal surveillance response (LySR) that reduces proteotoxicity and extends healthspan

“…In agreement with such a hypothesis, many cathepsins have been shown to be secreted into the extracellular space and serum, and thus implicated in a wide range of physiological processes in mammalian systems via tissue-to-tissue crosstalks (Vidak et al, 2019; Yadati et al, 2020). Likewise, a recent study suggested that induced lysosomal lipolysis in peripheral fat storage tissue activated a neuropeptide signaling pathway in the nervous system to promote longevity (Savini et al, 2022). Interestingly, unlike cco-1 , whose knockdown induces UPR mt and extends the worm lifespan only when the RNAi was fed during larval development (Durieux et al, 2011), vha-6 RNAi extends C. elegans lifespan even when the knockdown starts at the L4/young adult stage (Figure S1R) (Curran and Ruvkun, 2007), indicating that the anti-aging effects of LySR are likely maintained even in adult or aged animals.…”

Balancing p38 MAPK Signaling with Proteostasis Mechanisms Supports Tissue Integrity during Aging inC. elegans

“…Recent findings have illuminated roles for p38 MAPK in coordinating stress signaling within cells including modulating ER stress resistance by cell surface hyaluronidase TMEM2 independent of canonical UPR (Schinzel et al 2019) and PERK-dependent recruitment of MKK4 and p38 targeting LAMP2A on lysosomes to activate chaperone-mediated autophagy (Li et al 2017). Lysosomes have recently been identified in a fat-to-neuron lipid-signaling function in C. elegans by mobilizing a polyunsaturated fatty acid with lipolysis then subsequent transport by a lipid binding protein to activate the nuclear receptor NHR-49, and activation of neuropeptide signaling to promote longevity (Savini et al 2022). Our current study unmasked p38 MAPK signaling working with a complex network of transcriptional factors to maintain lysosome function during aging in the absence of stress.…”