{"doi":"10.1016/j.celrep.2024.113899","title":"LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans","abstract":"Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.","journal":"Cell Reports","year":2024,"id":452940,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":577094,"name":"Bingying Wang","orcid":"0000-0001-7362-7371","position":1,"is_corresponding":false},{"id":577950,"name":"Changnan Wang","orcid":null,"position":2,"is_corresponding":false},{"id":1174882,"name":"Jenny Zu","orcid":null,"position":3,"is_corresponding":false},{"id":871107,"name":"Huichao Deng","orcid":"0000-0002-1758-1820","position":4,"is_corresponding":false},{"id":314620,"name":"Kang Shen","orcid":"0000-0003-4059-8249","position":5,"is_corresponding":false},{"id":264051,"name":"Gonçalo Vale","orcid":"0000-0003-1104-0289","position":6,"is_corresponding":false},{"id":228441,"name":"Jeffrey G. McDonald","orcid":"0000-0003-1570-4142","position":7,"is_corresponding":false},{"id":142695,"name":"Dengke K. Ma","orcid":"0000-0002-5619-7485","position":8,"is_corresponding":false},{"id":871103,"name":"Taruna Pandey","orcid":"0000-0001-7278-6434","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:02:54.415477Z","pmid":"38446666","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}