{"doi":"10.14336/ad.2019.0416","title":"Statins Induce a DAF-16/Foxo-dependent Longevity Phenotype via JNK-1 through Mevalonate Depletion in C. elegans","abstract":"Statins belong to the most pre-scribed cholesterol lowering drugs in western countries. Their competitive inhibition of the HMG-CoA reductase causes a reduction in the mevalonate pool, resulting in reduced cholesterol biosynthesis, impaired protein prenylation and glycosylation. Recently, a cohort study showed a decreased mortality rate in humans between age 78-90 going along with statin therapy, which is independent of blood cholesterol levels. As <i>C. elegans</i> harbors the mevalonate pathway, but is cholesterol-auxotroph, it is particularly suitable to study cholesterol-independent effects of statins on aging-associated phenotypes. Here, we show that low doses of lovastatin or a mild HMG-CoA reductase knockdown via <i>hmgr-1(RNAi)</i> in <i>C. elegans</i> substantially attenuate aging pigment accumulation, which is a well-established surrogate marker for biological age. Consistently, for two statins we found dosages, which prolonged the lifespan of <i>C. elegans</i>. Together with an observed reduced fertility, slower developmental timing and thermal stress resistance this complex of outcomes point to the involvement of DAF-16/hFOXO3a, the master regulator of stress resistance and longevity. Accordingly, prolonged low-dose statin exposure leads to an increased expression of <i>jnk-1</i>, a known activator of DAF-16. Moreover, the beneficial effects of statins on aging pigments and lifespan depend on DAF-16 and JNK-1, as shown in epistasis analyses. These effects can be reverted by mevalonate supplementation. In conclusion, we describe a lifespan extension in <i>C. elegans</i>, which is conferred via two well-conserved stress-related factors (JNK-1, DAF-16) and results from mevalonate depletion.","journal":"Aging and Disease","year":2020,"id":75022,"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":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":393796,"name":"Scherer Bo","orcid":null,"position":1,"is_corresponding":false},{"id":393797,"name":"Gerhard Fritz","orcid":null,"position":2,"is_corresponding":false},{"id":392119,"name":"Sebastian Honnen","orcid":"0000-0002-7845-7807","position":3,"is_corresponding":false},{"id":393795,"name":"Jahn Andreas","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T21:46:33.313355Z","pmid":"32010481","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":[]}