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Homoharringtonine, a novel senotherapeutic, mitigates diet- and age-associated obesity and insulin resistance and extends the lifespan of mice

ABSTRACT: The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2,150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells. HHT treatment prevents diet- or age-induced metabolic abnormalities in mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE296679 | GEO | 2026/05/08

REPOSITORIES: GEO

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Discovery of cephalotaxinone enzymes reveals a whole plant model for homoharringtonine biosynthesis

Project description:Plants produce diverse molecules that inhibit protein translation. A lead example is homoharringtonine (HHT), both a key tool for ribosomal profiling and an FDA-approved treatment for chronic myeloid leukemia. HHT is commercially produced through semi-synthesis by esterifying the alkaloid core cephalotaxine (CET) extracted from endangered Cephalotaxus species. Despite its medicinal significance, a biosynthetic pathway to CET and HHT has not been described. Here, we use paired untargeted metabolomics (stable-isotope labeled precursor feeding) and transcriptomics to elucidate a near-complete biosynthesis to CET without prior knowledge of intermediates and biosynthetic genes. We show that while CET alkaloid core is actively biosynthesized only in growing root tips, both CET and HHT accumulate throughout the plant. We discovered and characterized seven CET pathway intermediates and six novel biosynthetic enzymes that can be used to produce cephalotaxinone, the likely direct precursor of CET. Included are non-canonical cytochrome P450s, an atypical short-chain dehydrogenase, and a 2-oxoglutarate-dependent dioxygenase that together result in carbon excision and pentacyclic backbone formation of HHT alkaloids. This study establishes a metabolic route to the core scaffold of HHT and suggests a whole plant coordination model for biosynthesis of eukaryotic ribosomal toxins in Cephalotaxus, where cephalotaxinone is the last pathway intermediate produced in root tips and distributed throughout the plant for subsequent elaboration to HHT.

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Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice

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Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor

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Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models

Project description:Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models

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Achilles Heels of Senescent Cells: From Transcriptome to Senolytic Drugs

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Gene expression data from lung tissues of C57BL/6J mice

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2021-07-24 | GSE180750 | GEO

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Repurposing homoharringtonine for thyroid cancer therapy through TIMP1/FAK/PI3K/AKT signaling pathway

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Identification of Homoharringtonine as a potent inhibitor of glioblastoma cell proliferation and migration.

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