Researchers at Macau University of Science and Technology discover ZYZ-384, a potent SMYD3 inhibitor that suppresses H3K4 trimethylation to lower senescence markers in human endothelial cells and mouse aging models, restoring cell proliferation and tissue function.
Key points
ZYZ-384 selectively inhibits SMYD3 histone methyltransferase, reducing H3K4me3 in endothelial cells.
Administered in vitro (HMEC-1, SVEC4-10) and in vivo (D-galactose and natural aging mouse models) to evaluate anti-senescence.
Results show reduced p16/p21, lowered SASP cytokines, improved cell proliferation and motor performance.
Why it matters:
This targeted SMYD3 inhibitor offers a novel epigenetic approach to slow aging processes and improve healthspan.
Q&A
What is SMYD3?
How does ZYZ-384 inhibit aging?
Why use the D-galactose model?
What is SASP and its relevance?
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Academy
SMYD3 and Histone Methylation in Aging
Overview: Epigenetic modifications regulate gene expression without altering DNA sequence. Among these, histone methylation plays a key role in aging by altering chromatin accessibility. SMYD3 is a histone methyltransferase that catalyzes trimethylation of lysine 4 on histone H3 (H3K4me3), a mark associated with active gene transcription. Elevated SMYD3 activity increases H3K4me3, promoting expression of genes that drive cellular senescence.
Role of SMYD3: SMYD3 belongs to the SET and Mynd domain-containing family of methyltransferases. It binds specific histone tails and transfers methyl groups from S-adenosyl methionine (SAM) to lysine residues on histones. In aging cells, SMYD3-mediated H3K4me3 increases transcription of senescence regulators, such as p16 and p21, leading to cell cycle arrest and the senescence-associated secretory phenotype (SASP).
Mechanism of Aging: During aging, accumulation of senescent cells contributes to tissue dysfunction. Senescent cells secrete inflammatory cytokines and matrix-degrading enzymes (SASP), disrupting tissue homeostasis. H3K4me3 marks regulate expression of many SASP components, linking epigenetic changes to chronic inflammation and aging pathology.
Targeting SMYD3: Inhibiting SMYD3 reduces H3K4me3 levels, downregulating pro-senescence genes. ZYZ-384 is a small-molecule inhibitor that binds the SMYD3 catalytic site, preventing histone methylation. Preclinical studies show ZYZ-384 reduces p16/p21 expression, decreases SASP factors, restores cell proliferation, and delays organ aging in mice.
Implications for Longevity: Epigenetic interventions offer reversible modulation of gene expression. SMYD3 inhibitors represent a novel class of epigenetic drugs targeting the aging process at its chromatin level. By fine-tuning histone methylation, these therapies may improve healthspan and counteract age-related diseases.
Key Concepts:
- Histone Methylation: Addition of methyl groups to histone lysines, altering chromatin structure.
- H3K4me3: Trimethylation of histone H3 at lysine 4, linked to active transcription.
- Senescence-associated Secretory Phenotype (SASP): Pro-inflammatory and tissue-remodeling factors secreted by senescent cells.
- Epigenetic Therapy: Drugs targeting chromatin modifiers to alter gene expression in diseases and aging.
Understanding SMYD3’s role provides a roadmap for epigenetic strategies in longevity science, opening doors to targeted anti-aging therapies.
