Researchers report AGGF1 delays endothelial cellular senescence through the TGFB3-TAK1-AMPK axis

A study in Biogerontology reports that the angiogenic factor AGGF1 mitigates endothelial cellular senescence and preserves mitochondrial morphology through a newly identified TGFB3-TAK1-AMPK signaling module, offering a potential molecular target for vascular aging.

According to a study published in Biogerontology, researchers identified that the angiogenic factor with G-patch and FHA domain 1 (AGGF1) plays a direct role in regulating endothelial cellular senescence.

The researchers reported that AGGF1 expression is significantly downregulated at both the mRNA and protein levels in replicative (population doubling level 30) and doxorubicin-induced senescent human umbilical vein endothelial cells (HUVECs).

Short hairpin RNA-mediated knockdown of AGGF1 accelerated cellular senescence, as demonstrated by elevated SA-β-gal activity, increased DNA damage (γH2AX foci), reduced Ki-67 proliferation marker expression, and elevated interleukin-6 (IL-6) levels.

Adenoviral-mediated overexpression of AGGF1 was shown to attenuate doxorubicin- and mitomycin C-induced senescence and suppress mitochondrial fragmentation in vitro.

Transcriptomic profiling of the overexpressing cells revealed 467 differentially expressed genes (312 upregulated and 155 downregulated), with approximately 53.3% of the senescence-associated genes linked to mitochondrial biology.

Mechanistically, the study demonstrated that AGGF1 transcriptionally upregulates TGFB3, which is associated with the activation of TGF-beta-activated kinase 1 (TAK1) and subsequent phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK), ultimately suppressing dynamin-related protein 1 (DRP1) and upregulating mitofusin 2 (MFN2).

Vascular endothelial cell senescence drives the progression of systemic age-related cardiovascular diseases, and finding endogenous molecules that arrest this process is crucial for cardiovascular therapy.

The study maps a specific connection between mitochondrial dynamics and cellular senescence, illustrating how a metabolic sensor (AMPK) can preserve mitochondrial architecture (balancing DRP1 and MFN2) under senescent stress.

The work highlights a senomorphic approach, which focuses on maintaining cellular health and preventing the transition to a senescent phenotype, rather than eliminating existing senescent cells via senolysis.

The identification of the AGGF1-TGFB3-TAK1-AMPK axis expands the potential drug discovery pipeline for vascular aging, offering a novel therapeutic target for metabolic and mitochondrial homeostasis.

Biotech companies focused on cardiovascular health and age-related vascular diseases may look to leverage therapies targeting upstream regulators of mitochondrial fission and fusion.

This mechanism reinforces the commercial viability of targeting mitochondrial morphology and AMPK pathways, which are increasingly seen as key therapeutic pillars in the longevity sector.

Validation of AGGF1 gene therapy or protein administration in animal models of vascular aging and natural physiological aging to confirm in vivo efficacy.

Clarification of the precise biochemical mechanisms by which AGGF1 regulates TGFB3 transcriptional activation.

Direct biochemical verification of the physical phosphorylation cascade between TGFB3, TAK1, and AMPK to confirm direct causal pathways.