Astragaloside IV delays vascular aging by enhancing mitochondrial fatty acid β-oxidation via the MLXIPL-PPARα/PGC-1α axis.

BACKGROUND

Mitochondrial dysfunction and the dysregulation of lipid metabolism are significant contributors to vascular aging, which in turn raises the risk of age-related cardiovascular diseases (CVDs). Buyang Huanwu decoction (BHD), a traditional formula widely used for treating CVDs, has not been thoroughly investigated in terms of its active components and the molecular mechanisms by which it may delay vascular aging.

PURPOSE: This study aims to investigate the effects and mechanisms of BHD and its primary active component, Astragaloside IV (AS-IV), in mitigating vascular aging, focusing on mitochondrial function and lipid metabolism.

METHODS

Experiments were conducted using naturally aged mice and a D-galactose-induced model of vascular smooth muscle cells (VSMCs) senescence. Vascular aging was evaluated through aortic histopathology, assessment of senescence markers and senescence-associated secretory phenotype (SASP) factors. Transcriptomics and lipidomics analyses were employed to uncover critical pathways and identify differential lipid profiles. Mitochondrial structure and function were examined using transmission electron microscopy (TEM), Mitochondrial DNA (mtDNA) copy number, and mitochondrial membrane potential (MMP). The molecular mechanisms were further validated through molecular biology and MLX Interacting Protein-Like (MLXIPL) knockdown and overexpression techniques.

RESULTS

Both BHD and AS-IV improved age-related vascular morphological changes, mitigated elastic fiber disruption, diminished collagen deposition, and downregulated senescence markers along with SASP factors. Transcriptomic analysis identified MLXIPL as a key transcription factor, emphasizing the involvement of the peroxisome proliferator-activated receptor (PPAR) signaling pathway and mitochondrial fatty acid β-oxidation as critical processes. Lipidomic profiling indicated reduced serum acylcarnitine levels in aged mice, suggesting compromised fatty acid β-oxidation. Both BHD and AS-IV were found to suppress MLXIPL, activate PPARα, increase mtDNA copy number, enhance MMP, improve mitochondrial ultrastructure, and upregulate the expression of key genes and proteins associated with mitochondrial biogenesis and fatty acid β-oxidation. Co-immunoprecipitation assays confirmed that AS-IV facilitated PPARα-PGC-1α interaction. Functional validation established that MLXIPL knockdown produced a stronger effect than AS-IV, whereas MLXIPL overexpression negated the beneficial effects of AS-IV on mitochondrial function, lipid accumulation, and cellular senescence.

CONCLUSION

BHD and its active component AS-IV delay vascular aging by inhibiting MLXIPL, thereby activating the PPARα/PGC-1α signaling pathway to promote mitochondrial fatty acid β-oxidation and reduce lipid accumulation. This elucidates a mechanistic basis for BHD's traditional use and highlights AS-IV as a key active principle with therapeutic potential.