Targeting proprotein convertase subtilisin/kexin type 9 in aging-associated cardiometabolic and neurological disorders

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a crucial regulator of cholesterol metabolism, is gaining recognition for its broader involvement in aging-related disorders. Emerging evidence indicates that PCSK9 is closely linked to cardiovascular aging, neurodegenerative disorders, and metabolic dysfunction. This review synthesizes up-to-date understanding on PCSK9’s multifaceted contributions, emphasizing its role in oxidative stress, inflammation, and cellular senescence, alongside potential therapeutic implications. PCSK9 inhibition not only confers cardiovascular benefits via low-density lipoprotein-dependent and independent pathways but also exhibits broader therapeutic potential. For instance, PCSK9 inhibitors show promise in cancer immunotherapy by enhancing major histocompatibility complex class I-mediated tumor antigen presentation and in attenuating inflammation through suppressing the Toll-like receptor 4/nuclear factor kappa B pathway. However, clinical translation remains limited by tissue-specific responses and the incomplete understanding of long-term systemic effects. Overall, this review underscores the complex role of PCSK9 in the aging network and therefore highlights the need for further mechanistic studies to guide its therapeutic application.

Keywords

PCSK9 / aging / cardiovascular disease / neurodegeneration / lipid metabolism

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