Targeting cellular senescence in diabetic kidney disease: potential of regenerative, cell-based therapies and other senotherapeutic approaches

Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease globally. Although modern treatments can slow the progression of DKD, a substantial number of individuals still advance to kidney failure each year, attributed to complex, multifactorial pathophysiological processes that confer treatment resistance. Cellular senescence, an irreversible state of cell cycle arrest, has emerged as a recognized driver of DKD pathogenesis, which propagates chronic inflammation, leading to tissue damage. Over the past 5 years, investigations into novel therapeutic platforms that diminish senescence in DKD models and patients have increased exponentially. Senotherapeutics are agents that directly reduce senescence burden and can be classified as senolytics and senomorphics. Regenerative therapeutics encompass disciplines like cell-based therapies and tissue engineering, which aim to restore damaged tissues. Commonly studied cellular therapies in DKD include mesenchymal stem/stromal cells and their derived extracellular vesicles. Tissue engineering leverages biomaterials, like hydrogels and scaffolds, some of which are also in early-phase clinical trials for DKD. Other advanced technologies, including chimeric antigen receptor T cell, clustered regularly interspaced short palindromic repeats gene editing, and adeno-associated virus-mediated gene delivery, offer unique opportunities to expand the DKD armamentarium to reduce cellular senescence abundance and chronic inflammation. In this review, we summarize recent studies characterizing cellular senescence in DKD, highlight senescence-associated molecules and pathways comprising therapeutic targets, describe promising senotherapeutics and regenerative agents under investigation, and propose new strategies that magnify senotherapeutic properties in regenerative agents for maximized impact to halt DKD. These scientific advancements and others are expected to contribute to the development of new therapeutic agents that address cellular senescence and prevent DKD pathogenesis.