Aging is a natural process that is characterized by chronic, low-grade inflammation, which represents the primary risk factor in the pathogenesis of a variety of diseases, i.e. aging-related diseases. RIP kinases, in particular RIPK1 and RIPK3, have emerged as master regulators of proinflammatory responses that act either by causing apoptosis and necroptosis or by directly regulating intracellular inflammatory signaling. While, RIPK1/3 and necroptosis are intimately linked to multiple human diseases, the relationship among RIPK1/3, necroptosis, and aging remains unclear. In this review, we discuss current evidence arguing for the involvement of RIPK1/3 and necroptosis in the progression of aging. In addition, we provide updated information and knowledge on the role of RIPK1/3 and necroptosis in aging-related diseases. Leveraging these new mechanistic insights in aging, we postulate how our improved understanding of RIPK1/3 and necroptosis in aging may support the development of therapeutics targeting RIPK1/3 and necroptosis for the modulation of aging and treatment of aging-related diseases.

The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3; also called Machado-Joseph disease, MJD) is a trinucleotide repeat disorder caused by expansion of the CAG repeats in the ATXN3 gene. Here, we applied a CRISPR/Cas9-mediated approach using homologous recombination to achieve a one-step genetic correction in SCA3-specific induced pluripotent stem cells (iPSCs). The genetic correction reversed disease-associated phenotypes during cerebellar region-specific differentiation. In addition, we observed spontaneous ataxin-3 aggregates specifically in mature cerebellar neurons differentiated from SCA3 iPSCs rather than in SCA3 pan-neurons, SCA3 iPSCs or neural stem cells, suggesting that SCA3 iPSC-derived disease-specific and region-specific cerebellar neurons can provide unique cellular models for studying SCA3 pathogenesis in vitro. Importantly, the genetically corrected cerebellar neurons did not display typical SCA3 aggregates, suggesting that genetic correction can subsequently reverse SCA3 disease progression. Our strategy can be applied to other trinucleotide repeat disorders to facilitate disease modeling, mechanistic studies and drug discovery.