Defective prelamin A processing promotes RIPK1-driven necroptosis and inflammation in premature aging

Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and premature aging. Accumulation of progerin, a toxic isoform of lamin A, or prelamin A, the precursor protein of lamin A, is the major underlying cause of premature aging syndromes. However, the molecular mechanism that mediates premature aging remains poorly defined. Here we report that the accumulation of farnesylated forms of prelamin A at the nuclear lamina triggers RIPK1 kinase-dependent signaling that leads to inflammation and RIPK3-mediated necroptosis in multiple tissues of a mouse model of accelerated aging (Zmpste24-/- mice). We show that prelamin A recruits RIPK1 in the nucleus to facilitate its activation in response to TNFα stimulation. Inhibition of prelamin A farnesylation prevents its accumulation at the nuclear envelope, and consequently reduces RIPK1 activation and necroptosis. The causality of RIPK1-driven necroptosis and inflammation in premature aging was demonstrated by genetic inactivation of RIPK1 or knockout of RIPK3, which prevented the premature degeneration of multiple tissues and organs in Zmpste24-/- mice and significantly extended their longevity. Our findings provide in vivo proof of principle for the feasibility of inhibition of RIPK1 kinase to slow down the progression of physiological and pathological aging.