Necroptosis inhibition counteracts axonal degeneration, cognitive decline and key hallmarks of aging, promoting brain rejuvenation

Age is the main risk factor for cognitive impairment and the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction and brain disabilities in humans, primates, rodents, and invertebrates. Necroptosis activation mediates degeneration of mechanical and chemically injured axons, but whether this pathway triggers axonal degeneration and cognitive impairment during brain aging has not been studied. Here we show that necroptosis is activated in the hippocampus during aging, especially in axonal tracts. Loss of the main necroptotic effector, Mlkl, was sufficient to delay age-associated axonal degeneration. Accordingly, aged Mlkl-KO mice also displayed a youthful phenotype at the synaptic and functional level, protecting against decreased synaptic transmission and memory decline. Short-term pharmacologic inhibition of necroptosis by targeting RIPK3 in aged mice, proved to be extraordinarily effective at reverting axonal degeneration and hippocampal-dependent functional impairment at the electrophysiological and behavioral level. Remarkably, a comprehensive quantitative proteomic analysis uncovered a set of aging hallmarks that were recovered in both, the genetic and pharmacologic models of necroptosis inhibition, including molecular biofunctions associated with brain rejuvenation. Taken together, these findings demonstrate that necroptosis contributes to the age-associated deterioration of axonal integrity, affecting hippocampal neuronal connectivity and cognitive function in aged individuals. We therefore propose necroptosis as an attractive target for the future development of geroprotective tools to treat age-related disabilities.