PT  - JOURNAL ARTICLE
AU  - Arrázola, Macarena S.
AU  - Lira, Matías
AU  - Quiroz, Gabriel
AU  - Iqbal, Somya
AU  - Eaton, Samantha L
AU  - Kline, Rachel A
AU  - Lamont, Douglas J
AU  - Huerta, Hernán
AU  - Ureta, Gonzalo
AU  - Bernales, Sebastián
AU  - Cárdenas, J César
AU  - Cerpa, Waldo
AU  - Wishart, Thomas M.
AU  - Court, Felipe A.
TI  - Necroptosis inhibition counteracts axonal degeneration, cognitive decline and key hallmarks of aging, promoting brain rejuvenation
AID  - 10.1101/2021.11.10.468052
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.11.10.468052
4099  - http://biorxiv.org/content/early/2022/04/18/2021.11.10.468052.short
4100  - http://biorxiv.org/content/early/2022/04/18/2021.11.10.468052.full
AB  - Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities. Necroptosis activation mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here we show necroptosis activation in hippocampal axons during aging. Loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis in aged mice reverted structural and functional hippocampal impairment. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including molecular biofunctions associated with brain rejuvenation. Our results demonstrate that necroptosis contributes to the functional decline of the aged brain, and necroptosis inhibition constitute a potential geroprotective strategy to treat age-related disabilities.Competing Interest StatementThe authors have declared no competing interest.