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Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition

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Ekpenyong-Akiba, AE, Poblocka, M, Althubiti, M, Rada, M, Jurk, D, Germano, S, Kocsis-Fodor, G, Shi, Y, Canales, JJ ORCID: 0000-0003-2884-5227 and Macip, S 2020 , 'Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition' , Aging Cell, vol. 19, no. 1 , pp. 1-11 , doi: 10.1111/acel.13079.

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Abstract

One of the hallmarks of aging is the progressive accumulation of senescent cells inorganisms, which has been proposed to be a contributing factor to age-dependentorgan dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is anupstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent withthis, blocking BTK impairs p53-induced senescence. This suggests that sustainedBTK inhibition could have an effect on organismal aging by reducing the presence ofsenescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalentinhibitor of BTK, prolonged the maximum lifespan of a Zmpste24−/− progeroid mice,which also showed a reduction in general age-related fitness loss. Importantly, wefound that certain brain functions were preserved, as seen by reduced anxiety-likebehaviour and better long-term spatial memory. This was concomitant to a decreasein the expression of specific markers of senescence in the brain, which confirms alower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24−/− mice and protects them froma decline in brain performance. This suggests that specific inhibitors could be used inhumans to treat progeroid syndromes and prevent the age-related degeneration oforgans such as the brain.

Item Type: Article
Authors/Creators:Ekpenyong-Akiba, AE and Poblocka, M and Althubiti, M and Rada, M and Jurk, D and Germano, S and Kocsis-Fodor, G and Shi, Y and Canales, JJ and Macip, S
Keywords: BTK, cellular senescence, healthspan, p53, progeria
Journal or Publication Title: Aging Cell
Publisher: Blackwell Publ Ltd
ISSN: 1474-9718
DOI / ID Number: 10.1111/acel.13079
Copyright Information:

Copyright 2019 the authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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