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

Citation

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, Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition, Aging Cell, 19, (1) pp. 1-11. ISSN 1474-9718 (2020) [Refereed Article]


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

DOI: doi:10.1111/acel.13079

Abstract

One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age-dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53-induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24−/− progeroid mice, which also showed a reduction in general age-related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety-like behaviour and better long-term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower 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 from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.

Item Details

Item Type:Refereed Article
Keywords:BTK, cellular senescence, healthspan, p53, progeria
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell neurochemistry
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Canales, JJ (Professor Juan Canales)
ID Code:140237
Year Published:2020
Web of Science® Times Cited:3
Deposited By:Psychology
Deposited On:2020-08-03
Last Modified:2020-09-07
Downloads:4 View Download Statistics

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