@article{10bda94e4d1941e8a2a9213073c98992,
title = "Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition",
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.",
keywords = "BTK, cellular senescence, healthspan, p53, progeria",
author = "Ekpenyong-Akiba, {Akang E.} and Marta Poblocka and Mohammad Althubiti and Miran Rada and Diana Jurk and Sandra Germano and Gabriella Kocsis-Fodor and Yu Shi and Canales, {Juan J.} and Salvador Macip",
note = "Funding Information: In vivo studies were carried out using the zinc metalloproteinase STE24 (ZMPSTE24) deficient mouse model of progeria, which has an average lifespan of 6–8 months (Pendas et al., ; Varela et al., ). Cryopreserved spermatozoa were purchased from the Mutant Mouse Resource & Research Centre at University of California, Davis, which is supported by the National Institutes of Health (NIH). The sperm was implanted into recipient female wild‐type C57BL/6J mice. Heterozygous offspring of the founder lines were further bred to create genetically altered strains deficient in the gene. All research done using animals were conducted in adherence to the UK Home Office Animals (Scientific Procedures) Act 1986. For humane reasons, animals were allowed to be kept for a maximum of 8 months of age or when a humane end point was reached (see Table S1 ). All experiments were started when animals reached 2 months of age. mice received either ibrutinib (dissolved in DMSO) or water with DMSO (controls). Animals from the same group were paired in cages, matched by sex and age. No two animals from the same experimental group were placed into the same cage. Animals were administered either 10 mg or 20 mg of Ibrutinib (PCI‐32765, Selleck) per kilogram body weight, twice weekly by oral gavage, using a 1 ml syringe (Terumo) and a 20 ga × 38 mm plastic feeding tube (Instech Laboratories). Zmpste24 −/− Zmpste24 Zmpste24 −/− Funding Information: Work in SM's laboratory was supported by an Innovation Fellowship from the University of Leicester and the M.C. Andreu Memorial Fund. AEEA was supported by a TETFUND PhD fellowship. MP was supported by an MIBTP fellowship. We thank Dr Kees Straatman and the Advanced Imaging Facility for their help in obtaining images and the staff of the Division of Biomedical Services, Preclinical Research Facility, for technical support and care of experimental animals. We thank Prof Martin J. S. Dyer and Dr Jo{\~a}o F. Passos for critically reviewing the manuscript. Publisher Copyright: {\textcopyright} 2019 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd",
year = "2020",
month = jan,
day = "1",
doi = "10.1111/acel.13079",
language = "English (US)",
volume = "19",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "1",
}