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

Akang E Ekpenyong‐Akiba,Marta Poblocka,Gabriella Kocsis‐Fodor,Sandra Germano,Juan J Canales,Mohammad Althubiti,Salvador Macip,Diana Jurk,Yu Shi,Miran Rada

doi:10.1111/acel.13079

Akang E Ekpenyong‐Akiba, Marta Poblocka + Show 8 more

Open Access

https://doi.org/10.1111/acel.13079

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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.

Highlights

Aging is associated with a time-dependent functional decline induced by the interaction of several mechanisms (Lopez-Otin, Blasco, Partridge, Serrano, & Kroemer, 2013)
We identified several new specific markers, including the Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase that belongs to the Tec family and is essential for B-cell maturation (Mohamed et al, 2009)
We have reported that BTK is a crucial part of the p53 pathway, where it acts as a modulator of p53 activity (Althubiti et al, 2016)

Summary

| INTRODUCTION

Aging is associated with a time-dependent functional decline induced by the interaction of several mechanisms (Lopez-Otin, Blasco, Partridge, Serrano, & Kroemer, 2013). To further explore the impact of BTK inhibition in cognitive functions of old mice, we used the Barnes maze (Capilla-Gonzalez et al, 2012) to assess long-term spatial memory, since memory loss is associated with aging (Esiri, 2007; Figure 5a) This experiment was chosen because it relies on extra-maze visual cues and does not use strong aversive stimuli, thereby inducing less stress in the FIGURE 3 Ibrutinib reduces the accumulation of senescent cells in the aging brain. When the experiment was repeated 2 weeks later, mice treated with 20 mg/kg ibrutinib were significantly faster at recalling the location of the escape box (Figure 5c and Videos S1 and S2) These results together indicate that ibrutinib can prevent the loss of different brain functions and link for the first time BTK expression with age-related organ decay

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES