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

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

CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL.

CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1. Moreover, CUDC-907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF-induced NF-κB signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC-907. These data indicated that CUDC-907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC-907 with inhibitors of BCL2, BTK, or the NF-κB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors

Detecting and targeting senescent cells using molecularly imprinted nanoparticles

The progressive accumulation of senescent cells in tissues in response to damage importantly contributes to pathophysiological conditions such as fibrosis, diabetes, cancer, Alzheimer's and ageing. Consistent with this, eliminating senescent cells prolongs the lifespan and healthspan in animals and ameliorates certain diseases. Detecting and clearing senescent cells from human tissues could therefore have a significant diagnostic and prognostic impact. However, identifying senescent cells in vivo has proven to be complex. To address this, we characterized and validated a panel of novel membrane markers of senescence. Here, we show the application of molecularly imprinted nanoparticles (nanoMIPs) against an extracellular epitope of one of these markers, B2M, to detect senescent cells in vitro and in vivo. We show that nanoMIPs do not elicit toxic responses in the cells or in mice and successfully recognize old animals, which have a higher proportion of senescent cells in their organs. Importantly, nanoMIPs loaded with drugs can specifically kill senescent cells. Our results provide a proof-of-principle assessment of specific and safe nanotechnology-based approaches for senescent cell detection and clearance with potential clinical relevance