Ameliorating Ageing and Age-Related Diseases by Targeting Senescent Cells

Senescence is a state of permanent cell cycle arrest with specific phenotypic features. Senescent cells have a positive role during wound healing, embryogenesis and as an anti-cancer mechanism, but they also accumulate in tissues with age, contributing towards the pathology of ageing and age-related diseases. This happens primarily through the release of the senescence-associated secretory phenotype (SASP).

Removal of senescent cells is known to improve health and life span in animal models; therefore, it is important to devise strategies to prevent senescent cell accumulation that could be used in humans. Here, we show that Ibrutinib, a BTK inhibitor, can ameliorate liver ageing in Zmpste24-deficient mouse model of progeria by reducing the accumulation of senescent cells. We used mass spectrometry to define the ageing proteomes and metabolomes of mice livers in response to ibrutinib. Three proteins, Fggy, Mtbp and Myo19, were reduced in aged livers compared to the livers of ibrutinib-treated and young mice, while Ceacam5 was increased. A proteolysis targeting chimera (PROTAC) for BTK was also investigated but showed no ability to prevent senescence.

Additionally, we tested drugs that could selectively eliminate senescent cells (senolytics). For instance, previous data suggested 9-OH-Ellipticine and A1331852 had a synergistic senolytic effect. The drugs were trialled as monotherapies and in combination in mice, but there was no evidence they had an in vivo effect.