Multiomic profiling of responses to clinical and novel bisphosphonates reveals extraskeletal effects on ageing related signatures.

Bisphosphonates (BPs) have been used effectively to treat excessive bone loss for over 50 years. Recent clinical evidence suggests extra-skeletal benefits but how this occurs remains unknown. Here we use a panel of human, murine and cellular assessments to chart BP-induced ageing-related changes both systemically and at local organ sites. In vivo spatial transcriptomics in aged mice treated with zoledronate showed a shift in cellular composition towards that of young animals specifically in heart, liver and intestine, with upregulation of genes governing detoxification, mitochondrial stability, energy metabolism, and antioxidation. A 5000-plex randomized trial based human proteomic analysis showed significant alterations in ~400 proteins after zoledronate treatment, with downregulation of proteins linked to genomic instability, proteostasis loss, mitochondrial dysfunction, stem cell exhaustion, and SASPs. Fluorescent labeling and tracing confirmed uptake of bisphosphonates by non-skeletal cells. In addition, low doses of several common, clinically utilized BPs stimulated growth and protected against DNA damage-induced senescence in multiple human cell types, with strongest effects in cardiomyocytes. Finally, proteome-wide target deconvolution with AlphaFold identified previously unrecognized binding partners, including PHB2 and ASAH1, and downstream upregulation of MEF2A was validated to be a key mediator of zoledronate triggered benefits in cardiomyocytes. Collectively, these results identify potential geroprotective mechanisms for BP action in multiple non-skeletal tissues.