Bisphosphonates Trigger Anti-Ageing Effects Across Multiple Cell Types and Protect Against Senescence
Year: 2025
Type: preprint
Abstract: Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ∼400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro . Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.
Authors: Jinsen Lu, Srinivasa Rao Rao, Helen Knowles, Haoqun Zhan, Beatriz Gamez, Eleanor Platt, Lucy R. Frost, Tiffany-Jayne Allen, Gayle Marshall, Kilian V.M. Huber, Ludwig G. Bauer, Iolanda Vendrell, Benedikt Kessler, Anne Horne, Ian R Reid, Chas Bountra, James L Kirkland, Sundeep Khosla, F Hal Ebetino, Emilio Roldan, R Graham G Russell, James R Edwards
Language: English
Topic: Bone health and treatments
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institute on Aging
Awards: COVID-FIS: A PHASE 2 PLACEBO-CONTROLLED PILOT STUDY IN COVID-19 OF FISETIN TO ALLEVIATE DYSFUNCTION AND EXCESSIVE INFLAMMATORY RESPONSE IN OLDER ADULTS IN NURSING HOMES, Translational Geroscience Network, Effect of Aging on Preadipocyte Differentiation, Targeting Cellular Senescence to Extend Healthspan, Characterization of senescent cell populations in skeletal aging
OpenAlex ID: W4408869484