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Area of Science:

  • Gerontology
  • Molecular Biology
  • Pharmacology

Background:

  • Bisphosphonates (BPs) are established treatments for bone loss disorders.
  • Emerging evidence suggests BPs possess significant extra-skeletal benefits, including reduced mortality and improved age-related conditions.
  • These benefits may extend to cancer and cardiovascular disease.

Purpose of the Study:

  • To investigate the non-skeletal effects of bisphosphonates.
  • To identify novel mechanisms and cellular targets of bisphosphonates beyond bone.
  • To explore the impact of bisphosphonates on aging and senescence.

Main Methods:

  • Spatial transcriptomics in aged mice treated with BPs.
  • 5000-plex plasma proteome analysis in osteopenic patients before and after BP treatment.
  • In vitro senescence assays and proteome-wide target deconvolution (2D thermal profiling).
  • RNA- and ATAC-seq analyses of BP-treated cells and patient data.

Main Results:

  • Bisphosphonates co-localize with endosomal/lysosomal organelles and stimulate non-skeletal cell growth at low doses.
  • BP treatment altered senescence markers and cellular composition in multiple organs of aged mice, shifting towards younger profiles.
  • Plasma proteome analysis revealed significant changes in ~400 proteins, including markers of senescence, autophagy, apoptosis, and inflammation, in osteopenic patients post-BP treatment.
  • BPs demonstrated protection against in vitro senescence onset.
  • Novel BP targets (PHB2, ASAH1) were identified, suggesting downstream regulation of MEF2A in the heart.

Conclusions:

  • Bisphosphonates beneficially modify the plasma proteome and impact non-skeletal cell types through novel protein interactions.
  • These effects influence pathways related to senescence and aging, offering new therapeutic possibilities.
  • The findings provide a molecular basis for the observed extra-skeletal benefits of bisphosphonates.