Evidence map›Paper›PMID 42448670›Full record

ArticleSignal transduction and targeted therapy2026

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

Jinsen Lu, Srinivasa Rao Rao, Helen Knowles, Haoqun Zhan, Beatriz Gamez, Mingyu Qin, Eleanor Platt, Lucy R Frost, Tiffany-Jayne Allen, Gayle Marshall and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Signal transduction and targeted therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Jinsen LuBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Srinivasa Rao RaoNuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
Helen KnowlesBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Haoqun ZhanBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.ORCID http://orcid.org/0009-0003-1032-1641
Beatriz GamezNuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
Mingyu QinDepartment of Biochemistry, University of Oxford, Oxford, UK.
Eleanor PlattMedicines Discovery Catapult, Cheshire, UK.
Lucy R FrostMedicines Discovery Catapult, Cheshire, UK.
Tiffany-Jayne AllenMedicines Discovery Catapult, Cheshire, UK.
Gayle MarshallMedicines Discovery Catapult, Cheshire, UK.ORCID http://orcid.org/0000-0002-5839-1150
Kilian V M HuberTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-1103-5300
Ludwig G BauerTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Iolanda VendrellTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Darragh P O'BrienTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Benedikt KesslerTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Anne HorneFaculty of Medical and Health Sciences, University of Auckland, Auckland, NZ, New Zealand.
Ian R ReidFaculty of Medical and Health Sciences, University of Auckland, Auckland, NZ, New Zealand.
Chas BountraCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
James L KirklandCenter for Advanced Gerotherapeutics, Cedars-Sinai Health Sciences University, Los Angeles, USA.ORCID http://orcid.org/0000-0003-1676-4905
Sundeep KhoslaRobert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0002-2936-4372
Frank H EbetinoBioVinc LLC, Pasadena, CA, US.
Emilio RoldanQualix DoT, Barcelona, Spain.
R Graham G RussellBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
James R EdwardsBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. James.Edwards@ndorms.ox.ac.uk.

Funding

Targeting Cellular Senescence to Extend HealthspanP01AG062413 · NIA · MAYO CLINIC ROCHESTER · PI David G Monroe · 2019 to 2026
$28.7M
Characterization of senescent cell populations in skeletal agingR01AG086085 · NIA · MAYO CLINIC ROCHESTER · PI Sundeep Khosla, David G Monroe · 2024 to 2026
$1.6M
Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R01AG072301Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R33AG61456Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R37AG13925NIA NIH HHS P01 AG062413NIA NIH HHS R01 AG086085
6 · The paper itself

Abstract

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.

Indexed as

AgingDiphosphonatesZoledronic AcidAnimalsCellular SenescenceDNA DamageHumansMiceMultiomicsMyocytes, CardiacProhibitinsProteomeProteomicsRepressor ProteinsDiphosphonatesPHB protein, humanProhibitinsProteomeRepressor ProteinsZoledronic Acid

Identifiers

PMID42448670
PMCPMC13370019

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.