Roadmap for alleviating the manifestations of ageing in the cardiovascular system

Luca Liberale^#^{1

2}, Simon Tual-Chalot^#³, Simon Sedej⁴, Stefano Ministrini⁵, Georgios Georgiopoulos⁶, Myriam Grunewald⁷, Magnus Bäck^{8

9}, Marie-Luce Bochaton-Piallat¹⁰, Reinier A Boon¹¹, Gustavo Campos Ramos¹², Menno P J de Winther¹³, Konstantinos Drosatos¹⁴, Paul C Evans¹⁵, Jane F Ferguson¹⁶, Sofia K Forslund-Startceva¹⁷, Claudia Goettsch¹⁸, Mauro Giacca¹⁹, Judith Haendeler²⁰, Marinos Kallikourdis²¹, Daniel F J Ketelhuth²², Rory R Koenen²³, Patrick Lacolley⁹, Esther Lutgens²⁴, Pasquale Maffia²⁵, Satomi Miwa²⁶, Claudia Monaco²⁷, Fabrizio Montecucco^{1

2}, Giuseppe Danilo Norata²⁸, Elena Osto²⁹, Gavin D Richardson²⁶, Niels P Riksen³⁰, Oliver Soehnlein³¹, Ioakim Spyridopoulos³², Sophie Van Linthout³³, Gemma Vilahur³⁴, Jolanda J Wentzel³⁵, Vicente Andrés³⁶, Lina Badimon³⁷, Athanase Benetos³⁸, Christoph J Binder³⁹, Ralf P Brandes⁴⁰, Filippo Crea⁴¹, David Furman⁴², Vera Gorbunova⁴³, Tomasz J Guzik⁴⁴, Joseph A Hill⁴⁵, Thomas F Lüscher⁴⁶, María Mittelbrunn⁴⁷, Alessio Nencioni^{2

48}, Mihai G Netea⁴⁹, João F Passos⁵⁰, Kimon S Stamatelopoulos⁵¹, Nektarios Tavernarakis⁵², Zoltan Ungvari⁵³, Joseph C Wu⁵⁴, James L Kirkland⁵⁵, Giovanni G Camici⁵, Stefanie Dimmeler⁵⁶, Guido Kroemer⁵⁷, Mahmoud Abdellatif⁴, Konstantinos Stellos⁵⁸

Affiliations

¹ First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.
² IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.
³ Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK. simon.tual-chalot@newcastle.ac.uk.
⁴ Department of Cardiology, Medical University of Graz, Graz, Austria.
⁵ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
⁶ Department of Physiology, School of Medicine, University of Patras, Patras, Greece.
⁷ Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁸ Translational Cardiology, Centre for Molecular Medicine, Department of Medicine Solna, and Department of Cardiology, Heart and Vascular Centre, Karolinska Institutet, Stockholm, Sweden.
⁹ Inserm, DCAC, Université de Lorraine, Nancy, France.
¹⁰ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
¹¹ Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC location VUmc, Amsterdam, Netherlands.
¹² Department of Internal Medicine I/Comprehensive Heart Failure Centre, University Hospital Würzburg, Würzburg, Germany.
¹³ Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis and Ischaemic Syndromes; Amsterdam Infection and Immunity: Inflammatory Diseases, Amsterdam UMC location AMC, Amsterdam, Netherlands.
¹⁴ Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁵ William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁶ Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁸ Department of Internal Medicine I, Division of Cardiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹⁹ British Heart foundation Centre of Reseach Excellence, King's College London, London, UK.
²⁰ Cardiovascular Degeneration, Medical Faculty, University Hospital and Heinrich-Heine University, Düsseldorf, Germany.
²¹ Adaptive Immunity Lab, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
²² Cardiovascular and Renal Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
²³ CARIM-School for Cardiovascular Diseases, Department of Biochemistry, Maastricht University, Maastricht, Netherlands.
²⁴ Department of Cardiovascular Medicine & Immunology, Mayo Clinic, Rochester, MN, USA.
²⁵ School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
²⁶ Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
²⁷ Kennedy Institute, NDORMS, University of Oxford, Oxford, UK.
²⁸ Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
²⁹ Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria.
³⁰ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
³¹ Institute of Experimental Pathology, University of Münster, Münster, Germany.
³² Translational and Clinical Research Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
³³ BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätmedizin Berlin, Berlin, Germany.
³⁴ Research Institute, Hospital de la Santa Creu y Sant Pau l, IIB-Sant Pau, Barcelona, Spain.
³⁵ Cardiology, Biomedical Engineering, Erasmus MC, Rotterdam, Netherlands.
³⁶ Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBERCV, Madrid, Spain.
³⁷ Cardiovascular Health and Innovation Research Foundation (FICSI) and Cardiovascular Health and Network Medicine Department, University of Vic (UVIC-UCC), Barcelona, Spain.
³⁸ Department of Geriatrics, University Hospital of Nancy and Inserm DCAC, Université de Lorraine, Nancy, France.
³⁹ Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁴⁰ Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany.
⁴¹ Centre of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina - Gemelli Isola, Roma, Italy.
⁴² Buck Institute for Research on Aging, Novato, CA, USA.
⁴³ Departments of Biology and Medicine, University of Rochester, Rochester, NY, USA.
⁴⁴ Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.
⁴⁵ University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴⁶ Heart Division, Royal Brompton and Harefield Hospital and National Heart and Lung Institute, Imperial College, London, UK.
⁴⁷ Consejo Superior de Investigaciones Científicas (CSIC), Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
⁴⁸ Dipartimento di Medicina Interna e Specialità Mediche-DIMI, Università degli Studi di Genova, Genova, Italy.
⁴⁹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
⁵⁰ Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
⁵¹ Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
⁵² Medical School, University of Crete, and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
⁵³ Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵⁴ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁵⁵ Center for Advanced Gerotherapeutics, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵⁶ Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.
⁵⁷ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm, Institut Universitaire de France, Paris, France.
⁵⁸ Department of Cardiovascular Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. konstantinos.stellos@medma.uni-heidelberg.de.

^# Contributed equally.

PMID: 39972009
DOI: 10.1038/s41569-025-01130-5

Review

Roadmap for alleviating the manifestations of ageing in the cardiovascular system

Luca Liberale et al. Nat Rev Cardiol. 2025 Aug.

. 2025 Aug;22(8):577-605.

doi: 10.1038/s41569-025-01130-5. Epub 2025 Feb 19.

Authors

Affiliations

¹ First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.
² IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.
³ Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK. simon.tual-chalot@newcastle.ac.uk.
⁴ Department of Cardiology, Medical University of Graz, Graz, Austria.
⁵ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
⁶ Department of Physiology, School of Medicine, University of Patras, Patras, Greece.
⁷ Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁸ Translational Cardiology, Centre for Molecular Medicine, Department of Medicine Solna, and Department of Cardiology, Heart and Vascular Centre, Karolinska Institutet, Stockholm, Sweden.
⁹ Inserm, DCAC, Université de Lorraine, Nancy, France.
¹⁰ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
¹¹ Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC location VUmc, Amsterdam, Netherlands.
¹² Department of Internal Medicine I/Comprehensive Heart Failure Centre, University Hospital Würzburg, Würzburg, Germany.
¹³ Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis and Ischaemic Syndromes; Amsterdam Infection and Immunity: Inflammatory Diseases, Amsterdam UMC location AMC, Amsterdam, Netherlands.
¹⁴ Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁵ William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁶ Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁸ Department of Internal Medicine I, Division of Cardiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹⁹ British Heart foundation Centre of Reseach Excellence, King's College London, London, UK.
²⁰ Cardiovascular Degeneration, Medical Faculty, University Hospital and Heinrich-Heine University, Düsseldorf, Germany.
²¹ Adaptive Immunity Lab, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
²² Cardiovascular and Renal Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
²³ CARIM-School for Cardiovascular Diseases, Department of Biochemistry, Maastricht University, Maastricht, Netherlands.
²⁴ Department of Cardiovascular Medicine & Immunology, Mayo Clinic, Rochester, MN, USA.
²⁵ School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
²⁶ Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
²⁷ Kennedy Institute, NDORMS, University of Oxford, Oxford, UK.
²⁸ Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
²⁹ Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria.
³⁰ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
³¹ Institute of Experimental Pathology, University of Münster, Münster, Germany.
³² Translational and Clinical Research Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
³³ BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätmedizin Berlin, Berlin, Germany.
³⁴ Research Institute, Hospital de la Santa Creu y Sant Pau l, IIB-Sant Pau, Barcelona, Spain.
³⁵ Cardiology, Biomedical Engineering, Erasmus MC, Rotterdam, Netherlands.
³⁶ Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBERCV, Madrid, Spain.
³⁷ Cardiovascular Health and Innovation Research Foundation (FICSI) and Cardiovascular Health and Network Medicine Department, University of Vic (UVIC-UCC), Barcelona, Spain.
³⁸ Department of Geriatrics, University Hospital of Nancy and Inserm DCAC, Université de Lorraine, Nancy, France.
³⁹ Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁴⁰ Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany.
⁴¹ Centre of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina - Gemelli Isola, Roma, Italy.
⁴² Buck Institute for Research on Aging, Novato, CA, USA.
⁴³ Departments of Biology and Medicine, University of Rochester, Rochester, NY, USA.
⁴⁴ Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.
⁴⁵ University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴⁶ Heart Division, Royal Brompton and Harefield Hospital and National Heart and Lung Institute, Imperial College, London, UK.
⁴⁷ Consejo Superior de Investigaciones Científicas (CSIC), Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
⁴⁸ Dipartimento di Medicina Interna e Specialità Mediche-DIMI, Università degli Studi di Genova, Genova, Italy.
⁴⁹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
⁵⁰ Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
⁵¹ Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
⁵² Medical School, University of Crete, and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
⁵³ Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵⁴ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁵⁵ Center for Advanced Gerotherapeutics, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵⁶ Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.
⁵⁷ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm, Institut Universitaire de France, Paris, France.
⁵⁸ Department of Cardiovascular Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. konstantinos.stellos@medma.uni-heidelberg.de.

^# Contributed equally.

PMID: 39972009
DOI: 10.1038/s41569-025-01130-5

Abstract

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.

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Conflict of interest statement

Competing interests: L.L. is co-inventor on international patent WO/2020/226993 filed in April 2020, relating to the use of antibodies that specifically bind to IL-1α to reduce the sequelae of ischaemia–reperfusion injury to the central nervous system, and has received financial support from the Swiss Heart Foundation and the Novartis Foundation for Medical–Biological Research outside the topic of this Review. M. Giacca is a scientific founder, consultant, member of the board and equity holder in Forcefield Therapeutics, Heqet Therapeutics and Purespring Therapeutics. M.K. is listed as inventor in patents related to the manipulation of adaptive immunity for the prevention or treatment of cardiovascular disease. P.M. reports consulting fees from Pangea Botanica and Orion Biotechnology. G.D.N. declares research grants from Novartis, consultancy fees from Amarin, Amgen, Meda Pharma and MSD, and speaker bureau fee from MSD. O.S. receives funding from Novo Nordisk and serves as consultant to Roche and Novo Nordisk. L.B. acts as scientific adviser of the Berlin Institute of Health, Sanofi, Ionnis, Pfizer and Novo Nordisk; receives educational grants from Sanofi and Bayer; and founded the Spin-off Ivastatin Therapeutics SL (all unrelated to this work). V.G. is scientific advisory board member for GenFlow, MatrixBio, DoNotAge and BellSant. T.F.L. reports educational and research funding from Abbot, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Eli Lilly, Novartis, Novo Nordisk, Sanofi and Vifor. M.G.N. is the scientific founder of Biotrip, Lemba and TTxD. J.C.W. is the scientific founder of Greenstone Biosciences. J.L.K. has a financial interest related to this area including patents and pending patents covering senolytic drugs and their uses, which are held by the Mayo Clinic; this Review article has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic conflict of interest policies. G.G.C. is coinventor on international patent WO/2020/226993 filed in April 2020, which relates to the use of antibodies that specifically bind to IL-1α to reduce sequelae of ischaemia–reperfusion injury to the central nervous system. G.K. has held research contracts with Daiichi-Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage; is on the Board of Directors of the Bristol Myers Squibb Foundation France; is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio; is on the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences; and is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders; G.K.’s wife, L. Zitvogel, has held research contracts with GSK, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi-Sankyo, Pilege, Merus, Transgene, 9m, Tusk and Roche, was on the Board of Directors of Transgene, is a co-founder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota; G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer Ingelheim. M.A. is involved in patents dealing with the cardiometabolic benefits of spermidine, nicotinamide and acyl coenzyme A binding protein. The other authors declare no competing interests.

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Roadmap for alleviating the manifestations of ageing in the cardiovascular system

Affiliations

Roadmap for alleviating the manifestations of ageing in the cardiovascular system

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials