Roadmap for alleviating the manifestations of ageing in the cardiovascular system
Open accessAbstract
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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Under stressors such as hypoxia, inflammation, and hemodynamic changes, vascular smooth muscle cells transition from a differentiated contractile phenotype to a synthetic, proliferative state.
“However, under stressors such as hypoxia, inflammation, and hemodynamic changes, VSMCs transition into a synthetic, proliferative state, producing extracellular matrix components, secreting proinflammatory cytokines, recruiting immune cells, and exacerbating vascular inflammation 2 .”
From Targeting autophagy to treat neointimal hyperplasia in vascular disease (2025) · cites this paper as [2]
The Introduction’s “Vascular ageing” section says that immune-cell infiltration can cause VSMCs to switch to a synthetic phenotype with reduced contractile-protein expression and increased proliferation. It also identifies mechanical forces as influences on VSMCs, but does not identify hypoxia as a trigger of this switch; its discussion of hypoxia and haemodynamic stress concerns endothelial cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNeointimal hyperplasia is driven by pathological alterations in vascular smooth muscle cell function.
“At the cellular level, neointimal hyperplasia is driven by pathological alterations in VSMC function.”
From Targeting autophagy to treat neointimal hyperplasia in vascular disease (2025) · cites this paper as [2]
The Introduction’s ‘Vascular ageing’ section (page unavailable) describes intimal thickening as part of vascular remodelling and reports pathological VSMC changes, including increased proliferation and migration. It does not specifically identify altered VSMC function as the driver of neointimal hyperplasia. (LLM, conf=0.78)
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References 495 · Cited by 59
- Authors
- Liberale, L., Tual-Chalot, S., Sedej, S., Ministrini, S., Georgiopoulos, G., Grunewald, M., Bäck, M., Bochaton-Piallat, M.-L., Boon, R. A., Ramos, G. C., de Winther, M. P. J., Drosatos, K., Evans, P. C., Ferguson, J. F., Forslund-Startceva, S. K., Goettsch, C., Giacca, M., Haendeler, J., Kallikourdis, M., Ketelhuth, D. F. J., Koenen, R. R., Lacolley, P., Lutgens, E., Maffia, P., Miwa, S., Monaco, C., Montecucco, F., Norata, G. D., Osto, E., Richardson, G. D., Riksen, N. P., Soehnlein, O., Spyridopoulos, I., Van Linthout, S., Vilahur, G., Wentzel, J. J., Andrés, V., Badimon, L., Benetos, A., Binder, C. J., Brandes, R. P., Crea, F., Furman, D., Gorbunova, V., Guzik, T. J., Hill, J. A., Lüscher, T. F., Mittelbrunn, M., Nencioni, A., Netea, M. G., Passos, J. F., Stamatelopoulos, K. S., Tavernarakis, N., Ungvari, Z., Wu, J. C., Kirkland, J. L., Camici, G. G., Dimmeler, S., Kroemer, G., Abdellatif, M., & Stellos, K.
- Affiliations
- Ospedale Policlinico San Martino (IT)
- Medical University of Graz (AT)
- University of Zurich (CH)
- University of Patras (GR)
- Hebrew University of Jerusalem (IL)
- Inserm (FR)
- Amsterdam Cardiovascular Sciences (NL)
- Universitätsklinikum Würzburg (DE)
- University of Cincinnati (US)
- Queen Mary University of London (GB)
- Vanderbilt University Medical Center (US)
- RWTH Aachen University (DE)
- King's College London (GB)
- Düsseldorf University Hospital (DE)
- IRCCS Humanitas Research Hospital (IT)
- University of Southern Denmark (DK)
- Maastricht University (NL)
- Mayo Clinic (US)
- University of Glasgow (GB)
- Newcastle University (GB)
- University of Oxford (GB)
- University of Milan (IT)
- Radboud University Medical Center (NL)
- University of Münster (DE)
- Hospital de Sant Pau (ES)
- Erasmus MC (NL)
- Spanish National Centre for Cardiovascular Research (ES)
- Medical University of Vienna (AT)
- Goethe University Frankfurt (DE)
- Agostino Gemelli University Polyclinic (IT)
- Buck Institute for Research on Aging (US)
- University of Rochester (US)
- University of Edinburgh (GB)
- The University of Texas Southwestern Medical Center (US)
- Harefield Hospital (GB)
- Radboud University Nijmegen (NL)
- National and Kapodistrian University of Athens (GR)
- University of Crete (GR)
- University of Oklahoma Health Sciences Center (US)
- Stanford Medicine (US)
- Cedars-Sinai Medical Center (US)
- Heidelberg University (DE)
- Corresponding author
- Stellos, Konstantinos
- ORCID
- Liberale, Luca
- Sedej, Simon
- Ministrini, Stefano
- Georgiopoulos, Georgios
- Grunewald, Myriam
- Bäck, Magnus
- Boon, Reinier A.
- Ramos, Gustavo Campos
- Drosatos, Konstantinos
- Evans, Paul C.
- Ferguson, Jane F.
- Goettsch, Claudia
- Giacca, Mauro
- Haendeler, Judith
- Kallikourdis, Marinos
- Ketelhuth, Daniel F. J.
- Koenen, Rory R.
- Lacolley, Patrick
- Lutgens, Esther
- Maffia, Pasquale
- Miwa, Satomi
- Monaco, Claudia
- Montecucco, Fabrizio
- Norata, Giuseppe Danilo
- Osto, Elena
- Richardson, Gavin D.
- Riksen, Niels P.
- Soehnlein, Oliver
- Spyridopoulos, Ioakim
- Vilahur, Gemma
- Wentzel, Jolanda J.
- Andrés, Vicente
- Binder, Christoph J.
- Brandes, Ralf P.
- Crea, Filippo
- Furman, David
- Gorbunova, Vera
- Guzik, Tomasz J.
- Hill, Joseph A.
- Lüscher, Thomas F.
- Nencioni, Alessio
- Netea, Mihai G.
- Passos, João F.
- Stamatelopoulos, Kimon S.
- Tavernarakis, Nektarios
- Ungvari, Zoltan
- Wu, Joseph C.
- Kirkland, James L.
- Camici, Giovanni G.
- Dimmeler, Stefanie
- Kroemer, Guido
- Abdellatif, Mahmoud
- Stellos, Konstantinos
- Venue
- Nature Reviews Cardiology
- Published
- 2025-02-19
- Volume
- 22
- Issue
- 8
- Pages
- 577-605
- ISSN
- 1759-5002 (ISSN-L)
- 1759-5010
- PMC
- PMC13383118
- OpenAlex
- W4407760968
- Cited by
- 59
- References
- 495
- Citations by year
- 2026: 31 · 2025: 28
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature Reviews Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Radboud Repository (Radboud University) (submittedVersion)
- HAL (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute on Aging (R01AG027237, R01AG068048)
- National Heart, Lung, and Blood Institute (R01HL151924)
- National Cancer Institute (UH3CA268103, UG3CA268103)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cardiovascular aging, healthy aging, frailty, age-related cardiovascular disease, gerotherapeutics, hallmarks of aging, cardiovascular system, clinical trial design, healthspan
- MeSH terms
- Age Factors, Aging, Cardiovascular Diseases, Cardiovascular System, Humans
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