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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L.L., S.T.-C., S.S., S. Ministrini, G.G., K.S.S., M.A. and K.S. researched data for article. L.L., S.T.-C., S.S., S. Ministrini, G.G. K.S.S., G.G.C., M.A. and K.S wrote the manuscript. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.
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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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Supplementary information
Glossary
- Amyloid
-
Abnormal protein aggregates that accumulate in various tissues and organs, potentially causing dysfunction.
- Disseminated intravascular coagulation
-
Systemic disorder characterized by the aberrant activation of the coagulation cascade, leading to widespread formation of fibrin clots in the microcirculation. This widespread clotting results in the consumption of clotting factors and platelets, leading to a paradoxical increased risk of bleeding.
- Endothelial cell-dependent vasodilatation
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Process by which blood vessels dilate in response to nitric oxide, which is released by the endothelium in response to specific stimuli such as increased blood flow or acetylcholine.
- Lacunar stroke
-
Ischaemic stroke caused by the occlusion of a small penetrating artery deep within the brain. These small arteries supply deep structures such as the basal ganglia, thalamus and internal capsule. The term lacunar refers to the small, cavity-like lesions that result from the stroke.
- Lipoprotein (a)
-
Complex lipoprotein particle composed of LDL and the glycoprotein apolipoprotein (a), which is covalently attached to the apolipoprotein B-100 component of the LDL particle.
- Macular degeneration
-
Progressive eye disease that affects the macula (the central part of the retina responsible for sharp, detailed vision), leading to a gradual loss of central vision while peripheral vision remains intact.
- Mosaic loss of the Y chromosome
-
Clonal loss of the Y chromosome in a proportion of somatic cells, resulting in a mosaic pattern in which some cells retain the Y chromosome whereas others do not. This phenomenon is commonly observed in ageing populations and is associated with increased genomic instability.
- Myeloid skewing
-
Phenomenon in which haematopoietic stem cells preferentially differentiate into myeloid lineages (such as granulocytes, monocytes and platelets) over lymphoid lineages (such as B cells, T cells and natural killer cells).
- Myogenic tone
-
Intrinsic capacity of smooth muscle cells in blood vessels to maintain a baseline level of contraction and resistance in response to changes in intravascular pressure.
- Neutrophil extracellular traps
-
Web-like structures composed of chromatin and granular proteins that are released by activated neutrophils to trap and kill pathogens in a process called NETosis.
- Pulmonary fibrosis
-
Progressive lung disease characterized by the thickening and scarring (fibrosis) of lung tissue, which leads to a gradual loss of lung function. This scarring impairs the capacity of the lungs to transfer oxygen into the bloodstream, potentially resulting in respiratory failure.
- Pulse wave velocity
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The speed at which pressure waves move through the arteries, typically used to assess arterial stiffness. It is calculated by measuring the time it takes for the blood pressure pulse generated by the heartbeat to travel between two points along an artery, usually between the carotid and femoral arteries.
- Senomorphic
-
Describes interventions, compounds or mechanisms that do not induce senolysis of senescent cells, but instead suppress the harmful effects of their secretome, thereby limiting the spread of senescence through bystander effects.
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Cite this article
Liberale, L., Tual-Chalot, S., Sedej, S. et al. Roadmap for alleviating the manifestations of ageing in the cardiovascular system. Nat Rev Cardiol 22, 577–605 (2025). https://doi.org/10.1038/s41569-025-01130-5
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DOI: https://doi.org/10.1038/s41569-025-01130-5
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