Abstract
Normal circulatory function is a key determinant of disease-free life expectancy (healthspan). Indeed, pathologies affecting the cardiovascular system, which are growing in prevalence, are the leading cause of global morbidity, disability and mortality, whereas the maintenance of cardiovascular health is necessary to promote both organismal healthspan and lifespan. Therefore, cardiovascular ageing might precede or even underlie body-wide, age-related health deterioration. In this Review, we posit that eight molecular hallmarks are common denominators in cardiovascular ageing, namely disabled macroautophagy, loss of proteostasis, genomic instability (in particular, clonal haematopoiesis of indeterminate potential), epigenetic alterations, mitochondrial dysfunction, cell senescence, dysregulated neurohormonal signalling and inflammation. We also propose a hierarchical order that distinguishes primary (upstream) from antagonistic and integrative (downstream) hallmarks of cardiovascular ageing. Finally, we discuss how targeting each of the eight hallmarks might be therapeutically exploited to attenuate residual cardiovascular risk in older individuals.
Key points
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Age is one of the strongest determinants of cardiovascular health.
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The cardiovascular system operates under constant mechanical and metabolic stress, which progressively increases the risk of dysfunction at the molecular, cellular and whole-organ levels with increasing age.
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Disabled macroautophagy, loss of proteostasis, genomic instability, epigenetic alterations, mitochondrial dysfunction, cell senescence, dysregulated neurohormonal signalling and inflammation emerge as common molecular hallmarks of cardiovascular ageing.
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The hallmarks of cardiovascular ageing are strongly intertwined, and accentuation or attenuation of individual hallmarks affects most, if not all, the others.
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Targeting the hallmarks of cardiovascular ageing holds promise for the treatment of major cardiovascular disorders and to reduce residual cardiovascular risk beyond the management of conventional risk factors.
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Acknowledgements
The authors thank the reviewers for their valuable constructive feedback and apologize to the authors of several high-quality articles on cardiovascular ageing that could not be discussed and cited owing to space limitations. The authors are also grateful to Leen Assil Companioni (CBmed, Graz, Austria) for designing the figures before submission, Sylvère Durand (Institute Gustave Roussy, Villejuif, France) for spermidine measurements as well as Nathaly Anto Michel (Medical University of Graz, Graz, Austria) and Andrew L. Koenig (Washington University School of Medicine, St. Louis, MO, USA) for extracting and providing the single-cell data reported in Fig. 1. M.A. acknowledges support from the European Commission (H2020-MSCA-IF), the Austrian Society of Cardiology (Präsidentenstipendium-ÖKG), the Medical University of Graz (Start Fund), BioTechMed-Graz (Young Researcher Group) and the Austrian Science Fund (FWF; P34926). P.P.R. and S.S. acknowledge support from the Medical University of Graz (Flagship project VASC-HEALTH) and BioTechMed-Graz (Flagship project INTERACD+). G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; European Research Council Advanced Investigator Grand ‘ICD-Cancer’, Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council (ICD-Cancer), European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.
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M.A. and G.K. conceptualized the article. The authors contributed substantially to all other aspects of the article.
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M.A. and S.S. are involved in patent applications related to the cardiometabolic effects of caloric restriction mimetics. G.K. holds research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, Osasuna Therapeutics, PharmaMar, Samsara Therapeutics, Sanofi, Tollys and Vascage. G.K. is a consultant for Reithera and is on the Board of Directors of the Bristol Myers Squibb Foundation, France. G.K. is also a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. G.K.’s wife, Laurence Zitvogel, has held research contracts with 9 Meters Biopharma, Daiichi Sankyo and Pilege, was on the Board of Directors of Transgene, is a co-founder of everImmune, and holds patents covering the treatment of cancer and therapeutic manipulation of the microbiota. G.K.’s brother, Romano Kroemer, was an employee of Sanofi and consulted for Boehringer-Ingelheim. P.P.R. declares no competing interests.
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Glossary
- Autophagy
-
An evolutionarily conserved homeostatic process through which old, dysfunctional or potentially hazardous cytoplasmic components undergo lysosomal degradation; three types of autophagy exist in mammalian cells: microautophagy, macroautophagy and chaperone-mediated autophagy.
- Clonal haematopoiesis of indeterminate potential
-
(CHIP). A process by which stem cells in the blood or bone marrow randomly accrues somatic mutations during ageing, leading to exaggerated representation of a single clone.
- Inflammageing
-
The phenomenon of low-grade, subclinical sterile inflammation commonly observed with ageing, leading to increased circulating and tissue cytokine levels.
- Inflammasome
-
A supramolecular complex, the formation of which is triggered by a range of exogenous and endogenous pro-inflammatory factors, culminating in the activation of caspase 1, which proteolytically activates the pro-inflammatory cytokines IL-1β and IL-18.
- Non-coding RNAs
-
(ncRNAs). RNA molecules that are not translated into proteins but regulate the expression levels of target genes; there are several subfamilies of ncRNAs, including microRNAs (<200 nucleotides), long non-coding RNAs (>200 nucleotides) and covalently closed circular RNAs.
- Proteostasis
-
A network of cellular processes that maintain the health and integrity of the proteome, including protein biogenesis, folding, trafficking and degradation.
- Senescence
-
Permanent arrest of the cell cycle with irreversible loss of replicative capacity, leading to the loss of specific cellular functions, and the acquisition of a secretory and metabolically active phenotype with pro-inflammatory features.
- Senolytic therapy
-
Elimination of senescent cells by molecules that specifically induce cell death in senescent cells to improve organismal health.
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Abdellatif, M., Rainer, P.P., Sedej, S. et al. Hallmarks of cardiovascular ageing. Nat Rev Cardiol 20, 754–777 (2023). https://doi.org/10.1038/s41569-023-00881-3
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DOI: https://doi.org/10.1038/s41569-023-00881-3
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