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New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary
Open accessAbstract
Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.
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![Figure 2 The force of natural selection in ageing. The force that selects different traits declines as a function of age after reproductive age. Natural selection benefits survival to maturity and reproduction. Therefore, traits that present harmful effects late in life (selection shadow) will likely have already been passed to the next generation. The figure was generated based on the reference [34].](/paper-figures/b467c0630faa42d0a54925adc9c62d3b/new-hallmarks-of-ageing-a-2022-copenhagen-ageing-meeting-summary-figure-2.jpg)
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“Maintenance of organizational spatial compartmentalization is a hallmark of organismal health, while aging is associated with a decline in this capacity.56”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [56]
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“The accumulation of senescent cells contributes to tissue and organismal aging and is a well-known aging hallmark.56”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [56]
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“…“ger-oscience theory,” assuming that aging process is the main culprit of the development of the most common age-related diseases, inflammaging can be defined as a “hallmark of aging” and, at the same time, as the most clinically relevant risk factors for the most common age-related diseases [33].”
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“5 altered proteostasis, deregulated nutrient-sensing, DNA damage, and mitochondrial dysfunction (López-Otín et al., 2023; Schmauck-Medina et al., 2022).”
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Complexity of Sex Differences and Their Impact on Alzheimer’s Disease
Kadlecová, M., Freude, K., & Haukedal, H. (2023) · Biomedicines · doi:10.3390/biomedicines11051261 · Cited by 27
Cellular senescence and frailty: a comprehensive insight into the causal links
Marcozzi, S., Bigossi, G., Giuliani, M. E., Giacconi, R., Piacenza, F., Cardelli, M., Brunetti, D., Segala, A., Valerio, A., Nisoli, E., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00960-w · Cited by 24
“Although cellular senescence is not a primary hallmark of aging [61] [15], senescent cells can represent a source of damage that is able to rapidly propagate resembling a contagious process [62].”
BackgroundBody-wide multi-omic counteraction of aging with GLP-1R agonism
Huang, J., Kwok, A. J., Li, J. C. Y., Chiu, C. L. H., Ip, B. Y. M., Tung, L. Y., Chan, R. C. H., Chan, D. T.-M., Wang, Z., Zheng, X., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.10.014 · Cited by 31
Self-citationDifferent Aspects of Aging in Migraine
Fila, M., Pawłowska, E., Szczepańska, J., & Błasiak, J. (2023) · Aging and Disease · doi:10.14336/ad.2023.0313 · Cited by 24
“Stem cells play an important role in organismal aging and stem cell exhaustion is a well-established molecular marker of aging [10].”
BackgroundInfluentialMitochondrial transplantation as a possible therapeutic option for sarcopenia
Türkel, İ., Özerkliğ, B., Yılmaz, M., Ülger, Ö., Kubat, G. B., & Tuncer, M. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02326-3 · Cited by 25
Exploring the Prospective Role of Propolis in Modifying Aging Hallmarks
Scorza, C. A., Gonçalves, V., Finsterer, J., Scorza, F. A., & Fonseca, F. L. A. (2024) · Cells · doi:10.3390/cells13050390 · Cited by 29
Cerantonio, A., Citrigno, L., Greco, B. M., Benedittis, S. D., Passarino, G., Maletta, R., Qualtieri, A., Montesanto, A., Spadafora, P., & Cavalcanti, F. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25116062 · Cited by 25
Picca, A., Triolo, M., Wohlgemuth, S. E., Martenson, M. S., Mankowski, R. T., Anton, S. D., Marzetti, E., Leeuwenburgh, C., & Hood, D. A. (2023) · Cells · doi:10.3390/cells12010183 · Cited by 23
“Notably, mitochondrial dysfunction and mitophagy alterations are acknowledged as hallmarks of aging [36].”
BackgroundThe Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging
Romero-García, N., Huete-Acevedo, J., Mas‐Bargues, C., Sanz‐Ros, J., Dromant, M., & Borrás, C. (2023) · Biomolecules · doi:10.3390/biom13010165 · Cited by 25
New insight into the causes, consequences, and correction of hematopoietic stem cell aging
Mansell, E., Lin, D. S. Y., Loughran, S. J., Milsom, M. D., & Trowbridge, J. J. (2023) · Experimental Hematology · doi:10.1016/j.exphem.2023.07.002 · Cited by 21
Self-citationSenescent endothelial cells promote pathogenic neutrophil trafficking in inflamed tissues
Rolas, L., Stein, M., Barkaway, A., Reglero-Real, N., Sciacca, E., Yaseen, M., Wang, H., Vázquez-Martínez, L., Golding, M., Blacksell, I. A., et al. (2024) · EMBO Reports · doi:10.1038/s44319-024-00182-x · Cited by 22
“Of relevance, we have previously shown that compromised EC autophagy, a hallmark of aging (Schmauck-Medina et al, 2022), induces excessive neutrophil in fi ltration in multiple models of acute in fl ammation (Reglero-Real et al, 2021).”
BackgroundVučić, V., Ristić-Medić, D., Arsić, A., Petrović, S., Paunović, M., Vasiljević, N., & Ilich, J. Z. (2023) · Nutrients · doi:10.3390/nu15071619 · Cited by 20
The role of cannabidiol in aging
Ni, B., Liu, Y., Dai, M., Zhao, J., Yu, L., Yang, X. C., Han, B., & Jiang, M. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115074 · Cited by 21
The link between obesity and aging - insights into cardiac energy metabolism
Owesny, P., & Grune, T. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111870 · Cited by 24
“All these hallmarks represent essential factors in the aging process, and the interplay between them can ultimately determine the health outcomes of older individuals (L ´ opez-Otín et al., 2013; Calabrese et al., 2015; Schmauck-Medina et al., 2022).”
BackgroundComparative lifespan and healthspan of nonhuman primate species common to biomedical research
Huber, H. F., Ainsworth, H. C., Quillen, E. E., Salmon, A., Ross, C. N., Azhar, A. D., Bales, K. L., Basso, M. A., Coleman, K., Colman, R. J., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01421-8 · Cited by 24
“Five new hallmarks have been recently proposed: autophagy, micro-biome disturbance, altered mechanical properties, splicing dysregulation, and inflammation [48].”
Self-citationFunctional Aging: Integrating Functionality to a Multidimensional Assessment of Healthy Aging
Frangos, E., Graf, C. E., & Samaras, N. (2023) · Current Gerontology and Geriatrics Research · doi:10.1155/2023/9409918 · Cited by 27
“Indeed, the hallmarks of aging, which include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, compromised autophagy, microbiome disturbance, al…”
BackgroundAortic Stiffness: A Major Risk Factor for Multimorbidity in the Elderly
Triposkiadis, F. K., Xanthopoulos, A. V., Lampropoulos, K. M., Briasoulis, Α., Sarafidis, P. A., Skoularigis, J. S., & Boudoulas, H. K. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12062321 · Cited by 25
Kumar, P., Osahon, O. W., & Sekhar, R. V. (2023) · Antioxidants · doi:10.3390/antiox12051042 · Cited by 22
A revisiting of “the hallmarks of aging” in domestic dogs: current status of the literature
Jiménez, A. G. (2023) · GeroScience · doi:10.1007/s11357-023-00911-5 · Cited by 24
“Each of the biomarkers of the hallmarks of aging described in López-Otín et al. [93] and Schmauck-Medina et al. [124] was searched, in turn, with “and dogs” and “and canines” using googlescholar.com.”
InfluentialRepurposing digoxin for geroprotection in patients with frailty and multimorbidity
Lee, H., Wilson, D. V., Bunting, K. V., Kotecha, D., & Jackson, T. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101860 · Cited by 19
Bensalem, J., Teong, X. T., Hattersley, K. J., Hein, L. K., Fourrier, C., Liu, K., Hutchison, A. T., Heilbronn, L. K., & Sargeant, T. J. (2023) · GeroScience · doi:10.1007/s11357-023-00884-5 · Cited by 21
“In this way, autophagy limits cell damage and slows biological aging [1], and autophagic dysfunction itself has recently been discussed as a hallmark of aging [2].”
BackgroundCardiac iron metabolism during aging – Role of inflammation and proteolysis
Walter, S., Mertens, C., Muckenthaler, M. U., & Ott, C. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111869 · Cited by 19
The Use of Gut Microbial Modulation Strategies as Interventional Strategies for Ageing
Siddiqui, R., Mungroo, M. R., Alharbi, A. M., Alfahemi, H. H., & Khan, N. A. (2022) · Microorganisms · doi:10.3390/microorganisms10091869 · Cited by 19
“In this regard, the disturbance of the microbiome has been suggested as a new hallmark of ageing in the recent meeting held in Copenhagen on March 2022, in addition to the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013 [13].”
BackgroundTargeting multiple hallmarks of mammalian aging with combinations of interventions
Panchin, A. Y., Ogmen, A., Blagodatski, A. S., Egorova, A., Batin, M., & Glinin, T. S. (2024) · Aging · doi:10.18632/aging.206078 · Cited by 21
The Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease
Ayoub, M., Jaoude, C. A., Ayoub, M., Hamadé, A., & Rima, M. (2025) · Immunology · doi:10.1111/imm.70036 · Cited by 24
Xiong, W., Li, R., Li, B., Wang, X., Wang, H. H., Sun, Y., Wang, X., Li, Y., & Ren, F. (2023) · Nutrients · doi:10.3390/nu15092228 · Cited by 20
Autophagy and metabolic aging: Current understanding and future applications
Raza, S. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2024.119753 · Cited by 19
Suppression of thrombospondin-1–mediated inflammaging prolongs hematopoietic health span
Ramalingam, P., Gutkin, M. C., Poulos, M. G., Winiarski, A., Smith, A., Carter, C., Doughty, C., Tillery, T., Redmond, D., Freire, A. G., et al. (2025) · Science Immunology · doi:10.1126/sciimmunol.ads1556 · Cited by 17
Preconditioned Mesenchymal Stromal Cell-Derived Extracellular Vesicles (EVs) Counteract Inflammaging
Görgün, C., Africano, C., Ciferri, M. C., Bertola, N., Reverberi, D., Quarto, R., Ravera, S., & Tasso, R. (2022) · Cells · doi:10.3390/cells11223695 · Cited by 18
Relationships between circulating metabolites and facial skin aging: a Mendelian randomization study
Liu, Z., Mi, J., & Wu, H. (2023) · Human Genomics · doi:10.1186/s40246-023-00470-y · Cited by 18
“The process of skin aging is affected by circulating metabolites which are involved in a variety of cellular processes including cellular organization, post-translational modification as well as epigenetic changes [4, 5].”
BackgroundNurturing longevity through natural compounds: Where do we stand, and where do we go?
Todorova, M. N., Savova, M. S., Mihaylova, L. V., & Georgiev, M. I. (2024) · Food Frontiers · doi:10.1002/fft2.350 · Cited by 17
Aryl hydrocarbon receptor: Linking environment to aging process in elderly patients with asthma
Yang, T., Wan, R., Tu, W., Avvaru, S. N., & Gao, P. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002960 · Cited by 18
“[13,14] The updated hallmarks of aging may provide a better guide and advanced research on the biology of aging, as illustrated in Figure 1.”
BackgroundParticulate matter 2.5 accelerates aging: Exploring cellular senescence and age-related diseases
Wang, S., Shi, Y., Lin, S., & He, H.-F. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.116920 · Cited by 20
Ai, R., Mao, L., Jin, X., Campos‐Marques, C., Zhang, S., Pan, J., Lagartos-Donate, M. J., Cao, S., Barros‐Santos, B., Nóbrega‐Martins, R., et al. (2025) · Science Advances · doi:10.1126/sciadv.ady9811 · Cited by 19
“We found that ASEs in genes involved in RNA splicing are disproportionately dysregulated in tauopathies and aging worms, which is in line with the publications showing that ASE is a mark of aging and neurodegenerative disease ( 117–120 ).”
Self-citation
Metadata
- Authors
- Schmauck-Medina, T., Molière, A., Lautrup, S., Zhang, J., Chlopicki, S., Madsen, H. B., Cao, S., Soendenbroe, C., Mansell, E., Vestergaard, M. B., Li, Z., Shiloh, Y., Opresko, P. L., Egly, J.-M., Kirkwood, T., Verdin, E., Bohr, V. A., Cox, L. S., Stevnsner, T., Rasmussen, L. J., & Fang, E. F.
- Affiliations
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
- University of Oslo (NO)
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow 30-348, Poland
- University of Copenhagen (DK)
- Bispebjerg Hospital (DK)
- Lund University (SE)
- Copenhagen University Hospital (DK)
- Tel Aviv University (IL)
- University of Pittsburgh (US)
- Centre National de la Recherche Scientifique (FR)
- Buck Institute for Research on Aging (US)
- University of Oxford (GB)
- Aarhus University (DK)
- Corresponding author
- Stevnsner, Tinna
- Rasmussen, Lene Juel
- Fang, Evandro F.
- ORCID
- Molière, Adrian
- Lautrup, Sofie
- Zhang, Jianying
- Madsen, Helena Borland
- Cao, Shuqin
- Soendenbroe, Casper
- Mansell, Els
- Vestergaard, Mark Bitsch
- Li, Zhiquan
- Shiloh, Yosef
- Opresko, Patricia L.
- Egly, Jean-Marc
- Kirkwood, Thomas
- Verdin, Eric
- Bohr, Vilhelm A.
- Cox, Lynne S.
- Stevnsner, Tinna
- Rasmussen, Lene Juel
- Fang, Evandro F.
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2022-08-29
- Volume
- 14
- Issue
- 16
- Pages
- 6829-6839
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC9467401
- OpenAlex
- W4293462467
- Cited by
- 319
- References
- 58
- Citations by year
- 2026: 42 · 2025: 67 · 2024: 100 · 2023: 102 · 2022: 8
- FWCI
- 23.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Lundbeckfonden (R347-2020-2176)
- Novo Nordisk
- Biotechnology and Biological Sciences Research Council (BB/W01825X/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- hallmarks of aging, aging, autophagy, microbiome, mechanical properties, splicing dysregulation, inflammation, age-related diseases, cellular senescence, stem cell exhaustion, intercellular communication, proteostasis, nutrient sensing, telomere shortening, epigenetic modifications, mitochondrial dysfunction, genomic instability
- MeSH terms
- Aged, Aging, Humans, Telomere, Cellular Senescence, Genomic Instability, Epigenesis, Genetic
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