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A complex systems approach to aging biology
Open accessAbstract
Having made substantial progress understanding molecules, cells, genes and pathways, aging biology research is now moving toward integration of these parts, attempting to understand how their joint dynamics may contribute to aging. Such a shift of perspective requires the adoption of a formal complex systems framework, a transition being facilitated by large-scale data collection and new analytical tools. Here, we provide a theoretical framework to orient researchers around key concepts for this transition, notably emergence, interaction networks and resilience. Drawing on evolutionary theory, network theory and principles of homeostasis, we propose that organismal function is accomplished by the integration of regulatory mechanisms at multiple hierarchical scales, and that the disruption of this ensemble causes the phenotypic and functional manifestations of aging. We present key examples at scales ranging from sub-organismal biology to clinical geriatrics, outlining how this approach can potentially enrich our understanding of aging. The authors discuss how adopting a complex systems perspective is a crucial step in advancing our understanding of the aging process and requires fundamental alteration of the questions being asked and the methods used to answer them.
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“During ageing, adaptive responses are weakened due to deficits in the CAS network.83”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [83]
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“When a stimulus is too intense and exceeds the regulatory capacity of the adaptive response or when the compromised adaptive response is insufficient to recover from stimulus-induced perturbations, homoeostasis is disrupted, leading to the onset of disease.83–85”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [83]
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Self-citationWhat do we mean by “aging”? Questions and perspectives revealed by studies in Drosophila
Wodrich, A. P. K., Scott, A. W., & Giniger, E. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111839 · Cited by 10
Alfatah, M., Lim, J. J. J., Zhang, Y., Naaz, A., Cheng, T. Y. N., Yogasundaram, S., Faidzinn, N. A., Lin, J. J., Eisenhaber, B., & Eisenhaber, F. (2023) · eLife · doi:10.7554/elife.92178 · Cited by 8
“Identifying lifespan regulators, genetic networks, and connecting genetic nodes relevant to cellular aging provides functional insight into the complexity of aging biology Kennedy et al., 2014 ; Cohen et al., 2022 ; López-Otín et al., 2013 for the subsequent design of anti-aging interventions.”
BackgroundRodríguez-Rodríguez, S., Oviedo, G. R., López-de–Celis, C., Bosch, J., Jovell, E., Pérez‐Bellmunt, A., Cuadra-Llopart, L., & Rodríguez‐Sanz, J. (2025) · Life · doi:10.3390/life15030412 · Cited by 8
“…time, including hierarchical scales ranging from molecular to clinical manifestations, like decreased muscle strength and physical performance [2,3]. aging to encompass sub-organismal biological processes leading to declines in function with the passing time, including hierarchical scales…”
Uleman, J. F., Melis, R. J. F., Hoekstra, A. G., Rikkert, M. G. M. O., & Quax, R. (2023) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2023.104462 · Cited by 8
“First, it requires comprehensive background knowledge regarding the multicausal structure of AD ’ s etiology [3], including feedback mechanisms across multiple spatial and temporal scales [22,26 – 28].”
Complex system modeling reveals oxalate homeostasis is driven by diverse oxalate-degrading bacteria
Mukherjee, S., Batagello, C., Adler, A., Agudelo, J., Zampini, A. M., Suryavanshi, M. V., Nguyen, A. H., Orr, T. J., Dearing, M. D., Monga, M., et al. (2025) · eLife · doi:10.7554/elife.104121 · Cited by 10
Mosley, M. C., Kinser, H. E., Martin, O. M. F., Stroustrup, N., Schedl, T., Kornfeld, K., & Pincus, Z. (2024) · Aging Cell · doi:10.1111/acel.14428 · Cited by 7
“Another (not mutually exclusive) theory is that organismal homeostasis is maintained by a web of interconnected systems, and individuals are canalized into one of a discrete number of failure states depending on which critical nodes are the first to fail (Cohen et al., 2022 ).”
Self-citationBiomarkers of aging through the life course: a recent literature update
Gaylord, A., Cohen, A. A., & Kupsco, A. J. (2023) · Current Opinion in Epidemiology and Public Health · doi:10.1097/pxh.0000000000000018 · Cited by 7
Self-citationWhat matters in aging is signaling for responsiveness
Park, S. C., Lee, Y., Cho, K. A., Kim, S. Y., Lee, Y., Lee, S.-R., & Lim, I. K. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108560 · Cited by 7
The network structural entropy for single-cell RNA sequencing data during skin aging
Liu, Z., Lin, H., Li, X., Xue, H., Lu, Y., Xu, F., & Shuai, J. (2024) · Briefings in Bioinformatics · doi:10.1093/bib/bbae698 · Cited by 6
Langeard, A., Milot, E., Quarck, G., & Stoffregen, T. A. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae063 · Cited by 7
Understanding age and society using natural populations
Firth, J. A., Albery, G. F., Bouwhuis, S., Brent, L. J. N., & Salguero‐Gómez, R. (2024) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0469 · Cited by 6
“The different ‘hallmarks’ of biological ageing, which include molecular, physiological, and physical domains, have received a lot of attention in human health research [6,52] and will be helpful to consider by those hoping to generate a new ecological and evolutionary understanding of social ageing.”
BackgroundOral health: integral component of overall health and important determinant of ageing
Yu, Y.-H. (2024) · The Lancet Healthy Longevity · doi:10.1016/j.lanhl.2024.100641 · Cited by 6
Longitudinal Trajectories of Aperiodic EEG Activity in Early to Middle Childhood
Sacks, D. D., Valdes, V., Wilkinson, C. L., Levin, A. R., Nelson, C. A., & Enlow, M. B. (2025) · Child Development · doi:10.1111/cdev.14261 · Cited by 6
Zhang, L., Yu, J., Jia, X., Su, Z., Hu, Y., Zhang, J., Yang, W. Y. L., Chen, X., Hoogendijk, E. O., Huang, H., et al. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13862 · Cited by 6
Aging as Informational Closure
Tkemaladze, J. (2026) · Longevity Horizon · doi:10.65649/n8grhs05 · Cited by 16
Xiong, M., Hu, H., & Huang, Y. (2023) · Disaster Prevention and Resilience · doi:10.20517/dpr.2023.27 · Cited by 6
Bencivenga, L., Strumia, M., Rolland, Y., Guyonnet, S., Parini, A., Cestac, P., Andrieu, S., Barreto, P. D. S., & Rouch, L. (2024) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2024.03.001 · Cited by 7
Fustolo-Gunnink, S. F., de Boode, W. P., Dekkers, O. M., Greisen, G. O., Lopriore, E., & Federica Russo, B. (2024) · Pediatric Research · doi:10.1038/s41390-024-03677-4 · Cited by 7
“7,8 Social, environmental, economic and many other systems are considered complex as well and there have been strong pleas for the use of a complexity approach in public health.”
Pridham, G., & Rutenberg, A. D. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae021 · Cited by 7
“Aging is putatively an interacting multivariate, multicausal process (12–15), as has borne out explicitly in computational studies (16–18).”
InfluentialSelf-citationAlfatah, M., Lim, J. J. J., Zhang, Y., Naaz, A., Cheng, T. Y. N., Yogasundaram, S., Faidzinn, N. A., Lin, J. J., Eisenhaber, B., & Eisenhaber, F. (2023) · eLife · doi:10.7554/elife.92178.1 · Cited by 5
Histological aging signatures enable tissue-specific disease prediction from bloodPreprint
Abila, E., Buljan, I., Zheng, Y., Veres, T., Weng, Z., Nackenhorst, M. C., Hulla, W., Tolkach, Y., Wöehrer, A., & Rendeiro, A. F. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.14.618081 · Cited by 8
“To address these challenges, it is imperative to move beyond a gene, cell, or focus to a holistic view of the aging organism 19 .”
Hao, M., Zhang, H., Jiang, S., Hu, Z., Jiang, X., Wu, J., Li, Y., Li, J., & Wang, X. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae268 · Cited by 5
Life expectancy in ants explains variation in helpfulness regardless of phylogenetic relatedness
Turza, F., Stec, D., Fontaneto, D., & Miler, K. (2024) · Behavioral Ecology · doi:10.1093/beheco/arae104 · Cited by 4
“Aging is the most widespread and inevitable phenomenon in biology (Cohen et al. 2022).”
Design principles of gene circuits for longevity
Godoy, P., & Hao, N. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.02.006 · Cited by 5
Self-citationJellyfish collagen peptides: anti-aging mechanism and potential application in skincare
Yu, J., Xing, S., Sun, R., Wang, L., Yang, X., & Zeng, M. (2025) · Journal of Functional Foods · doi:10.1016/j.jff.2025.107070 · Cited by 5
Koivunen, K., Löppönen, A., Palmberg, L., Rantalainen, T., Rantanen, T., & Karavirta, L. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112292 · Cited by 5
Exploring Patterns of Human Mortality and Aging: A Reliability Theory Viewpoint
Gavrilov, L. A., & Gavrilova, N. S. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924020123 · Cited by 5
“While we can pinpoint specific genes, pathways, and molecules, the integration of these elements into a comprehensive understanding of aging, including the emergence of functional phenotypes like mortality laws, remains a complex puzzle [1].”
Li, Q., Legault, V., Honfo, S. H., Milot, E., Jia, Q., Wang, F., Ferrucci, L., Bandinelli, S., & Cohen, A. A. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad146 · Cited by 5
Self-citationBioinspired Engineering beyond Homeostasis
Moreddu, R. (2025) · Advanced Intelligent Systems · doi:10.1002/aisy.202500435 · Cited by 6
Systems Biology of Aging, Metabolism, and Mitochondria
Aon, M. A., & Cortassa, S. C. (2026) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-021424-011852 · Cited by 4
The cellular choreography of brain aging: a neuroimmune network perspective
Müller, L., Benedetto, S. D., & Müller, V. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1848642 · Cited by 5
“Integrating these datasets through systems biology frameworks can reveal relationships between molecular pathways that may not be detectable using single-omics approaches (Cohen et al., 2022; Adewale et al., 2021; Vitorino, 2024).”
Su, H., & Hao, N. (2025) · Quantitative Biology · doi:10.1002/qub2.70007 · Cited by 4
“In recent years, computational systems biology has demonstrated its potential to contribute to a transformation in aging research, enabling a more systematic and quantitative view of aging [12].”
Self-citationScott, A. W., Wodrich, A. P. K., Chaouhan, H. S., Shukla, A. K., Johnson, K. R., McQueen, P. G., & Giniger, E. (2025) · iScience · doi:10.1016/j.isci.2025.113115 · Cited by 4
“1,2,19,60,61 The concepts are presumably linked but the nature of that linkage is not clear.”
InfluentialBioelectric characterization of senescing human keratinocytes
Sediqi, H., & Levin, M. G. (2025) · iScience · doi:10.1016/j.isci.2025.113275 · Cited by 4
Molecular and Cellular Mechanisms of Neuropathic Pain in Aging
Huang, H., Wu, J., Chang, Y., Wang, H., Tian, Y., Chen, Z., Feng, J., & Wang, H. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00010 · Cited by 5
The Power of a Complex Systems Perspective to Elucidate Aging
Cohen, A. A., & Rikkert, M. G. M. O. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae210 · Cited by 5
Self-citationAgelessness is possible under the disposable soma theory but system complexity makes it unlikely
Rodriguez, C. W., & Reddien, P. W. (2024) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2024.111958 · Cited by 4
Metadata
- Authors
- Cohen, A. A., Ferrucci, L., Fülöp, T., Gravel, D., Hao, N., Kriete, A., Levine, M. E., Lipsitz, L. A., Olde Rikkert, M. G. M., Rutenberg, A., Stroustrup, N., & Varadhan, R.
- Affiliations
- Université de Sherbrooke (CA)
- National Institute on Aging (US)
- University of California San Diego (US)
- Drexel University (US)
- Yale University (US)
- Beth Israel Deaconess Medical Center (US)
- Dalhousie University (CA)
- Universitat Pompeu Fabra (ES)
- Johns Hopkins University (US)
- Corresponding author
- Cohen, Alan A.
- ORCID
- Venue
- Nature Aging
- Published
- 2022-07-20
- Volume
- 2
- Issue
- 7
- Pages
- 580-591
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC12007111
- OpenAlex
- W4286008101
- Cited by
- 221
- References
- 140
- Citations by year
- 2026: 53 · 2025: 61 · 2024: 60 · 2023: 44 · 2022: 3
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Aging (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Drexel University
- ZonMw (09120012010063)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (645.003.002, COMPL.21COV.001)
- National Institutes of Health
- Canadian Institutes of Health Research (153011)
- National Institute on Aging (R01AG056440, R01AG068112)
- National Institute of General Medical Sciences (R01GM111458)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Social Sciences › Arts and Humanities › History and Philosophy of Science › Philosophy of Biology and Scientific Explanation
- Physical Sciences › Physics and Astronomy › Statistical and Nonlinear Physics › Complex Systems and Dynamics
- Keywords
- biological aging, complex systems, emergence, interaction networks, resilience, homeostasis, hierarchical regulation, network theory, evolutionary theory, multiscale integration, geriatrics
- MeSH terms
- Biology, Geriatrics, Homeostasis, Systems Analysis
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