A complex systems approach to aging biology

Cohen, Alan A.; Ferrucci, Luigi; Fülöp, Tamàs; Gravel, Dominique; Hao, Nan; Kriete, Andres; Levine, Morgan E.; Lipsitz, Lewis A.; Olde Rikkert, Marcel G. M.; Rutenberg, Andrew; Stroustrup, Nicholas; Varadhan, Ravi

doi:10.1038/s43587-022-00252-6

Cited by 221Genetics, Aging, and Longevity in Model OrganismsPhilosophy and History of ScienceComplex Systems and Dynamics

A complex systems approach to aging biology

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Cohen, Alan A., Ferrucci, Luigi, Fülöp, Tamàs, Gravel, Dominique, Hao, Nan, Kriete, Andres, Levine, Morgan E., Lipsitz, Lewis A. +4 more·2022·Nature Aging

DOI 10.1038/s43587-022-00252-6PMC PMC12007111

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Abstract

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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Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J MicePreprint
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“Therefore, comprehending the integration of regulatory mechanisms at multiple hierarchical scales is necessary to understand the dynamics of cellular senescence and organ-ismal ageing 273 .”
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“Aging could then be viewed as deterioration of a physiological network active within and between cells rather than being due to one primary damage initiating a linear chain of molecular events (8).”
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Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle
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“…complex nature of aging biology and highlights the challenge of assessing which factors mutually affect each other when causality becomes circular (Cohen et al., 2022; e.g., aging leads to a decline in physical activity/fitness levels, and a decline in physical activity/fitness levels leads to…”
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The brain–body energy conservation model of aging
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“Aging organisms are therefore best defined as complex dynamical systems 23 in which ‘control’ over behavior, physiology, anatomy and metabolism is shared across micro-level (genes, proteins and cells) and macro-level (endocrine, central nervous system and subjective experiences) processes 24,25 .”
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The genetic architecture of biological age in nine human organ systems
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“This research can include a better understanding of the various aspects that contribute to the disease, such as adopting a complex systems approach (Cohen et al., 2022).”
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Nonuniversality of inflammaging across human populations
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“The MiSBIE data platform represents a unique opportunity to formulate and test several novel hypotheses linking subjective human experience with molecular, biological, physiological, cognitive, behavioral, and other processes re ﬂ ecting the (inter)action of multiple organ systems over time (see…”
The Cutting Edge of Epigenetic Clocks: In Search of Mechanisms Linking Aging and Mental Health
Harvanek, Z. M., Boks, M. P., Vinkers, C. H., & Higgins‐Chen, A. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.02.001 · Cited by 31 · see citing works
Adopting a complex systems approach to functional ageing: bridging the gap between gerontological theory and empirical research
Kok, A. A. L., Huisman, M. A., Giltay, E. J., & Lunansky, G. (2025) · The Lancet Healthy Longevity · doi:10.1016/j.lanhl.2024.100673 · Cited by 32 · see citing works
[Ru(dpp) 3 ]Cl 2 ‐Embedded Oxygen Nano Polymeric Sensors: A Promising Tool for Monitoring Intracellular and Intratumoral Oxygen Gradients with High Quantum Yield and Long Lifetime
Kumar, A., Goudar, V. S., Nahak, B. K., Tsai, P., Lin, H., & Tseng, F. (2023) · Small · doi:10.1002/smll.202307955 · Cited by 27 · see citing works
Review: Environmental enrichment builds functional capacity and improves resilience as an aspect of positive welfare in production animals
Colditz, I. G., Campbell, D. L. M., Ingham, A. B., & Lee, C. (2024) · animal · doi:10.1016/j.animal.2024.101173 · Cited by 27 · see citing works
Periodic Distribution Entropy: Unveiling the complexity of physiological time series through multidimensional dynamics
Xiao, Y., Li, W., Yang, B. J., Li, X., Chen, J., & Fu, G. (2024) · Information Fusion · doi:10.1016/j.inffus.2024.102391 · Cited by 24 · see citing works
Neuropharmacology of synaptic plasticity: pathways to cognitive resilience in healthy aging
Goel, F., Singh, P., Nand, S., & Yadav, D. K. (2026) · 3 Biotech · doi:10.1007/s13205-025-04673-z · Cited by 23 · see citing works
Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony
Eder, M., Martin, O. M. F., Oswal, N., Sedlackova, L., Moutinho, C., Carmen-Fabregat, A. D., Bravo, S. M., Sebé-Pedrós, A., Heyn, H., & Stroustrup, N. (2024) · Cell · doi:10.1016/j.cell.2024.05.050 · Cited by 23 · see citing works
Self-citation
Pace of Aging analysis of healthspan and lifespan in older adults in the US and UK
Balachandran, A., Pei, H., Shi, Y., Beard, J., Caspi, A., Cohen, A. A., Domingue, B. W., Indik, C. E., Ferrucci, L., Furuya, A., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00866-6 · Cited by 22 · see citing works
Self-citation
Longitudinal machine learning uncouples healthy aging factors from chronic disease risks
Cohen, N. M., Lifshitz, A., Jaschek, R., Rinott, E., Balicer, R. D., Shlush, L. I., Barbash, G. I., & Tanay, A. (2023) · Nature Aging · doi:10.1038/s43587-023-00536-5 · Cited by 20 · see citing works
Decoding senescence of aging single cells at the nexus of biomaterials, microfluidics, and spatial omics
Venkataraman, A., Kordic, I., Li, J., Zhang, N. Y., Bharadwaj, N. S., Fang, Z., Das, S., & Coskun, A. F. (2024) · npj Aging · doi:10.1038/s41514-024-00178-w · Cited by 22 · see citing works
The Association Between Accelerated Biological Aging and the Physical, Psychological, and Cognitive Multimorbidity and Life Expectancy: Cohort Study
Talifu, Z., Ren, Z., Chen, C., Guo, S., Wu, Y., Li, Y., Su, B., & Zheng, X. (2025) · Aging Cell · doi:10.1111/acel.70142 · Cited by 19 · see citing works
Using Inflammatory Biological Age To Evaluate the Preventing Aging Effect of a Polyphenol-Probiotic-Enhanced Dietary Pattern in Adults Aged 50 Years and Older
Meng, N., Zhou, Y., Zhang, Q., Yu, X., Li, H., Liu, Y., Liu, M., & Li, Q. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c07241 · Cited by 19 · see citing works
Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers
Watanabe, K., Wilmanski, T. M., Baloni, P., Robinson, M., Garcia, G. G., Hoopmann, M. R., Midha, M. K., Baxter, D. H., Maes, M., Morrone, S. R., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05128-y · Cited by 20 · see citing works
Microphysiological systems for human aging research
Park, S., Laskow, T. C., Chen, J., Guha, P., Dawn, B., & Kim, D. (2024) · Aging Cell · doi:10.1111/acel.14070 · Cited by 20 · see citing works
“…genes, pathways, molecules, organelles, cells, and their interactions within the mechanisms that influence aging; however, there remains an outstanding challenge to integrate these mechanisms into a whole organism for understanding of aging from a complex systems perspective (Cohen et al., 2022).”
Background
Compression of morbidity by interventions that steepen the survival curve
Yang, Y., Mayo, A., Levy, T., Raz, N., Shenhar, B., Jarosz, D. F., & Alon, U. (2025) · Nature Communications · doi:10.1038/s41467-025-57807-5 · Cited by 16 · see citing works
“There is a need for theoretical frameworks to integrate these empirical ﬁ ndings 76 .”
Investigating Resilience Through Intrinsic Capacity Networks in Older Adults
Koivunen, K., Lindeman, K., Välimaa, M., & Rantanen, T. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae048 · Cited by 18 · see citing works
“The complex systems approach may be a meaningful way to link 2 central concepts of aging research, IC and resilience, to move away from a reductionist perspective where different factors are studied in silos (38).”
Background
Abnormalities in gut virome signatures linked with cognitive impairment in older adults
James, A. S., Adil, N. A., Goltz, D., Tangudu, D., Chaudhari, D. S., Shukla, R., Kumar, V., Kumar, A., Masternak, M. M., Holland, P. J., et al. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2431648 · Cited by 16 · see citing works
Efficient representations of binarized health deficit data: the frailty index and beyond
Pridham, G., Rockwood, K., & Rutenberg, A. (2023) · GeroScience · doi:10.1007/s11357-022-00723-z · Cited by 18 · see citing works
“Aging is widely considered to be multidimensional [1–3 , 9– 11].”
BackgroundSelf-citation
Organoids as complex (bio)systems
Fernandes, T. G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1268540 · Cited by 17 · see citing works
“By understanding the behavior of complex systems, researchers can gain insights into the underlying mechanisms that drive their dynamics, and develop strategies for controlling or optimizing their behavior (Cohen et al., 2022; San Miguel, 2023).”
Background
The Gompertz Law emerges naturally from the inter-dependencies between sub-components in complex organisms
Yde, P., Jensen, M. K., Mitarai, N., & Bhatt, S. (2024) · Scientific Reports · doi:10.1038/s41598-024-51669-5 · Cited by 18 · see citing works
“It has recently been argued that we may enrich our general understanding of aging by shifting focus towards interactions occurring on multiple hierarchical scales ranging from molecular to clinical 1,9,10 , as opposed to focusing solely on cellular and molecular scales.”
Complexity of life sciences in quantum and AI era
Pyrkov, A. N., Aliper, A., Bezrukov, D. S., Podolskiy, D. I., Ren, F., & Zhavoronkov, A. A. (2024) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1701 · Cited by 17 · see citing works
Simulating the multicausality of Alzheimer's disease with system dynamics
Uleman, J. F., Melis, R. J. F., Ntanasi, E., Scarmeas, N., Hoekstra, A. G., Quax, R., Rikkert, M. G. M. O., & Initiative, T. A. D. N. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.12923 · Cited by 16 · see citing works
“Healthy dietary patterns** Mediterranean diet score (1-55) 34.”
Biomarkers of aging remain elusive as researchers try to slow the biological clock
May, M. (2023) · Nature Medicine · doi:10.1038/s41591-023-02560-9 · Cited by 15 · see citing works
The need for systems thinking to advance Alzheimer's disease research
Uleman, J. F., Quax, R., Melis, R. J. F., Hoekstra, A. G., & Rikkert, M. G. M. O. (2024) · Psychiatry Research · doi:10.1016/j.psychres.2024.115741 · Cited by 15 · see citing works
Measurements of damage and repair of binary health attributes in aging mice and humans reveal that robustness and resilience decrease with age, operate over broad timescales, and are affected differently by interventions
Farrell, S., Kane, A. E., Bisset, E. S., Howlett, S. E., & Rutenberg, A. D. (2022) · eLife · doi:10.7554/elife.77632 · Cited by 14 · see citing works
Self-citation
Cross‐sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments
Moaddel, R., Ubaida‐Mohien, C., Tanaka, T., Tian, Q., Candia, J., Moore, A. Z., Lovett, J., Fantoni, G., Shehadeh, N., Turek, L., et al. (2023) · Aging Cell · doi:10.1111/acel.13902 · Cited by 13 · see citing works
“…system (RAS), REN and ACE generate Angiotensin II (Ang II) from Angiotensinogen, and ACE2 catalyzes angiotensin II conversion to angiotensin-(Cohen et al., 2022; Johnson et al., 2019; O'Sullivan et al., 2017; Tanaka et al., 2018; Teruya et al., 2020; Ubaida-Mohien, Lyashkov, et al., 2019;…”
BackgroundSelf-citation
Robotics-assisted modular assembly of bioactive soft materials for enhanced organ fabrication
Kang, D., Hong, S. J., Kim, S. J., Choi, H., Kim, K., & Jang, J. (2024) · Virtual and Physical Prototyping · doi:10.1080/17452759.2024.2390484 · Cited by 14 · see citing works
“Integrating multiple tissues is crucial for studying complex biological systems since only by examining how different tissues interact can we gain insights into the overall behaviour of biological systems [9, 179, 180].”
Biological Theories of Morphogenesis Based on Holistic Biophysical Thinking
Palmquist, K. H., Ko, C. S., Shyer, A. E., & Rodrigues, A. R. (2024) · Biological Theory · doi:10.1007/s13752-024-00477-1 · Cited by 14 · see citing works
“Holistic biophysical thinking, as exemplified by Thompson, can be brought to bear on the study of many processes in development as well as disease (Clark 1995; Cohen et al. 2022).”
Is Aging an Inevitable Characteristic of Organic Life or an Evolutionary Adaptation?
Lidsky, P. V., Yuan, J.-J., Rulison, J. M., & Andino-Pavlovsky, R. (2022) · Biochemistry (Moscow) · doi:10.1134/s0006297922120021 · Cited by 10 · see citing works
Nutrigenomics and redox regulation: Concepts relating to the Special Issue on nutrigenomics
Klotz, L., & Carlberg, C. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102920 · Cited by 14 · see citing works
Using Physiological System Networks to Elaborate Resilience Across Frailty States
Hao, M., Zhang, H., Li, Y., Hu, X., Hu, Z., Jiang, X., Wang, J., Sun, X., Liu, Z., Davis, D., et al. (2024) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glad243 · Cited by 12 · see citing works
Grand challenges for human factors and ergonomics
Karwowski, W., Salvendy, G., Endsley, M. R., Rouse, W. B., Salmon, P. M., Stanney, K. M., Thatcher, A., Andre, T., Yang, X. J., Ayaz, H., et al. (2025) · Theoretical Issues in Ergonomics Science · doi:10.1080/1463922x.2024.2431336 · Cited by 16 · see citing works
Retinal biomarkers for early Alzheimer’s detection: a systematic review of optical coherence tomography (OCT) findings
Lepoittevin, M., Greig, J., Erol, O., Benani, A., Bauvin, P., Azzolini, C., Donati, S., Dubois, B., Boscher, C., & Bodard, S. (2026) · BMJ Open Ophthalmology · doi:10.1136/bmjophth-2025-002328 · Cited by 11 · see citing works
Ageing as a two-phase process: theoretical framework
Zane, F., MacMurray, C., Guillermain, C., Cansell, C., Todd, N., & Rera, M. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1378351 · Cited by 11 · see citing works
Age-related physiological dysregulation progresses slowly in semi-free-ranging chimpanzees
Cole, M. F., Barnes, P., Monroe, I. G., Rukundo, J., Thompson, M. E., & Rosati, A. G. (2024) · Evolution Medicine and Public Health · doi:10.1093/emph/eoae010 · Cited by 12 · see citing works
“Physiological dysregulation is an emergent phenomenon that reflects the breakdown of physiological regulatory networks’ ability to maintain homeostasis and is implicated as both a consequence and driver of the aging process [14–16].”
BackgroundResultInfluential
Balancing the promise and risks of geroscience interventions
Cohen, A. A., Beard, J., Ferrucci, L., Fülöp, T., Gladyshev, V. N., Moqri, M., Rikkert, M. G. M. O., & Picard, M. A. (2025) · Nature Aging · doi:10.1038/s43587-024-00788-9 · Cited by 14 · see citing works
Self-citation
Cellular age explains variation in age-related cell-to-cell transcriptome variability
Yang, M., Harrison, B. R., & Promislow, D. E. L. (2023) · Genome Research · doi:10.1101/gr.278144.123 · Cited by 11 · see citing works
The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop
Mathisen, A. F., Legøy, T. A., Larsen, U., Unger, L., Abadpour, S., Paulo, J. A., Scholz, H., Ghila, L., & Chera, S. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111951 · Cited by 10 · see citing works
“Pathway and network analysis of the transcriptomic landscape proved to be an efficient tool for pinpointing novel gene candidates regulating the ageing process (Kaletsky, 2018; Wang, 2022; Yang, 2016; Cohen, 2022).”
Method
Intrinsic health as a foundation for a science of health
Cohen, A. A., Picard, M. A., Beard, J., Belsky, D. W., Herbstman, J. B., Kuryla, C. L., Liu, M., Makarem, N., Malinsky, D., Pei, S., et al. (2025) · Science Advances · doi:10.1126/sciadv.adu8437 · Cited by 10 · see citing works
“Accordingly, an appropriate theory of health can be constructed from the bottom up ( 4 ), understanding the nature of life as a complex system ( 5 – 7 ), how it has been shaped by natural selection ( 8 , 9 ), and how this manifests dynamically in biological signals and dynamics within the organism…”
Self-citation
Network modeling and topology of aging
Li, F., Yang, D., Wu, S., Xue, C., Sang, M., Liu, X., Che, J., Wu, J., Gragnoli, C., Griffin, C. H., et al. (2024) · Physics Reports · doi:10.1016/j.physrep.2024.10.006 · Cited by 9 · see citing works
Expanding evolutionary theories of ageing to better account for symbioses and interactions throughout the Web of Life
Bapteste, E. P., Huneman, P., Keller, L., Teulière, J., Lopez, P., Teeling, E. C., Lindner, A. B., Baudisch, A., Ludington, W. B., & Franceschi, C. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101982 · Cited by 10 · see citing works
Dissipative scaling of development and aging in multicellular organisms
Kriete, A. (2024) · Biosystems · doi:10.1016/j.biosystems.2024.105157 · Cited by 9 · see citing works
Self-citation
What 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 9 · see citing works
Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms
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 · see citing works
“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.”
Background
Stay Active, Stay Healthy: A Cross-Sectional View of the Impact of Physical Activity Levels on Health Parameters of Older Adults Institutionalized in Nursing Homes of Barcelona
Rodríguez-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 · see citing works
“…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…”
Exploring the potential impact of multi-factor precision interventions in Alzheimer’s disease with system dynamics
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 · see citing works
“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 bacteriaPreprint
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 8 · see citing works
Similarities and differences in the gene expression signatures of physiological age versus future lifespan
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 · see citing works
“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-citation
Biomarkers 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 · see citing works
Self-citation
What 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 · see citing works
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 7 · see citing works
The Complexity of Center of Pressure Positions During Quiet Stance and Its Relationship to Cognition, Aging, and Falls
Langeard, A., Milot, E., Quarck, G., & Stoffregen, T. A. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae063 · Cited by 7 · see citing works
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 · see citing works
“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.”
Background
Oral 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 · see citing works
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 · see citing works
Delineating Life‐Course Percentile Curves and Normative Values of Multi‐Systemic Ageing Metrics in the United Kingdom, the United States, and China
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 · see citing works
Aging as Informational Closure
Tkemaladze, J. (2026) · Longevity Horizon · doi:10.65649/n8grhs05 · Cited by 6 · see citing works
From slope seismic resilience to regional road network resilience: an integrated framework for evaluating the seismic resilience of mountainous road networks
Xiong, M., Hu, H., & Huang, Y. (2023) · Disaster Prevention and Resilience · doi:10.20517/dpr.2023.27 · Cited by 6 · see citing works
Visit-to-visit blood pressure variability is associated with intrinsic capacity decline: Results from the MAPT Study
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 · see citing works
If things were simple, word would have gotten around. Can complexity science help us improve pediatric research?
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 · see citing works
“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.”
Dynamical Network Stability Analysis of Multiple Biological Ages Provides a Framework for Understanding the Aging Process
Pridham, G., & Rutenberg, A. D. (2024) · The Journals of Gerontology Series A · doi:10.1093/gerona/glae021 · Cited by 6 · see citing works
“Aging is putatively an interacting multivariate, multicausal process (12–15), as has borne out explicitly in computational studies (16–18).”
InfluentialSelf-citation
Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanismsPreprint
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.92178.1 · Cited by 5 · see citing works
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 · see citing works
“To address these challenges, it is imperative to move beyond a gene, cell, or focus to a holistic view of the aging organism 19 .”
Metrics of Physiological Network Topology Are Novel Biomarkers to Capture Functional Disability and Health
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 · see citing works
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 · see citing works
“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 · see citing works
Self-citation
Jellyfish 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 · see citing works
Autonomic nervous system and postural control regulation during orthostatic test as putative markers of physical resilience among community-dwelling older adults
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 · see citing works
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 · see citing works
“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].”
Physiological Dysregulation Proceeds and Predicts Health Outcomes Similarly in Chinese and Western Populations
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 · see citing works
Self-citation
Bioinspired Engineering beyond Homeostasis
Moreddu, R. (2025) · Advanced Intelligent Systems · doi:10.1002/aisy.202500435 · Cited by 4 · see citing works
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 · see citing works
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 · see citing works
“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).”
Computational systems biology approaches to cellular aging—Integrating network maps and dynamical models
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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: Cohen, Alan A.
Ferrucci, Luigi
Fülöp, Tamàs
Gravel, Dominique
Hao, Nan
Kriete, Andres
Levine, Morgan E.
Lipsitz, Lewis A.
Olde Rikkert, Marcel G. M.
Rutenberg, Andrew
Stroustrup, Nicholas
Varadhan, Ravi
Venue: Nature Aging
Publisher: Springer Science and Business Media LLC
Published: 2022-07-20
Volume: 2
Issue: 7
Pages: 580-591
ISSN: 2662-8465 (ISSN-L)
DOI: 10.1038/s43587-022-00252-6
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: cc-by
www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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 and History of Science
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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