{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:13:04Z","timestamp":1783660384087,"version":"3.55.0"},"reference-count":95,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aging is the dominant risk factor for most chronic diseases, yet the mechanisms driving this relationship remain poorly integrated across biological scales. Existing frameworks have catalogued key hallmarks of aging but do not explain how these processes converge to produce organism-level decline and multimorbidity. A systems-level framework is introduced in which aging is conceptualized as progressive destabilization of interacting regulatory networks. Mitochondrial quality control, nutrient-sensing pathways, and chronic inflammatory signaling form a putative high-centrality network core: mitochondria coordinate redox balance, bioenergetics, and transcriptional adaptation, while NAD+-dependent signaling and NLRP3 inflammasome activation propagate perturbations across regulatory layers. This architecture provides a mechanistic basis for the convergence of neurodegenerative, cardiovascular, metabolic, and oncological phenotypes as emergent consequences of shared network instability. Reframing the hallmarks as coupled network nodes shifts the explanatory focus from isolated mechanisms to system-level resilience and non-linear dynamics. This narrative and conceptual review integrates evidence across mitochondrial biology, metabolic signaling, and inflammatory pathways to develop these arguments, with explicit acknowledgment that the proposed framework is hypothesis-generating rather than formally validated. Interventions targeting high-centrality nodes, including mTOR modulation, NAD+ restoration, mitophagy activation, and anti-inflammatory strategies, may exert system-wide effects by reconfiguring network dynamics rather than correcting individual pathways. This perspective suggests that biomarker-stratified, network-calibrated interventions may offer a broader systems-level therapeutic rationale than single-pathway approaches.<\/jats:p>","DOI":"10.3390\/molecules31132317","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:50:33Z","timestamp":1782924633000},"page":"2317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4511-1498","authenticated-orcid":false,"given":"Wojciech","family":"Rzeski","sequence":"first","affiliation":[{"name":"Department of Functional Anatomy and Cytobiology, Institute of Biological Sciences, Maria Curie-Sk\u0142odowska University, Akademicka 19, 20-033 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Kroemer","year":"2023","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.cell.2014.10.039","article-title":"Geroscience: Linking aging to chronic disease","volume":"159","author":"Kennedy","year":"2014","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.cell.2005.01.027","article-title":"Understanding the odd science of aging","volume":"120","author":"Kirkwood","year":"2005","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature08980","article-title":"The genetics of ageing","volume":"464","author":"Kenyon","year":"2010","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1126\/science.aad3267","article-title":"Healthy aging: The ultimate preventative medicine","volume":"350","author":"Kaeberlein","year":"2015","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1126\/science.1069492","article-title":"Systems biology: A brief overview","volume":"295","author":"Kitano","year":"2002","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. 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