{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:13:00Z","timestamp":1788228780448,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>The dominant clinical manifestation of aging is not mortality but the progressive depletion of functional reserve\u2014the surplus physiological capacity separating independent function from disability. Existing geroscience frameworks describe molecular aging in detail yet give the point-of-care clinician little basis for prioritizing targets. We reframe functional aging as a control systems problem in which aging is modeled as progressive instability within a coupled, bidirectional mitochondrial\u2013epigenetic axis. That axis is called central in two limited senses only: network connectivity and therapeutic tractability; no causal primacy is claimed over mTOR signaling, inflammaging, senescence, proteostasis failure, telomere attrition, or stem cell exhaustion. Candidate capacities were scored against three conjunctive criteria\u2014independence, necessity, and modifiability. Five satisfy them at the thresholds stated, and sensitivity analysis reports which threshold changes would instead yield four or seven, so the count follows from a stated procedure rather than standing as a natural constant. Interventions are mapped onto these capacities in a separate layer. The result is a hierarchically ordered, clinically actionable, falsifiable architecture in which functional reserve is the primary therapeutic target and lifespan a downstream consequence\u2014and whose primary test, deletion of any single capacity from longitudinal models, is evaluable in existing cohorts without new data collection.<\/jats:p>","DOI":"10.3390\/life16091457","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:05:26Z","timestamp":1788224726000},"page":"1457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Preservation of Functional Reserve: A Control Systems Framework for Human Aging"],"prefix":"10.3390","volume":"16","author":[{"given":"Robert T.","family":"O\u2019Leary","sequence":"first","affiliation":[{"name":"Orlando College of Osteopathic Medicine, Orlando, FL 34787, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"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":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.cell.2022.12.027","article-title":"Loss of epigenetic information as a cause of mammalian aging","volume":"186","author":"Yang","year":"2023","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"M146","DOI":"10.1093\/gerona\/56.3.M146","article-title":"Frailty in older adults: Evidence for a phenotype","volume":"56","author":"Fried","year":"2001","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1093\/gerona\/62.7.722","article-title":"Frailty in relation to the accumulation of deficits","volume":"62","author":"Rockwood","year":"2007","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1001\/jama.1992.03480130122036","article-title":"Loss of \u201ccomplexity\u201d and aging: Potential applications of fractals and chaos theory to senescence","volume":"267","author":"Lipsitz","year":"1992","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"pe16","DOI":"10.1126\/sageke.2004.16.pe16","article-title":"Physiological complexity, aging, and the path to frailty","volume":"2004","author":"Lipsitz","year":"2004","journal-title":"Sci. Aging Knowl. Environ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.pnpbp.2012.08.020","article-title":"Physiologic complexity and aging: Implications for physical function and rehabilitation","volume":"45","author":"Manor","year":"2013","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1056\/NEJMoa011858","article-title":"Exercise capacity and mortality among men referred for exercise testing","volume":"346","author":"Myers","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1001\/jama.2010.1923","article-title":"Gait speed and survival in older adults","volume":"305","author":"Studenski","year":"2011","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.aac4854","article-title":"NAD+ in aging, metabolism, and neurodegeneration","volume":"350","author":"Verdin","year":"2015","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tcb.2014.04.002","article-title":"NAD+ and sirtuins in aging and disease","volume":"24","author":"Imai","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e70369","DOI":"10.1002\/mco2.70369","article-title":"Epigenetic regulation of aging and its rejuvenation","volume":"6","author":"An","year":"2025","journal-title":"MedComm"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s10522-025-10273-4","article-title":"Mitochondrial dysfunction and aging: Multidimensional mechanisms and therapeutic strategies","volume":"26","author":"Wei","year":"2025","journal-title":"Biogerontology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5135","DOI":"10.7150\/ijbs.115518","article-title":"Roles of SIRT3 in aging and aging-related diseases","volume":"21","author":"You","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nature11861","article-title":"mTOR is a key modulator of ageing and age-related disease","volume":"493","author":"Johnson","year":"2013","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nature06322","article-title":"mTOR controls mitochondrial oxidative function through a YY1\u2013PGC-1\u03b1 transcriptional complex","volume":"450","author":"Cunningham","year":"2007","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116811","DOI":"10.1016\/j.celrep.2025.116811","article-title":"PDX1 phosphorylation at S61 by mTORC1 links nutrient signaling to \u03b2 cell function and metabolic disease","volume":"45","author":"Fan","year":"2026","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"151240","DOI":"10.1016\/j.ejcb.2022.151240","article-title":"Amino acids control blood glucose levels through mTOR signaling","volume":"101","author":"Fan","year":"2022","journal-title":"Eur. J. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"543","DOI":"10.2106\/00004623-195335030-00003","article-title":"The major determinants in normal and pathological gait","volume":"35","author":"Saunders","year":"1953","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_23","unstructured":"Inman, V.T., Ralston, H.J., and Todd, F. (1981). Human Walking, Williams & Wilkins."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.humov.2007.04.003","article-title":"The six determinants of gait and the inverted pendulum analogy: A dynamic walking perspective","volume":"26","author":"Kuo","year":"2007","journal-title":"Hum. Mov. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1126\/science.1195027","article-title":"Circadian integration of metabolism and energetics","volume":"330","author":"Bass","year":"2010","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.1241224","article-title":"Sleep drives metabolite clearance from the adult brain","volume":"342","author":"Xie","year":"2013","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s10522-025-10299-8","article-title":"The intricate link between circadian rhythms and aging: Can resetting our circadian clock hold the key to longevity?","volume":"26","author":"Hassan","year":"2025","journal-title":"Biogerontology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e14803","DOI":"10.1111\/cns.14803","article-title":"Advances in the study of the glymphatic system and aging","volume":"30","author":"Xiong","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_29","first-page":"5","article-title":"Regulation by exercise of skeletal muscle content of mitochondria and GLUT4","volume":"59","author":"Holloszy","year":"2008","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20250055","DOI":"10.1515\/bmc-2025-0055","article-title":"The impact of exercise on mitochondrial biogenesis in skeletal muscle: A systematic review and meta-analysis of randomized trials","volume":"16","author":"Chiari","year":"2025","journal-title":"Biomol. Concepts"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1136\/bjsports-2023-107849","article-title":"Cardiorespiratory fitness is a strong and consistent predictor of morbidity and mortality among adults: An overview of meta-analyses representing over 20.9 million observations from 199 unique cohort studies","volume":"58","author":"Lang","year":"2024","journal-title":"Br. J. Sports Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.cell.2015.02.020","article-title":"Promoting health and longevity through diet","volume":"161","author":"Fontana","year":"2015","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12929-025-01188-w","article-title":"The impacts of different dietary restriction regimens on aging and longevity: From yeast to humans","volume":"32","author":"Ching","year":"2025","journal-title":"J. Biomed. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.mayocp.2018.04.008","article-title":"Cardiovascular and other health benefits of sauna bathing: A review of the evidence","volume":"93","author":"Laukkanen","year":"2018","journal-title":"Mayo Clin. Proc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/php.12864","article-title":"Mechanisms and mitochondrial redox signaling in photobiomodulation","volume":"94","author":"Hamblin","year":"2018","journal-title":"Photochem. Photobiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.yfrne.2018.01.001","article-title":"An energetic view of stress: Focus on mitochondria","volume":"49","author":"Picard","year":"2018","journal-title":"Front. Neuroendocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E6614","DOI":"10.1073\/pnas.1515733112","article-title":"Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress","volume":"112","author":"Picard","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1126\/science.aab3389","article-title":"Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection","volume":"350","author":"Blackburn","year":"2015","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/978-1-0716-4200-9_6","article-title":"Mitochondrial functioning: Front and center in defining psychosomatic mechanisms of allostasis in health and disease","volume":"2868","author":"Reid","year":"2025","journal-title":"Methods Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s44324-025-00067-0","article-title":"The role of NAD+ metabolism and its modulation of mitochondria in aging and disease","volume":"3","author":"Yusri","year":"2025","journal-title":"npj Metab. Health Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41580-024-00800-5","article-title":"Telomere function and regulation from mouse models to human aging and disease","volume":"26","author":"Mainz","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/php.13963","article-title":"Does photobiomodulation alter mitochondrial dynamics?","volume":"101","author":"Trajano","year":"2025","journal-title":"Photochem. Photobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.cmet.2015.02.009","article-title":"MOTS-c: A mitochondrial-derived peptide regulating muscle and fat metabolism","volume":"21","author":"Lee","year":"2015","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12967-023-03885-2","article-title":"Mitochondria-derived peptide MOTS-c: Effects and mechanisms related to stress, metabolism and aging","volume":"21","author":"Wan","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e73420","DOI":"10.7554\/eLife.73420","article-title":"DunedinPACE, a DNA methylation biomarker of the pace of aging","volume":"11","author":"Belsky","year":"2022","journal-title":"eLife"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/s43587-023-00432-y","article-title":"Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial","volume":"3","author":"Waziry","year":"2023","journal-title":"Nat. Aging"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S2213-8587(18)30171-2","article-title":"Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: Secondary analyses of the Testosterone Trials","volume":"6","author":"Bhasin","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e14039","DOI":"10.1111\/acel.14039","article-title":"Partial cellular reprogramming: A deep dive into an emerging rejuvenation technology","volume":"23","author":"Paine","year":"2024","journal-title":"Aging Cell"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1457\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:14:52Z","timestamp":1788225292000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["life16091457"],"URL":"https:\/\/doi.org\/10.3390\/life16091457","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}