Dynamics of stability: the physiologic basis of functional health and frailty
Abstract
Under basal resting conditions most healthy physiologic systems demonstrate highly irregular, complex dynamics that represent interacting regulatory processes operating over multiple time scales. These processes prime the organism for an adaptive response, making it ready and able to react to sudden physiologic stresses. When the organism is perturbed or deviates from a given set of boundary conditions, most physiologic systems evoke closed-loop responses that operate over relatively short periods of time to restore the organism to equilibrium. This transiently alters the dynamics to a less complex, dominant response mode, which is denoted "reactive tuning." Aging and disease are associated with a loss of complexity in resting dynamics and maladaptive responses to perturbations. These alterations in the dynamics of physiologic systems lead to functional decline and frailty. Nonlinear mathematical techniques that quantify physiologic dynamics may predict the onset of frailty, and interventions aimed toward restoring healthy dynamics may prevent functional decline.
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Most organ systems contain substantial spare capacity, giving reserve that offsets changes from ageing and disease.
“many organ systems exhibit considerable redundancy, which provides the physiological reserve required to compensate for age and disease-related changes (13)”
From Frailty in elderly people (2013) · cites this paper as [13]
Both brain and skeletal muscle possess more cells than are necessary for survival.
“For example, the brain contains more neurons and skeletal muscle more myocytes than are required for survival (13).”
From Frailty in elderly people (2013) · cites this paper as [13]
Cites
The Fractal Geometry of Nature
Mandelbrot, B. B., & WHEELER, J. A. (1983) · American Journal of Physics · doi:10.1119/1.13295 · Cited by 21,950 · see citing works
Quantification of scaling exponents and crossover phenomena in nonstationary heartbeat time series
Peng, C., Havlin, S., Stanley, E., & Goldberger, A. L. (1995) · Chaos An Interdisciplinary Journal of Nonlinear Science · doi:10.1063/1.166141 · Cited by 3,865 · see citing works
A Multicomponent Intervention to Prevent Delirium in Hospitalized Older Patients
Inouye, S. K., Bogardus, S. T., Charpentier, P. A., Leo-Summers, L. S., Acampora, D., Holford, T. R., & Cooney, L. M. (1999) · New England Journal of Medicine · doi:10.1056/nejm199903043400901 · Cited by 2,904 · see citing works
Tinetti, M. E., Baker, D. I., McAvay, G., Claus, E. B., Garrett, P., Gottschalk, M., Koch, M. L., Trainor, K. M., & Horwitz, R. I. (1994) · New England Journal of Medicine · doi:10.1056/nejm199409293311301 · Cited by 2,135 · see citing works
Brzezinski, A. (1997) · New England Journal of Medicine · doi:10.1056/nejm199701163360306 · Cited by 1,549 · see citing works
Influence of social network on occurrence of dementia: a community-based longitudinal study
Fratiglioni, L., Wang, H.-X., Ericsson, K., Maytan, M., & Winblad, B. (2000) · The Lancet · doi:10.1016/s0140-6736(00)02113-9 · Cited by 1,361 · see citing works
Physiological time-series analysis: what does regularity quantify?
Pincus, S. M., & Goldberger, A. L. (1994) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1994.266.4.h1643 · Cited by 1,321 · see citing works
Loss of 'Complexity' and Aging
Lipsitz, L. A. (1992) · JAMA · doi:10.1001/jama.1992.03480130122036 · Cited by 1,268 · see citing works
Self-citationComplexity, Pattern, and Evolutionary Trade-Offs in Animal Aggregation
Parrish, J. K., & Leah Edelstein-keshet, A. (1999) · Science · doi:10.1126/science.284.5411.99 · Cited by 1,230 · see citing works
Collins, J. J., & Luca, C. J. D. (1993) · Experimental Brain Research · doi:10.1007/bf00229788 · Cited by 1,208 · see citing works
Garfinkel, A., Spano, M. L., Ditto, W. L., & Weiss, J. N. (1992) · Science · doi:10.1126/science.1519060 · Cited by 920 · see citing works
Non-linear dynamics for clinicians: chaos theory, fractals, and complexity at the bedside
Goldberger, A. L. (1996) · The Lancet · doi:10.1016/s0140-6736(96)90948-4 · Cited by 859 · see citing works
Hausdorff, J. M., Mitchell, S. L., Firtion, R., Peng, C., Cudkowicz, M., Wei, J. Y., & Goldberger, A. L. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.82.1.262 · Cited by 848 · see citing works
Science in Pictures: Chaos and Fractals in Human Physiology
Goldberger, A. L., Rigney, D. R., & West, B. J. (1990) · Scientific American · doi:10.1038/scientificamerican0290-42 · Cited by 805 · see citing works
Huikuri, H. V., Mäkikallio, T. H., Peng, C., Goldberger, A. L., Hintze, U., & Møller, M. (2000) · Circulation · doi:10.1161/01.cir.101.1.47 · Cited by 668 · see citing works
Yates, F., Garfinkel, A., Walter, D., & Yates, G. B. (1987) · Life Science Monographs · doi:10.1007/978-1-4613-0883-6 · Cited by 542 · see citing works
Lipsitz, L. A., Mietus, J. E., Moody, G. B., & Goldberger, A. L. (1990) · Circulation · doi:10.1161/01.cir.81.6.1803 · Cited by 519 · see citing works
Self-citationHo, K. K. L., Moody, G. B., Peng, C.-K., Mietus, J. E., Larson, M. G., Levy, D., & Goldberger, A. L. (1997) · Circulation · doi:10.1161/01.cir.96.3.842 · Cited by 489 · see citing works
Aging and the complexity of cardiovascular dynamics
Kaplan, D. T., Furman, M. I., Pincus, S. M., Ryan, S. M., Lipsitz, L. A., & Goldberger, A. L. (1991) · Biophysical Journal · doi:10.1016/s0006-3495(91)82309-8 · Cited by 457 · see citing works
Self-citationMishima, M., Hirai, T., Itoh, H., Nakano, Y., Sakai, H., Muro, S., Nishimura, K., Oku, Y., Chin, K., Ohi, M., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.16.8829 · Cited by 353 · see citing works
Levy, W. C., Cerqueira, M. D., Harp, G. D., Johannessen, K.-A., Abrass, I. B., Schwartz, R. S., & Stratton, J. R. (1998) · The American Journal of Cardiology · doi:10.1016/s0002-9149(98)00611-0 · Cited by 312 · see citing works
Dynamic Regulation of Middle Cerebral Artery Blood Flow Velocity in Aging and Hypertension
Lipsitz, L. A., Mukai, S., Hamner, J. W., Gagnon, M. M., & Babikian, V. L. (2000) · Stroke · doi:10.1161/01.str.31.8.1897 · Cited by 276 · see citing works
Self-citationPower-Law Relationship of Heart Rate Variability as a Predictor of Mortality in the Elderly
Huikuri, H. V., Mäkikallio, T. H., Airaksinen, J. K. E., Seppänen, T., Puukka, P. J., Räihä, I. J., & Sourander, L. (1998) · Circulation · doi:10.1161/01.cir.97.20.2031 · Cited by 271 · see citing works
Mäkikallio, T. H., Huikuri, H. V., Hintze, U., Videbæk, J., Mitrani, R. D., Castellanos, A., Myerburg, R. J., & Møller, M. (2001) · The American Journal of Cardiology · doi:10.1016/s0002-9149(00)01312-6 · Cited by 252 · see citing works
The Brain in Fractal Time: 1/F-Like Power Spectrum Scaling of the Human Electroencephalogram
Pritchard, W. S. (1992) · International Journal of Neuroscience · doi:10.3109/00207459208999796 · Cited by 250 · see citing works
Vikman, S., Mäkikallio, T. H., Yli‐Mäyry, S., Pikkujämsä, S. M., Koivisto, A., Reinikainen, P., Airaksinen, J. K. E., & Huikuri, H. V. (1999) · Circulation · doi:10.1161/01.cir.100.20.2079 · Cited by 247 · see citing works
Hausdorff, J. M., Nelson, M. E., Kaliton, D., Layne, J. E., Bernstein, M., Nuernberger, A., & Singh, M. A. F. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.6.2117 · Cited by 236 · see citing works
Life-support system benefits from noise
Suki, B., Alencar, A. M., Sujeer, M. K., Lutchen, K. R., Collins, J. J., Andrade, J. S., Ingenito, E. P., Zapperi, S., & Stanley, E. (1998) · Nature · doi:10.1038/30130 · Cited by 213 · see citing works
Tulppo, M. P., Hughson, R. L., Mäkikallio, T. H., Airaksinen, J. K. E., Seppänen, T., & Huikuri, H. V. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.280.3.h1081 · Cited by 204 · see citing works
Yamamoto, Y., & Hughson, R. L. (1994) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1994.266.1.r40 · Cited by 185 · see citing works
Effects of Age and Gender on Autonomic Control of Blood Pressure Dynamics
Barnett, S. R., Morin, R. J., Kiely, D. K., Gagnon, M. M., Azhar, G., Knight, E. L., Nelson, J. C., & Lipsitz, L. A. (1999) · Hypertension · doi:10.1161/01.hyp.33.5.1195 · Cited by 184 · see citing works
Self-citationEffect of exercise training on heart rate variability in healthy older adults
Stein, P. K., Ehsani, A. A., Domitrovich, P. P., Kleiger, R. E., & Rottman, J. N. (1999) · American Heart Journal · doi:10.1016/s0002-8703(99)70162-6 · Cited by 181 · see citing works
Mäkikallio, T. H., Koistinen, J. M., Jordaens, L. J. L. M., Tulppo, M. P., Wood, N., Golosarsky, B., Peng, C., Goldberger, A. L., & Huikuri, H. V. (1999) · The American Journal of Cardiology · doi:10.1016/s0002-9149(98)01068-6 · Cited by 166 · see citing works
Long-range correlations in human standing
Duarte, M., & Zatsiorsky, V. M. (2001) · Physics Letters A · doi:10.1016/s0375-9601(01)00188-8 · Cited by 142 · see citing works
Decrease of non-linear structure in the EEG of Alzheimer patients compared to healthy controls
Jelles, B., van Birgelen, J. H., Slaets, J. P. J., Hekster, R. E. M., Jonkman, E. J., & Stam, C. J. (1999) · Clinical Neurophysiology · doi:10.1016/s1388-2457(99)00013-9 · Cited by 140 · see citing works
Exercise training and heart rate variability in older people
Schuit, A. J., van Amelsvoort, L. G. P. M., VERHEIJ, T. C., Rijneke, R. D., Maan, A. C., Swenne, C. A., & Schouten, E. G. (1999) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199906000-00009 · Cited by 132 · see citing works
Nonlinear-dynamical arrhythmia control in humans
Christini, D. J., Steín, K. M., Markowitz, S. M., Mittal, S., Slotwiner, D. J., Scheiner, M. A., Iwai, S., & Lerman, B. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091553398 · Cited by 117 · see citing works
Heart rate variability and fractal dimension during orthostatic challenges
Butler, G. C., Yamamoto, Y., Xing, H. C., et al. (1993) · Journal of Applied Physiology · doi:10.1152/jappl.1993.75.6.2602 · Cited by 106 · see citing works
Psychosocial Predictors of Stroke Outcomes in an Elderly Population
Colantonio, A., Kasl, S. V., Ostfeld, A. M., & Berkman, L. F. (1993) · Journal of Gerontology · doi:10.1093/geronj/48.5.s261 · Cited by 106 · see citing works
Hunt, B. E., Taylor, J. A., Hamner, J. W., Gagnon, M. M., & Lipsitz, L. A. (2001) · Circulation · doi:10.1161/01.cir.103.24.2909 · Cited by 99 · see citing works
Self-citationOn the fractal nature of heart rate variability in humans: effects of vagal blockade
Yamamoto, Y., Nakamura, Y., Satō, H., Yamamoto, M. P., Kato, K., & Hughson, R. L. (1995) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1995.269.4.r830 · Cited by 92 · see citing works
Lin, L., Lin, J.-L., DU, C., Lai, L., Tseng, Y.-Z., & Huang, S. K. S. (2001) · Journal of Cardiovascular Electrophysiology · doi:10.1046/j.1540-8167.2001.00026.x · Cited by 76 · see citing works
Human Balance out of Equilibrium: Nonequilibrium Statistical Mechanics in Posture Control
Lauk, M., Chow, C. C., Pavlik, A. E., & Collins, J. J. (1998) · Physical Review Letters · doi:10.1103/physrevlett.80.413 · Cited by 75 · see citing works
Sturis, J., Scheen, A. J., Leproult, R., Polonsky, K. S., & Cauter, E. V. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117817 · Cited by 69 · see citing works
Parkinsonian Tremor and Simplification in Network Dynamics
Edwards, R. (1999) · Bulletin of Mathematical Biology · doi:10.1006/bulm.1998.0086 · Cited by 51 · see citing works
Narayanan, K., Collins, J. J., Hamner, J. W., Mukai, S., & Lipsitz, L. A. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.281.3.r716 · Cited by 41 · see citing works
Self-citationAge-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation
Greenspan, S. L., Klibanski, A., Rowe, J. W., et al. (1991) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1991.260.3.e486 · Cited by 39 · see citing works
Lipsitz, L. A., Pincus, S. M., Morin, R. J., et al. (1997) · Journal of the Autonomic Nervous System · doi:10.1016/s0165-1838(97)00028-3 · Cited by 38 · see citing works
Self-citationKresh, J. Y., & Izrailtyan, I. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.3.r720 · Cited by 34 · see citing works
Velanovich, V. (1996) · The American Journal of the Medical Sciences · doi:10.1016/s0002-9629(15)41697-0 · Cited by 33 · see citing works
Vasomotor instability preceding tilt-induced syncope: does respiration play a role?
Lipsitz, L. A., Morin, R. J., Gagnon, M. M., Kiely, D. K., & Medina, A. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.83.2.383 · Cited by 28 · see citing works
Self-citationVelanovich, V. (1996) · The American Journal of the Medical Sciences · doi:10.1097/00000441-199605000-00003 · Cited by 14 · see citing works
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Fried, L. P., Ferrucci, L., Darer, J., Williamson, J. D., & Anderson, G. (2004) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/59.3.m255 · Cited by 4,032 · see citing works
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- Authors
- Lipsitz, L. A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Lipsitz, L. A.
- ORCID
- Lipsitz, L. A.
- Venue
- The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-03-01
- Volume
- 57
- Issue
- 3
- Pages
- B115-B125
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- OpenAlex
- W2142814341
- Cited by
- 646
- References
- 52
- Citations by year
- 2026: 32 · 2025: 28 · 2024: 39 · 2023: 24 · 2022: 28 · 2021: 43 · 2020: 43 · 2019: 43 · 2018: 32 · 2017: 41 · 2016: 31 · 2015: 23 · 2014: 21 · 2013: 22 · 2012: 23
- FWCI
- 8.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journals of Gerontology Series A (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-08812, P01AG004390, AG 04390, P50AG005134, AG 05134)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
- Health Sciences › Health Professions › Physical Therapy, Sports Therapy and Rehabilitation › Balance, Gait, and Falls Prevention
- Keywords
- functional health, frailty, aging, nonlinear dynamics, complexity, closed-loop regulation, functional decline, predictive biomarkers, perturbation response, adaptive response
- MeSH terms
- Aged, Aged, 80 and over, Aging, Health, Humans, Frail Elderly, Nonlinear Dynamics
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