Abstract
Frailty is a clinical syndrome often present in older adults and characterized by a heightened vulnerability to stressors. The biological antecedents and etiology of frailty are unclear despite decades of research: frailty is associated with dysregulation in a wide range of physiological systems, but no specific cause has been identified. Here, we test predictions stemming from the hypothesis that there is no specific cause: that frailty is an emergent property arising from the complex systems dynamics of the broad loss of organismal homeostasis. Specifically, we use dysregulation of six physiological systems using the Mahalanobis distance approach in two cohorts of older adults to test the breadth, diffuseness, and nonlinearity of associations between frailty and system-specific dysregulation. We find clear support for the breadth of associations between frailty and physiological dysregulation: positive associations of all systems with frailty in at least some analyses. We find partial support for diffuseness: the number of systems or total amount of dysregulation is more important than the identity of the systems dysregulated, but results only partially replicate across cohorts. We find partial support for nonlinearity: trends are exponential but not always significantly so, and power is limited for groups with very high levels of dysregulation. Overall, results are consistent with—but not definitive proof of—frailty as an emergent property of complex systems dynamics. Substantial work remains to understand how frailty relates to underlying physiological dynamics across systems.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Due to confidentiality concerns, transfer and sharing of individual-level data used in this study require prior approval from the management committees of WHAS and NuAge. For this reason, raw data cannot be made publicly available. Data are however available from the WHAS and NuAge committees upon reasonable request.
Code availability
All code is available upon request.
References
Akki A, Yang H, Gupta A et al (2014) Skeletal muscle ATP kinetics are impaired in frail mice. Age (Omaha). https://doi.org/10.1007/s11357-013-9540-0
Arbeev KG, Cohen AA, Arbeeva LS et al (2016) Optimal versus realized trajectories of physiological dysregulation in aging and their relation to sex-specific mortality risk. Front Public Health. https://doi.org/10.3389/fpubh.2016.00003
Bandeen-Roche K, Walston JD, Huang Y et al (2009) Measuring systemic inflammatory regulation in older adults: evidence and utility. Rejuvenation Res 12:403–410
Bates D, Mächler M, Bolker BM, Walker SC (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48. https://doi.org/10.18637/jss.v067.i01
Bates DM, Venables WN (2009) splines-package: regression spline functions and classes
Belsky DW, Moffitt TE, Cohen AA et al (2018) Eleven telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: do they measure the same thing? Am J Epidemiol. https://doi.org/10.1093/aje/kwx346
Cappola AR, Xue QL, Fried LP (2009) Multiple hormonal deficiencies in anabolic hormones are found in frail older women: the women’s health and aging studies. J Gerontol A. https://doi.org/10.1093/gerona/gln026
Christensen RHB (2019) Regression models for ordinal data. R package ordinal version 2019.12-10
Clegg A, Young J, Iliffe S et al (2013) Frailty in elderly people. Lancet 381:752–762. https://doi.org/10.1016/S0140-6736(12)62167-9
Cohen AA (2016) Complex systems dynamics in aging: new evidence, continuing questions. Biogerontology. https://doi.org/10.1007/s10522-015-9584-x
Cohen AA, Levasseur M, Raina PS et al (2020) Is aging biology ageist? J Gerontol A. https://doi.org/10.1093/gerona/glz190
Cohen AA, Li Q, Milot E et al (2015) Statistical distance as a measure of physiological dysregulation is largely robust to variation in its biomarker composition. PLoS ONE. https://doi.org/10.1371/journal.pone.0122541
Cohen AA, Milot E, Li Q et al (2014) Cross-population validation of statistical distance as a measure of physiological dysregulation during aging. Exp Gerontol. https://doi.org/10.1016/j.exger.2014.04.016
Cohen AA, Milot E, Li Q et al (2015) Detection of a novel, integrative aging process suggests complex physiological integration. PLoS ONE. https://doi.org/10.1371/journal.pone.0116489
Cohen AA, Milot E, Yong J et al (2013) A novel statistical approach shows evidence for multi-system physiological dysregulation during aging. Mech Ageing Dev. https://doi.org/10.1016/j.mad.2013.01.004
Dansereau G, Wey TW, Legault V et al (2019) Conservation of physiological dysregulation signatures of aging across primates. Aging Cell. https://doi.org/10.1111/acel.12925
El Assar M, Angulo J, Rodríguez-Mañas L (2020) Frailty as a phenotypic manifestation of underlying oxidative stress. Free Radic Biol Med. https://doi.org/10.1016/j.freeradbiomed.2019.08.011
Fried LP, Cohen AA, Xue QL et al (2020) Physical frailty in aging: from symphony to cacophony. Nat Aging (under review)
Fried LP, Tangen CM, Walston J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A 56:M146–M157. https://doi.org/10.1093/gerona/56.3.M146
Fried LP, Xue Q-L, Cappola AR et al (2009) Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment. J Gerontol A 64:1049–1057
Fried LP, Young Y, Rubin G, Bandeen-Roche K (2001) Self-reported preclinical disability identifies older women with early declines in performance and early disease. J Clin Epidemiol 54:889–901. https://doi.org/10.1016/S0895-4356(01)00357-2
Gaudreau P, Morais JA, Shatenstein B et al (2007) Nutrition as a determinant of successful aging: description of the Quebec Longitudinal Study NuAge and results from cross-sectional pilot studies. Rejuvenation Res 10:377–386. https://doi.org/10.1089/rej.2007.0596
Gavrilov LA, Gavrilova NS (2004) The reliability-engineering approach to the problem of biological aging. Ann NY Acad Sci 1019:509–512. https://doi.org/10.1196/annals.1297.094
Gijzel SMW, Van De Leemput IA, Scheffer M et al (2017) Dynamical resilience indicators in time series of self-rated health correspond to frailty levels in older adults. J Gerontol A. https://doi.org/10.1093/gerona/glx065
Guan ZH, Liu ZW, Feng G, Wang YW (2010) Synchronization of complex dynamical networks with time-varying delays via impulsive distributed control. IEEE Trans Circuits Syst I. https://doi.org/10.1109/TCSI.2009.2037848
Hubbard RE, O’Mahony MS, Calver BL, Woodhouse KW (2008) Nutrition, inflammation, and leptin levels in aging and frailty. J Am Geriatr Soc 56:279–284. https://doi.org/10.1111/j.1532-5415.2007.01548.x
Kalyani RR, Varadhan R, Weiss CO et al (2012) Frailty status and altered glucose-insulin dynamics. J Gerontol A 67:1300–1306
Kassambara A, Mundt F (2020) Package “factoextra” type package title extract and visualize the results of multivariate data analyses
Khalil A, Gaudreau P, Cherki M et al (2011) Antioxidant-rich food intakes and their association with blood total antioxidant status and vitamin C and E levels in community-dwelling seniors from the Quebec Longitudinal Study NuAge. Exp Gerontol 46:475–481. https://doi.org/10.1016/j.exger.2011.02.002
Kitano H (2004) Biological robustness. Nat Rev Genet 8:826–837
Kraft TS, Stieglitz J, Trumble BC, Garcia AR, Kaplan H, Gurven M (2020) Multi-system physiological dysregulation and ageing in a subsistence population. Philos Trans Royal Soc Lond Ser B Biol Sci 375(1811):20190610. https://doi.org/10.1098/rstb.2019.0610
Le Couteur DG, Simpson SJ (2011) Adaptive senectitude: the prolongevity effects of aging. J Gerontol A. https://doi.org/10.1093/gerona/glq171
Leek J, McShane BB, Gelman A et al (2017) Five ways to fix statistics. Nature 551:557–559
Leng S, Chaves P, Koenig K, Walston J (2002) Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc 50:1268–1271. https://doi.org/10.1046/j.1532-5415.2002.50315.x
Leng SX, Xue Q-L, Tian J et al (2007) Inflammation and frailty in older women. J Am Geriatr Soc 55:864–871. https://doi.org/10.1111/j.1532-5415.2007.01186.x
Leng SX, Xue QL, Tian J et al (2009) Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I. Exp Gerontol 44:511–516. https://doi.org/10.1016/j.exger.2009.05.005
Li Q, Wang S, Milot E et al (2015) Homeostatic dysregulation proceeds in parallel in multiple physiological systems. Aging Cell. https://doi.org/10.1111/acel.12402
Lumley T, Maintainer M, Lumley’ T (2020) Package “survey” title analysis of complex survey samples
Mahalanobis PC (1936) Mahalanobis distance. Proc Natl Inst Sci India 49:234–256
Mielke MM, Xue Q-L, Zhou J et al (2008) Baseline serum cholesterol is selectively associated with motor speed and not rates of cognitive decline: the Women’s Health and Aging Study II. J Gerontol A. https://doi.org/10.1093/gerona/63.6.619
Milot E, Morissette-Thomas V, Li Q et al (2014) Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations. Mech Ageing Dev. https://doi.org/10.1016/j.mad.2014.10.001
Mitnitski AB, Mogilner AJ, Rockwood K (2001) Accumulation of deficits as a proxy measure of aging. Sci World J 1:323–336
Mitnitski AB, Rutenberg AD, Farrell S, Rockwood K (2017) Aging, frailty and complex networks. Biogerontology. https://doi.org/10.1007/s10522-017-9684-x
Morrisette-Thomas V, Cohen AA, Fülöp T et al (2014) Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev. https://doi.org/10.1016/j.mad.2014.06.005
Nakazato Y, Sugiyama T, Ohno R et al (2020) Estimation of homeostatic dysregulation and frailty using biomarker variability: a principal component analysis of hemodialysis patients. Sci Rep. https://doi.org/10.1038/s41598-020-66861-6
Nijhout HF, Sadre-Marandi F, Best J, Reed MC (2017) Systems biology of phenotypic robustness and plasticity. Integr Comp Biol 57:171–184
Olde Rikkert MGM, Dakos V, Buchman TG et al (2016) Slowing down of recovery as generic risk marker for acute severity transitions in chronic diseases. Crit Care Med. https://doi.org/10.1097/CCM.0000000000001564
Qu T, Yang H, Walston JD et al (2009) Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. Cytokine 46:319–324. https://doi.org/10.1016/j.cyto.2009.02.015
Rockwood K, Mitnitski A, Song X et al (2006) Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc. https://doi.org/10.1111/j.1532-5415.2006.00738.x
Rockwood K, Song X, MacKnight C et al (2005) A global clinical measure of fitness and frailty in elderly people. CMAJ 173:489–495. https://doi.org/10.1503/cmaj.050051
Rutenberg AD, Mitnitski AB, Farrell SG, Rockwood K (2018) Unifying aging and frailty through complex dynamical networks. Exp Gerontol. https://doi.org/10.1016/j.exger.2017.08.027
Semba RD, Patel KV, Ferrucci L et al (2010) Serum antioxidants and inflammation predict red cell distribution width in older women: The Women’s Health and Aging Study I. Clin Nutr 29:600–604. https://doi.org/10.1016/j.clnu.2010.03.001
Seplaki CL, Goldman N, Glei D, Weinstein M (2005) A comparative analysis of measurement approaches for physiological dysregulation in an older population. Exp Gerontol 40:438–449. https://doi.org/10.1016/j.exger.2005.03.002
Shardell M, Hicks GE, Miller RM et al (2009) Association of low vitamin D levels with the frailty syndrome in men and women. J Gerontol A 64A:69–75
Simonsick EM, Maffeo CE, Rogers SK et al (1997) Methodology and feasibility of a home-based examination in disabled older women: the Women’s Health and Aging Study. J Gerontol A. https://doi.org/10.1093/gerona/52a.5.m264
Soysal P, Stubbs B, Lucato P et al (2016) Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res Rev. https://doi.org/10.1016/j.arr.2016.08.006
Theou O, Cann L, Blodgett J et al (2015) Modifications to the frailty phenotype criteria: systematic review of the current literature and investigation of 262 frailty phenotypes in the survey of health, ageing, and retirement in Europe. Ageing Res Rev. https://doi.org/10.1016/j.arr.2015.04.001
Varadhan R, Chaves PHM, Lipsitz LA et al (2009) Frailty and impaired cardiac autonomic control: new insights from principal components aggregation of traditional heart rate variability indices. J Gerontol A. https://doi.org/10.1093/gerona/glp013
Varadhan R, Walston J, Cappola AR et al (2008) Higher levels and blunted diurnal variation of cortisol in frail older women. J Gerontol A 63:190–195
Funding
The NuAge cohort was supported by the Canadian Institutes of Health Research (CIHR) Grant #62842. The NuAge Database and Biobank are supported by the Fonds de recherche du Québec (FRQ) Grant #2020-VICO-279753, the Quebec Network for Research on Aging, a thematic network funded by the FRQ - Santé (FRQS) and by the Merck-Frosst Chair funded by La Fondation de l’Université de Sherbrooke. This work was supported by Canadian Institutes of Health Research (CIHR, Grant #153011). AAC is supported by a CIHR New Investigator Salary Award and an FRQS Senior Research Fellowship, and is a Member of the FRQS funded Centre de recherche du CHUS and Centre de recherche sur le vieillissement. NP is a Junior 1 Research Scholar of the FRQS.
Author information
Authors and Affiliations
Contributions
AG, LPF, KB-R, and AAC contributed to the study conception and design. LPF, NP and PG participated in data collection and preparation. Data analysis was performed by AG and VL. The first draft of the manuscript was written by AG and AAC. All authors commented on the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
AAC is Founder and CSO at Oken Health.
Consent for publication
Not applicable.
Ethical approval
Both studies were approved by their Local Ethics Committee, in terms of study protocol and consent procedure. The NuAge Database and Biobank and secondary analysis for this project were approved by the Comité d’éthique de la recherche du CIUSSS de l’Estrie – CHUS (Projects 2019-2832 and 14-059, respectively).
Informed consent
All participants recruited in both studies signed informed consent.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ghachem, A., Fried, L.P., Legault, V. et al. Evidence from two cohorts for the frailty syndrome as an emergent state of parallel dysregulation in multiple physiological systems. Biogerontology 22, 63–79 (2021). https://doi.org/10.1007/s10522-020-09903-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-020-09903-w