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The physical frailty syndrome as a transition from homeostatic symphony to cacophony

Nature Aging volume 1, pages 36–46 (2021)Cite this article

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Abstract

Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. This Perspective synthesizes the evidence on the aging-related pathophysiology underpinning the clinical presentation of physical frailty as a phenotype of a clinical syndrome that is distinct from the cumulative-deficit-based frailty index. We focus on integrating the converging evidence on the conceptualization of physical frailty as a state, largely independent of chronic diseases, that emerges when the dysregulation of multiple interconnected physiological and biological systems crosses a threshold to critical dysfunction, severely compromising homeostasis. Our exegesis posits that the physiology underlying frailty is a critically dysregulated complex dynamical system. This conceptual framework implies that interventions such as physical activity that have multisystem effects are more promising to remedy frailty than interventions targeted at replenishing single systems. We then consider how this framework can drive future research to further understanding, prevention and treatment of frailty, which will likely preserve health and resilience in aging populations.

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Fig. 1: A hierarchical, multiscale representation of the physiological dysregulation and likely biological drivers of physical frailty.
Fig. 2: Stimulus–response experiments in older adults measuring physiological response to minor stressors in community-dwelling older adults who were characterized as nonfrail, prefrail or frail.
Fig. 3: Hypothesized natural history of frailty: deterioration of physiological integrity in response to repeated stressors and natural aging.
Fig. 4: Nonlinear increase in the prevalence of physical frailty by number of dysregulated physiological systems at baseline among women aged 70–79 years participating in the WHAS I and II studies (n = 704).

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Acknowledgements

We dedicate this article to Dr. Richard Suzman, who consistently envisioned and enabled transformative aging research. We are grateful for support by the National Institute on Aging, including for WHAS I (N01 AG012112), WHAS II (M01 R000052), Pathogenesis of Physical Disability in Aging Women (MERIT Award, R37 AG019905) and the frailty-focused Johns Hopkins University Claude D. Pepper Older Americans Independence Center (P30 AG021334). We thank M. A. O’Brien for her outstanding assistance in preparation of the manuscript.

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Author notes

  1. These authors jointly supervised this work: Karen Bandeen-Roche, Ravi Varadhan.

Authors and Affiliations

  1. Columbia University Mailman School of Public Health, New York, NY, USA

    Linda P. Fried

  2. Groupe de recherche PRIMUS, Department of Family Medicine, Université de Sherbrooke, Quebec City, Quebec, Canada

    Alan A. Cohen

  3. Johns Hopkins Center on Aging and Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Qian-Li Xue & Karen Bandeen-Roche

  4. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Jeremy Walston

  5. Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Karen Bandeen-Roche

  6. Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Ravi Varadhan

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  1. Linda P. Fried
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  3. Qian-Li Xue
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Corresponding author

Correspondence to Linda P. Fried.

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Peer review information Nature Aging thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Fried, L.P., Cohen, A.A., Xue, QL. et al. The physical frailty syndrome as a transition from homeostatic symphony to cacophony. Nat Aging 1, 36–46 (2021). https://doi.org/10.1038/s43587-020-00017-z

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