Can a Link Be Found Between Physical Resilience and Frailty in Older Adults by Studying Dynamical Systems?

Practitioners of Geriatric Medicine often help older patients decide whether proposed medical treatments or procedures are worth the risk of potentially devastating adverse outcomes. Although many studies have helped to identify risk factors that predispose to adverse health outcomes in older adults following medical treatments or procedures, few have allowed investigators to more deeply understand the complex biology that makes up a resilient response to medical treatments or procedures and their incumbent physical stress on the older adult. Indeed, why some older adults rebound when they experience such stressors—or are robust against insults in the first place, whereas others decline precipitously upon exposure to even mild challenges, remains largely unknown. Defining the basis of physical resilience remains one of the most complex challenges facing clinical investigators working to improve the health and safety of older adults. It is also potentially one of the most rewarding as it holds great promise for improving the health and well-being of older adults. Building on this need, and on our long-standing work to understand the biological basis of physical frailty, we have developed a conceptual framework for resiliency that hypothesizes a specific physiological underpinning, rooted in the dynamical interplay of stress-response systems. While we entertain that resiliency and frailty may entail dimensions that do not overlap, we have long hypothesized that physical or syndromic frailty is a disordered state of the same dynamical systems that produce resiliency when these same physiological systems are functioning in good order. Indeed, in our construct, frailty emerges as individual stress response systems or their networked connections erode past a functional threshold, while resiliency remains intact when the stress response systems remain functionally robust. Hence, in our view, robustness, resilience, and frailty are distinct but related and possibly overlapping concepts that tie back to homeostasis. Resiliency is a dynamic construct that can be best ascertained through “dynamic stimulation tests”. Indeed, this approach is also likely useful for identifying non-resilient persons before they encounter a major stressor as framed within a classical dynamical systems approach(1), as evidenced by a series of hallmark studies of physiological stimulation tests that were deployed in participants in the Women’s Health and Aging Studies (WHAS)(2–4). Building on this approach, we maintain that the capture of stimulated (dynamic) and unstimulated baseline measures from multiple physiological systems can be highly informative for ascertaining resiliency (5–8). Systems we have in mind include those that regulate glucose tolerance, hypothalamic pituitary adrenal (HPA) axis, autonomic nervous system, inflammatory response, and catecholamine production. This choice reflects our hypothesis that the stress response systems, represented on a measurable physiological level, lie at the center of physiological systems that either promote resilience when functioning optimally or drive frailty when functioning poorly. The dynamical systems framework by which we conceptualize the etiology of resiliency is in part informed by Csete and Doyle, who wrote that it “is in the nature of their robustness and complexity that biology and advanced engineering are most alike (9).” In engineering, robustness and resiliency are tied to a machine’s complexity, which confers flexibility by which to maintain functioning when faced with stressors. Hallmarks, and their analogy to human physiology, include: Modules - “sub-machines” or components which implement a part of the machine’s functioning. In humans, these could be cells, or organelles, or organs, or individual physiological systems. Robust health of each subcomponent tends to confer robust health of the machine as a whole. Protocols - rules by which processes governing functioning of modules and relationships between modules are managed. Even if all modules are intact, impaired protocols can lead to system failure. In the present context, protocols are the mechanisms by which physiological systems are internally regulated and co-regulated. Redundancy - well-designed complex systems have backup modules and protocols which can take over if primary modules or protocols become impaired. To implement a dynamical systems framework, we have designed research to collect measurements of physiological “modules” we hypothesize as central to resiliency and will use dynamic paradigms to assess the protocols by which they function and interact. Such a framework has clinical implications, as it might be able to distinguish whether resilience relies on the protection of key “modules” or instead on key “protocols” connecting systems to one other, or rather whether there are a multitude of ways to get to the endgame where resiliency is lost. Analysis will follow the approach proposed in Varadhan et al. (2008), where a stimulus-response modeling paradigm was detailed for deriving summary “parameters” of system functioning (1).