Implementation of the PFL in Clinical Practice

We introduced the concept of the physiological fitness landscape, which is a quantitative measure of the state of health or disease for each individual represented by a multi-dimensional topography. Each axis in this space of control parameters represents a potential stress factor that can be applied to the organism. For example, one such parameter can be nutritional intake (including non-food items and xenobiotics), another physical exertion and yet another the disturbances in circadian rhythmicity. On the other hand, an order parameter is a variable that the living system changes in response to the control parameters and whose value is a measure of health or disease. A classical example would be the maximum heart rate that correlates with the VO2 max in response to vigorous exercise, the latter being measured by speed of running or the maximum velocity attained on a stationary bike.

The rate of response of the order parameter, or its change, as a function of the control parameter is defined as generalized susceptibility. In measuring a healthy state, its response to stressors should be limited when the state is stable or robust. This is the premise for the proposition that the prototypical cardiac stress test be a model for analogous stress testing that assesses susceptibility states of other chronic diseases.

On the other hand, lack of susceptibility to therapeutic agents in the disease state is indicative of the therapy’s failure or the resistance to therapy by the disease, for example drug resistance in cancer. Conversely, normalizing the vital parameters (order parameters) in a dose-response manner with respect to an intervention is a manifestation of moving the disease state toward the state of health and hence a successful outcome of the therapy. Creating a detailed map of the physiological fitness landscape for each person is still a distant goal but it should be achieved in the coming decades. Navigating this map could lead to rationally-designed choices of a promising target for clinical intervention or indeed a time-dependent therapeutic plan, which is dynamically redesigned as therapy encounters resistance (low susceptibility) of the disease state to change.

Healthcare providers will play a vital role in their patient’s capacity to navigate the physiological fitness landscape by evaluating both psychogenic and physiologic factors that contribute to an individual’s state of “fitness” and how they will respond to stress during states of both health and disease. By incorporating a Physiological Fitness Landscape model of control and order parameters, both qualitative and quantitative assessments can be employed, the former for the immediate future; however, the latter requires a more scientifically integrated cultural shift in Medicine, thus dictating a longer term horizon. Adaptability and flexibility are paramount in navigating this topographic landscape of mountains and valleys to maintain a state of homeostasis and ultimately increase chances of survival. In this scenario, a valley represents the stable state of the system as it requires a minimal amount of free energy and is metabolically most efficient. The onset of a stressor would move the system out of equilibrium and metaphorically drive one to a less stable state, here represented as a mountain, that requires an increase in free energy as it is more metabolically demanding. Due to the unstable nature of the mountaintop, we will inevitably fall from it. If the stressor is removed, we may fall back into the original valley we came from, thus regaining stability and allostasis. However, if we have been pushed to the very peak, we may slide down into an alternate valley on the other side of the mountain, which represents a different physiological state resulting from allostatic overload (or a progressively more pathological state from more severe levels of perturbations in the parameters of allostatic overload, as the altitude of the valley diminishes within the topographic terrain). The fear of falling into such unknown valleys supports the development of psychogenic disturbances such as anxiety and depression. However, change is inescapable and a hallmark of the physiological fitness landscape itself. Our exquisite ability to adapt and respond flexibly to change is a strategy we must utilize to maintain allostasis and develop resilience.

Similar to these psychological factors in the way we navigate the Physiological Fitness Landscape is our innate physiological reaction to the stress response, which recruits the action of hormones, triggers autonomic arousal, and engages immune system function to protect the body and retain a position of equilibrium in the form of homeostasis. This is the biological underpinning of allostasis. However, in order to maintain these homeostatic parameters, we must exercise our capabilities to be flexible in response to stress in order to foster resilience to future psychological or physiological hardships. In other words, we need to experience both the lows of the valleys and the highs of the mountaintops in order to develop protection from future shifts in this metabolic landscape.

Uncharted valleys represent challenges to which we might lack the robustness to withstand. However, they are psychologically motivated to a fuller and richer life by searching for ways to adapt, that is building resilience via flexibility. Flexibility is achieved by finding resources, in the form of lifestyle habits, kinder personalities and larger personal networks that nurture the progression towards heterogeneity. That is, our current traits can adapt within ourselves and as a group with others to become part of a larger and greater system whole. This allows us to rise above challenges via flexibility when initial robustness is unsuccessful and is penetrated. Inviting challenges to enrich the heterogeneity of life is the crucial ingredient to vitalizing stress that motivates finding new paths to fulfilling joy or resilience to toxic stress.

The physiological fitness landscape is a dynamic and powerful system, which stress ultimately has the unique ability to disrupt and fracture. It requires delicate orchestration of psychological and biological factors that intersect to provide us with the skills necessary to maneuver through this continually changing environment of peaks and valleys in efforts to increase chances of survival.

The concept of physiological fitness landscape is borrowed from physics, a comparatively far more mature scientific discipline than biology, in order to better understand biological systems. This is especially useful in the context of medicine, where these insights may have the greatest impact on human life. Implications of this concept for medicine have a Nobel Prize worthy potential and its applicability to physiology has already been demonstrated. The compartmentalization of scientific disciplines, particularly clinical medicine from the branches of physics, should be recognized as a pathological isolation. Moreover, it should be described as an extraordinary and even tragic oversight that this model has not yet been invoked into the standards of clinical medicine. By honing in on various aspects of the stress response in the context of the metaphorical physiological fitness landscape, metabolic susceptibility states for disease can be identified as the control and order parameters for phase transitions from a healthy to a disease state. Further, the trajectory to chronic disease may be predicted on the basis of mathematical models of these parameters and their attractors. This has profound implications for both diagnostic and therapeutic purposes. Points of criticality may represent the threshold for phase transition from normal to the disease state and predictions can be made regarding this transition’s reversibility or irreversibility, which would be of enormous clinical value (cite figure here).

Thus, the model of physiological fitness landscape can serve as a critical tool and strategy to the development of therapeutic interventions capable of targeting control parameters and changing the trajectory of order parameters from reversible stages of disease or susceptibility states to normal states. Additionally, the neuroendocrine system, and the brain as the principle organ of allostasis along with the primary and secondary mediators of allostasis deserve center stage attention for the implementation of the model of physiological fitness landscape in medicine.

In the next section we discuss one such set of important concepts that is related to maintaining equilibrium under external perturbations and adapting to such perturbing forces that are always associated with being alive. However, these forces, which can be in general referred to as stress, can lead to responses that are maintaining robustness of the biological systems, sometimes even improving the state of health, but unfortunately in many cases the opposite is true. Chronic stress that is not properly handled may lead to addictions, mental disorders, psychopathologies and untimely demise. What is the measure of stress? What is the effect of stress on the human body, or stress response? When is the response healthy and when is it pathological? How do our bodies try to maintain metabolic and physiological equilibrium and when do they fail to do so? Finally, how can we best achieve prolonged state of optimal health facing both modern day’s stresses and our own inevitable aging processes?