Frailty Disease: Physiologic Vulnerability and Homeostasis

There are several dominant theories as to the underlying causes of physiologic vulnerability
and compromised homeostasis of frailty. The causes can be related or in some circumstances are separated from each other.

Frailty aging comes from accumulation of potentially unrelated diseases, subclinical dysfunctions, and disability across organs, parts, and systems of the body. This approach has been posited by Rockwood and colleagues, who have operationalized this theory in terms of a summary of all potential deficits present in an individual (symptoms, signs, diseases, geriatric conditions, laboratory abnormalities, disabilities); a simple count of all such deficits assessed has been shown to predict mortality. This approach indicates that a summary measure of deficit accumulation across many different types of health conditions at many levels (functional, clinical, physiological) predicts risk of mortality. Inferentially, frailty is an intermediary, almost latent, construct that is the summary effect of all of these deficits on homeostatic reserves; the number of deficits leads to a dose–response relationship with mortality, presumably through this intermediary mechanism.

Frailty is a unique pathophysiological process: This theory posits that frailty can be characterized as a primary defect, which involves the diminution of physiologic function and, eventually, breakdown of homeostatic mechanisms. This could result from alterations in a range of basic biological mechanisms, which then lead to dysregulation of multiple physiologic systems. These systems are known to mutually affect each other, providing a rich network of homeostatic regulation and ability to compensate, to a degree, if any one system is impaired. This redundant network, with intact function within and between systems, underlies reserves and resiliency to stressors. Dysregulation of multiple systems with aging, and decreased effectiveness of interconnections could lead to depletion of reserves and compromised ability to maintain homeostasis in the face of stressors. Ultimately, this could lead to a negative spiral of declining function. Basic biological systems involved may well include those that maintain a stable production, distribution, and utilization of energy, while key physiologic systems include hormones, immune, inflammatory, and neurological processes. Decreased energy available would diffusely affect multiple physiological systems, leading to compromised function both within and between systems. Further, decreased availability of energy could underlie decline in physical function, especially in tasks requiring endurance. A similar scenario could occur as a result of other basic biological alterations with aging, such as shortened telomeres or excessive free radical damage. Alternatively, or additionally, frailty may result from a progressive loss of complexity in the function of individual physiologic systems and in their regulation of homeostatic responses, leading to both chronic overor underfunction.