Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment

Frailty in older adults, defined as a constellation of signs and symptoms, is associated with abnormal levels in individual physiological systems. We tested the hypothesis that it is the critical mass of physiological systems abnormal that is associated with frailty, over and above the status of each individual system, and that the relationship is nonlinear. Using data on women aged 70-79 years from the Women's Health and Aging Studies I and II, multiple analytic approaches assessed the cross-sectional association of frailty with eight physiological measures. Abnormality in each system (anemia, inflammation, insulin-like growth factor-1, dehydroepiandrosterone-sulfate, hemoglobin A1c, micronutrients, adiposity, and fine motor speed) was significantly associated with frailty status. However, adjusting for the level of each system measure, the mean number of systems impaired significantly and nonlinearly predicted frailty. Those with three or more systems impaired were most likely to be frail, with odds of frailty increasing with number of systems at abnormal level, from odds ratios (ORs) of 4.8 to 11 to 26 for those with one to two, three to four, and five or more systems abnormal (p < .05 for all). Finally, two subgroups were identified, one with isolated or no systems abnormal and a second (in 30%) with multiple systems abnormal. The latter group was independently associated with being frail (OR = 2.6, p < .05), adjusting for confounders and chronic diseases and then controlling for individual systems. Overall, these findings indicate that the likelihood of frailty increases nonlinearly in relationship to the number of physiological systems abnormal, and the number of abnormal systems is more predictive than the individual abnormal system. These findings support theories that aggregate loss of complexity, with aging, in physiological systems is an important cause of frailty. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes. It further suggests that replacement of any one deficient system may not be sufficient to prevent or ameliorate frailty.