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

Abstract

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.

Homeostatic dysregulation proceeds in parallel in multiple physiological systems

“…While numerous authors have discussed the possibility of multi‐system dysregulation (Crimmins et al ., 2003; Ferrucci, 2005; Seplaki et al ., 2005; Varadhan et al ., 2008; Fried et al ., 2009; Arbeev et al ., 2011; Maggio et al ., 2014), empirical studies have been sparse. Lipsitz has demonstrated loss of complexity in cardiac rhythms and other aspects of physiology (Lipsitz, 2004), but the link to dysregulation is still unclear.…”

“…Research on aging biomarkers has traditionally focused on individual biomarkers; however, this has been changing as single‐mechanism explanations of aging such as oxidative stress, telomeres, and inflammation increasingly give way to multi‐factorial explanations, in which many mechanisms interact (Weinert & Timiras, 2003; Ferrucci, 2005; Fried et al ., 2009; Cohen et al ., 2013). In particular, much attention is focusing on physiological dysregulation (alternatively referred to as allostatic load or homeostenosis) (McEwen, 1998; Karlamangla et al ., 2002; Crimmins et al ., 2003).…”

“…Perhaps the best evidence to date has come from two key studies: Lipsitz (2004) has demonstrated that declines in complexity of traits like heart rate variability are linked to aging, and Fried et al . (2009) showed coordinated, non‐linear changes with age in biomarkers representing several physiological systems.…”

Dysregulated homeostatic pathways in sarcopenia among frail older adults

“…Circulating insulin (Barzilay et al, 2007; Cleasby, Jamieson, & Atherton, 2016), testosterone (Auyeung et al, 2011), insulin‐like growth factor‐1 (IGF‐1; Gielen et al, 2015), and dehydroepiandrosterone sulfate (DHEAS; Tajar et al (2011)) have been interrogated in a majority of studies mostly in isolation and with conflicting results. In contrast, several studies, such as the InCHIANTI Study, the WHAS I and II, and the MSSA (Fried et al, 2009; Gruenewald, Seeman, Karlamangla, & Sarkisian, 2009; Maggio et al, 2010), have found that an increased number of multiple hormonal biomarker abnormalities strongly predict physical frailty when individual biomarker abnormalities did not. Determining the effect of a single physiological derangement in sarcopenia is complicated by the effects of intermediary changes in the complex network of physiological pathways that are deranged in sarcopenia.…”

“…Also, the results tend to be inconsistent for individual biomarkers, whereas the number of biomarker impairments across multiple physiological systems strongly predicted physical frailty (Fried et al, 2009; Gruenewald et al, 2009). …”