“Physiological Dysregulation” as a Promising Measure of Robustness and Resilience in Studies of Aging and a New Indicator of Preclinical Disease

Abstract

Recently suggested novel implementation of the statistical distance measure (DM) for evaluating "physiological dysregulation" (PD) in aging individuals (based on measuring deviations of multiple biomarkers from baseline/normal physiological states) allows reducing high-dimensional biomarker space into a single PD estimate. Here we constructed DM using biomarker profiles from FRAMCOHORT (Framingham Heart Study) and CHS (Cardiovascular Health Study) Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center, and estimated effect of PD on total survival, onset of unhealthy life (proxy for "robustness") and survival following the onset of unhealthy life (proxy for "resilience"). We investigated relationships between PD and declines in stress resistance and adaptive capacity not directly observed in data. PD was more strongly associated with the onset of unhealthy life than with survival after disease suggesting that declines in robustness and resilience with age may have overlapping as well as distinct mechanisms. We conclude that multiple deviations of physiological markers from their normal states (reflected in higher PD) may contribute to increased vulnerability to many diseases and precede their clinical manifestation. This supports potential use of PD in health care as a preclinical indicator of transition from healthy to unhealthy state.

Composite Measure of Physiological Dysregulation as a Predictor of Mortality: The Long Life Family Study

“…In this paper, we confirmed that the composite measure of physiological dysregulation (D M ) is associated with mortality in LLFS (with larger D M associated with increased mortality risk), similar to other studies (2,7,9,12). We showed also that addition of D M significantly improves mortality predictions compared to the reference model (containing age, sex, and other relevant covariates) in the total LLFS sample.…”

“…As other studies showed, D M is associated not only with mortality but also with other health and aging related outcomes (7,9,11,32). In particular, as discussed in our recent study (7), D M can be a promising indicator of declining robustness and resilience during aging, and may precede clinical manifestation of not just one but many diseases even in the absence of strong clinical diagnostic markers pointing out to a specific pathology. Given that, D M could be an especially useful predictor of mortality among the elderly without major chronic diseases.…”

“…There are additional opportunities for improving the power of such studies if appropriate methods are used (31). As other studies showed, D M is associated not only with mortality but also with other health and aging related outcomes (7,9,11,32). In particular, as discussed in our recent study (7), D M can be a promising indicator of declining robustness and resilience during aging, and may precede clinical manifestation of not just one but many diseases even in the absence of strong clinical diagnostic markers pointing out to a specific pathology.…”

“…First, we considered different sets of biomarkers in computations of D M . We added the biomarkers used in our previous applications of D M in the Framingham Heart Study (7,12) to the list of the original 19 biomarkers from Sebastiani et al (19). We also created D M variants focusing on the subsets of biomarkers with absolute values of correlations with age exceeding specific thresholds (0.05, 0.1, 0.15, 0.2) and removing highly correlated biomarkers (one of a pair of biomarkers with absolute value of correlation between the biomarkers exceeding 0.8).…”

“…Recently, the statistical (Mahalanobis) distance (denoted as D M ) constructed for the joint distribution of multiple biomarkers was suggested as a composite measure that can represent the level of physiological dysregulation in an organism (2) and aging-related declines in robustness and resilience (7). This measure was associated with mortality and agingrelated outcomes in numerous studies [see e.g., (2,(7)(8)(9)(10)(11)(12)]. In this paper, we constructed D M using measurements of multiple biomarkers collected at the baseline visit of the Long Life Family Study (LLFS) to test if the level of PD is associated with mortality in this study, and whether it improves mortality predictions compared to the models with age and common individual risk factors.…”