Men Sustain Higher Dysregulation Levels Than Women Without Becoming Frail

Abstract

The aging process differs in important ways between the sexes, with women living longer but at higher risk for frailty (the male-female health-survival paradox). The underlying biological mechanisms remain poorly understood, but may relate to sex differences in physiological dysregulation patterns. Here, using biomarkers from two longitudinal cohort studies (InCHIANTI and BLSA) and one cross-sectional survey (NHANES), we assess sex differences in trajectories of dysregulation globally and for five physiological systems: oxygen transport, electrolytes, hematopoiesis, lipids, and liver/kidney function. We found higher dysregulation levels in men, both globally and in the oxygen transport and hematopoietic systems (p < .001 for all), though differences for other systems were mixed (electrolytes) or absent (lipids and liver/kidney). There was no clear evidence for sex differences in rates of change in dysregulation with age. Although risk of frailty and mortality increase with dysregulation, there was no evidence for differences in these effects between sexes. These findings imply that the greater susceptibility of women to frailty is not simply due to a tolerance for higher dysregulation; rather, it may actually be men that have a greater tolerance for dysregulation, creating a male-female dysregulation-frailty paradox. However, the precise physiological mechanisms underlying the sex differences appear to be diffuse and hard to pin down.

Keywords: Biomarker; Dysregulation trajectory; Homeostasis; Physiological systems; Statistical distance.

Figure 1.

Unadjusted D_M levels by sex, globally and by physiological system. Mean D_M levels were calculated using all individuals (black; n = 13,909), or stratifying by data set: InCHIANTI (blue; n = 1,147), BLSA (red; n = 1,024), and NHANES (green; n = 11,738). For longitudinal cohorts, we used the mean of all available D_M. Analyses were repeated using all individuals (n ranging from 993 to 13,830 depending on data sets included and physiological systems analyzed), or stratifying by age at first visit: “young”, individuals between 55 and 74 years old (n ranging from 686 to 9,518), and “old”, individuals aged 75 and over (n ranging from 401 to 4,823). Variance explained by age, sex, and data set were calculated with an ANOVA.

Figure 2.

D _M rates by sex, globally and by physiological system. D_M longitudinal changes (slopes) were calculated using all available subjects (black, n = 2,171), or stratifying by data set: InCHIANTI (blue; n = 1,147) and BLSA (red; n = 1,024). Analyses were repeated using all individuals (n ranging from 993 to 2,169 depending on data sets included and physiological systems analyzed), or stratifying by age at first visit: “young”, individuals between 55 and 74 years old (n ranging from 686 to 1,412), and “old”, individuals aged 75 and over (n ranging from 401 to 1,269).

Figure 3.

The male–female dysregulation-frailty paradox. Men have higher dysregulation levels than women, but despite this women are more frail. This parallels the male–female health-survival paradox, where women are more frail but despite this men are more susceptible to mortality.