Sex Differences in the Relation Between Frailty and Endothelial Function in Old Mice

Abstract

Frailty is an accumulation of deficits that stem from impairments in multiple organ systems, potentially including the vasculature. Older women typically have higher frailty scores than older men, but it is unknown if there are sex differences in the relation of frailty to physiological function. Endothelial function declines with age on average, but there is a high variability in the amount of decline. Thus, we sought to determine sex differences in the relation of frailty to endothelial dysfunction among old mice. In young male (n= 24, 8.5±0.27 mo), young female (n=20, 4.9±0.01 mo), old male (n=32, 28±0.56 mo) and old female (n= 17, 25.8±0.47 mo) C57BL/6 mice, we evaluated frailty by a 31-item frailty index (FI) based on established signs of deterioration. We assessed endothelial function by endothelium-dependent dilation (EDD, maximal response to acetylcholine) ex vivo in isolated, pressurized mesentery arteries and middle cerebral arteries (MCAs). We also assessed EDD after incubation with the superoxide scavenger TEMPOL and endothelium-independent dilation (EID, maximal response to sodium nitroprusside). We quantified gene expression for pro-inflammatory interleukin-1β (Il1b), pro-oxidant NADPH oxidase 2 (Nox2), and antioxidants superoxide dismutases (Sod1, Sod2, and Sod3) in mesentery arteries. Old mice had a greater FI compared with young mice (old: 5.53±2.3, young: 1.01±0.67, p=0.003), but FI did not differ between old male and female mice (p=0.41). When specific FI components were examined, old female mice had higher scores for alopecia, rectal prolapse, and cataracts but lower scores for vaginal/penile prolapse and grimace scale compared with old male mice (p<0.05). Old mice had a 25% impairment in MCA EDD and 16% impairment in mesentery artery EDD compared with young mice (p<0.05). While EDD did not differ between arteries from old male and female mice (p>0.05), there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female (r=-0.49, p=0.02), but not old male mice (r=0.15, p=0.24). In contrast, for the mesentery artery, FI was inversely related to EDD among old males (r=-0.42, p=0.01), but not old female mice (r=0.37, p=0.07). EID did not differ with sex or age group (p>0.05). A higher FI was related to a greater improvement in EDD with TEMPOL in the MCA in only old female mice and in the mesentery arteries in only old male mice (p<0.05). In mesentery arteries from old compared with young mice, gene expression was 42% higher for Il1b, 34% lower for Sod2 and 54% lower for Sod3 (p<0.05), but not different between ages for Sod1 or Nox2 (p>0.05). Among old mice, Il1b expression was23% higher in mesenteries from old male compared with female mice (p=0.001), but sex differences were not present for the other genes (p>0.05). In summary, we found no sex differences for composite FI scores or endothelial impairment among old mice. However, there are sex differences in the individual components of FI and in the relations of frailty to endothelial function, and these may be mediated by sex differences in arterial oxidative stress and pro-inflammatory signaling.