Kelly Reihl

The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction

Dysfunction in the adipose tissue, characterized by reduced adipocyte size, tissue fibrosis and ectopic lipid accumulation, has been implicated in age‐associated metabolic dysfunction, but it is not known how ageing affects the function of the arteries and mitochondria within the adipose tissue. Mitochondrial lipid utilization is impaired in adipose tissue of old mice, evidenced by reduced substrate control ratios in the presence of lipid substrates and is concomitant with increased oxidative stress. Ageing leads to endothelial dysfunction, evidenced by reduced endothelium‐dependent dilation in resistance arteries, reduced angiogenic capacity and reduced vascularity of the adipose tissue. These results indicate that arterial and mitochondrial dysfunction accompany age‐associated adipose tissue and systemic metabolic dysfunction and suggest that targeting arterial or mitochondrial function to improve adipose tissue function may have important application in the treatment of age‐associated metabolic dysfunction.

Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness.

Increased large artery stiffness is a hallmark of arterial dysfunction with advancing age and is also present in other disease conditions such as diabetes. Increased large artery stiffness is correlated with resistance artery dysfunction in humans. Using a mouse model of altered arterial elastin content, this is the first study to examine the cause‐and‐effect relationship between large artery stiffness and peripheral resistance artery function. Our results indicate that mice with genetically greater large artery stiffness have impaired cerebral artery endothelial function, but generally preserved skeletal muscle feed artery endothelial function. The mechanisms for impaired cerebral artery endothelial function are reduced nitric oxide bioavailability and increased oxidative stress. These findings suggest that interventions that target large artery stiffness may be important to reduce disease risk associated with cerebral artery dysfunction in conditions such as advancing age.

Dichotomous mechanisms of aortic stiffening in high‐fat diet fed young and old B6D2F1 mice

Advancing age is associated with increased stiffness of large elastic arteries as assessed by aortic pulse wave velocity (PWV). Greater PWV, associated with increased risk of cardiovascular diseases, may result from altered expression of the extracellular matrix proteins, collagen and elastin, as well as cross‐linking of proteins by advanced glycation end products (AGEs). Indeed, aortic PWV is greater in old (28–31 months) normal chow (NC, 16% fat by kcal)‐fed male B6D2F1 mice compared with young (Y: 5–7 months) NC‐fed mice (397 ± 8 vs. 324 ± 14 cm/s, P < 0.05). Aging also induces a ~120% increase in total aortic collagen content assessed by picosirius red stain, a ~40% reduction in medial elastin assessed by Verhoeffs Van Geison stain, as well as a 90% greater abundance of AGEs in the aorta (P < 0.05). The typical American diet contains high dietary fat and may contribute to the etiology of arterial stiffening. To that end, we hypothesized that the age‐associated detriments in arterial stiffening are exacerbated in the face of high dietary fat. In young animals, high‐fat (40% fat by kcal) diet increases aortic stiffness by 120 ± 18 cm/s relative to age‐matched NC‐fed mice (P < 0.001). High‐fat was without effect on aortic collagen or AGEs content in young animals; however, elastin was greatly reduced (~30%) after high‐fat in young mice. In old animals, high‐fat increased aortic stiffness by 108 ± 47 cm/s but was without effect on total collagen content, medial elastin, or AGEs. These data demonstrate that both aging and high‐fat diet increase aortic stiffness, and although a reduction in medial elastin may underlie increased stiffness in young mice, stiffening of the aorta in old mice after high‐fat diet does not appear to result from a similar structural modification.