Maladaptive Changes Associated With Cardiac Aging Are Sex-Specific and Graded by Frailty and Inflammation in C57BL/6 Mice

Abstract

We investigated whether late-life changes in cardiac structure and function were related to high levels of frailty and inflammation in male and female mice. Frailty (frailty index), ventricular structure/function (echocardiography) and serum cytokines (multiplex immunoassay) were measured in 16 and 23-month-old mice. Left ventricular (LV) mass and septal wall thickness increased with age in both sexes. Ejection fraction increased with age in males (60.4±1.4 vs 68.9±1.8%; p<0.05) but not females (58.8±2.5 vs 62.6±2.4%). E/A ratios declined with age in males (1.6±0.1 vs 1.3±0.1; p<0.05) but not females (1.4±0.1 vs 1.3±0.1) and this was accompanied by increased ventricular collagen levels in males. These changes in ejection fraction (r=0.52; p=0.01), septal wall thickness (r=0.59; p=0.002), E/A ratios (r=-0.49; p=0.04) and fibrosis (r=0.82; p=0.002) were closely graded by frailty scores in males. Only septal wall thickness and LV mass increased with frailty in females. Serum cytokines changed modestly with age in both sexes. Nonetheless, in males, E/A ratios, LV mass, LV posterior wall thickness and septal wall thickness increased as serum cytokines increased (e.g. IL-6, IL-3, IL-1α IL-1ß, TNF-α, eotaxin and MIP-1α), while ejection fraction declined with increasing IL-3 and GM-CSF. Cardiac outcomes were not correlated with inflammatory cytokines in females. Thus, changes in cardiac structure and function in late life are closely graded by both frailty and markers of inflammation, but this occurs primarily in males. This suggests poor overall health and inflammation drive maladaptive changes in older male hearts, while older females may be resistant to these adverse effects of frailty

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage

“…Recently, a study revealed increased mass and collagen level of the left ventricle, as well as the thickness of the septal wall in aged mice, associated with increased expressions of IL-1α, IL-6 and TNFα, suggesting that cardiac structural and functional changes with age are closely graded with frailty and inflammation markers [ 52 ]. NLRP3 inflammasome-related inflammaging has been activated with age in most body tissues and organs including heart [ 15 , 16 ].…”

“…The induction of fibrosis and IL-1α and IL-6 inflammatory cytokines genes observed here were less remarkable in the NLRP3 −/− mice. Recently, interstitial and perivascular cardiac fibrosis was described in aged WT mice, with non-significant changes in aged NLRP3 −/− ones, where increased IL-6 serum and protein levels in the cardiac tissues of old WT and NLRP3 −/− mice were observed [ 48 ], and thus, the reduction of collagenous tissue infiltrations in the aged myocardium of NLRP3 −/− mice assured the attenuation of fibrosis upon NLRP3 depletion [ 52 ].…”

“…The age-dependent decline of autophagy in the heart [ 61 ] enhances impairments in cellular housekeeping functions that induce NF-κB signaling, which either directly or through inflammasomes stimulates age-related pro-inflammatory events [ 62 ]. Moreover, aging diminishes the autophagic/mitophagic capacity and thus leads to an accumulation of reactive oxygen species, which triggers the activation of NLRP3 inflammasome and induces inflammation in various tissues [ 52 , 62 ], while absence of NLRP3 improves mitochondrial dysfunction. Therefore, our results revealed reduction of autophagosome numbers and size in aged cardiac muscles of NLRP3 −/− mice, confirming the beneficial effect of NLRP3 inhibition in improvement of autophagy quality during cardiac aging, where NLRP3 inflammasome deletion protected mice against age-dependent induction of insulin sensitivity, avoiding a wide variety of age-associated cardiac changes, preserving cardiac functions of aged animals, and consequently, prolonging lifespan [ 58 ].…”

Cardiac response to adrenergic stress differs by sex and across the lifespan

“…While inclusion of three age groups is novel and advances current literature which at most compares two, we would benefit from additional age groups-i.e., middle aged, as some studies suggest that cardiac function begins to change at around 12 months-both because of aging per se and between sexes [26]. Sex differences in age-related declines in cardiac function have been previously reported [48], with worse systolic function in male compared to female mice [49], suggesting a lifecourse comparison in males and females is warranted. The higher heterogeneity in female mice is significant and warrants discussion.…”

IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH

“…Mice were randomized by body weight and assigned to CON diet-fed group (n = 10) or CDAA diet fed group (n = 10) and were treated with anti-IL-1β Mab (n = 9) or isotype control (n = 10) for 8 weeks. Older male mice were used, due to their susceptibility to frailty and chronic inflammation-driven cardiac function decline 74 . The animals were treated two times per week with a dose of 50 µg/mouse 75 .…”