Age-dependent cardiovascular effects of sepsis in a murine model of cecal ligation and puncture: implications for the design of interventional studies

Sepsis is more prevalent in the elderly population, with increased incidence and mortality occurring in patients aged 65 yr or older (Fig. 1) (6). Previous preclinical studies in murine models of cecal ligation and puncture-induced septic shock have demonstrated that aging significantly increases the severity of sepsis and exacerbates the development of multiple organ dysfunction syndrome (involving cardiovascular collapse) by multifaceted mechanisms, which include dysregulation of the innate immune response and adaptive immune response, excessive pulmonary and systemic inflammation, increased coagulation, proinflammatory alterations of the adipose tissue, gut apoptosis, and an age-related worsening of microvascular endothelial dysfunction and exacerbation of oxidative stress (1, 7–9).

Fig. 1.

Scheme depicting the interaction between aging and sepsis-induced cardiac injury. Aging increases susceptibility to sepsis and results in a decreased resilience to sepsis-induced cardiac pathologies promoting multiple organ failure and increased mortality. The study of Inata et al. (3) adds to the growing evidence that aging also negatively impacts the effectivity of therapeutic interventions, which often leads to treatment failure.

In an interesting study recently published in the American Journal of Physiology-Heart and Circulatory Physiology, using young (2–3 mo) and mature adult (11–13 mo) male mice, Inata et al. (3) investigated age-dependent myocardial injury and cardiac function in a model of sepsis induced by CLP and the potential contribution of AMP-activated protein kinase (AMPK) to these alterations. They found that 18 h after the onset of sepsis, mature adult male mice exhibited more severe cardiac damage with more inflammatory cell infiltration and intracellular edema as well as mitochondrial derangement compared with vehicle-treated young mice. In contrast, levels of troponin I and T as well as plasma proinflammatory cytokines and myokine follistatin were comparable in the two groups.

The field of geroscience, focusing on the interaction of aging processes and pathogenesis of diseases, has exploded in the past decade. This important study adds to the accumulating evidence that aging exacerbates cardiac pathologies associated with sepsis. Surprisingly, measurements of load-dependent indexes of myocardial function (ejection fraction and fractional shortening) by echocardiography revealed sepsis-induced left ventricular dysfunction only in young mice but not in mature adult mice (3). This paradox can be explained by differences in loading conditions in mature adult septic mice compared with young mice (e.g., differences in total peripheral resistance due to vasodilation or vasoconstriction of distinct vascular beds), which leads to an inability of load-dependent parameters of echo to accurately predict cardiac function under such conditions (4, 5). Additional studies using more sensitive methods (such as pressure-volume analysis) (5) enabling evaluation of load-independent indexes of cardiac function would be informative in that regard.

While investigating the molecular mechanisms of sepsis-induced cardiac dysfunction, the authors revealed that phosphorylation of the catalytic subunits (AMPK-α_1/2) of AMPK was associated with nuclear translocation of peroxisome proliferator-activated receptor-γ coactivator-α in vehicle-treated young mice only (3). Conversely, treatment with the AMPK activator 5-amino-4-imidazole carboxamide riboside attenuated the sepsis-induced systemic inflammatory response and cardiac dysfunction predominantly in young mice (3), suggesting an age-dependent regulation of AMPK-dependent metabolic pathways involved in cardioprotective mechanisms.

There is growing evidence demonstrating that cardiovascular comorbidities such as aging may interfere with cardiac protective mechanisms (2). An interesting outcome of translational studies on patients from diverse age groups as well as preclinical animal models of aging was the realization that in diverse diseases, many therapeutic interventions that are effective at younger ages fail to provide benefits later in life. Although the incidence of severe sepsis dramatically increases with age and older age is associated with increased mortality, a thorough analysis of the literature revealed that majority of basic research studies on sepsis has been conducted using only very young animals (6). This is a significant source of bias in preclinical studies as the biological effects of sepsis and the responsiveness to sepsis treatments, as also demonstrated by this interesting study, may be critically dependent on age. One should also note that aging may also alter the metabolism of certain cardioprotective drugs. Therefore, the results of Inata et al. (3) have also important implications for the design of interventional studies in the aging population with sepsis.

The ultimate goal of geroscience is to understand aging biology to improve health span, prevent disease, and reduce mortality. The general consequences of aging include an increase in frailty and an attendant decrease in resilience. As it is evident with the case of sepsis, aging both increases susceptibility to sepsis and results in a decreased ability to withstand the concomitant stress caused by the disease (Fig. 1). This age-related impairment in organismal and cellular resilience leads to multiple organ dysfunction and increased mortality in aging. The findings of Inata et al. will surely lead to followup mechanistic investigations to better understand the major molecular and cellular determinants of the cardiac aging process as it relates to the increased propensity for cardiovascular collapse and higher mortality in older adults. Subsequent investigations should also address why the cardiovascular system of a young organism recuperates easier after sepsis, whereas the same inflammatory challenge can become a chronically unsurmountable block for an older individual. Because there are also important sex differences in the incidence of sepsis, further studies should also focus on potential sex-dependent changes in both young and mature adult as well as in mice with advanced aging in sepsis-induced cardiac dysfunction.

GRANTS

P. Pacher is supported by the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health (NIH). G. Hasko is supported by NIH Grants R01-GM-066189 and R01-DK-113790.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

Z.I.U. and A.Y. prepared figures; Z.I.U., G.H., and P.P. drafted manuscript; Z.I.U., A.Y., G.H., and P.P. edited and revised manuscript; Z.I.U., A.Y., G.H., and P.P. approved final version of manuscript.