Where Metabolism Meets Senescence: Focus on Endothelial Cells

Abstract

Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

“…These latter findings also were consistent with impairments in hepatic fatty acid oxidation and glucose intolerance that have been described in the aging liver [1,30]. Taken together, our findings showed that the senescent AML12 cells showed many of the key changes that cause altered metabolism and mitochondrial function in the aging liver [1,8,27,28,30].…”

“…However, the reciprocal actions of AMP and MTOR in maintaining metabolic homeostatic becomes impaired during senescence, and leads to concurrent activation of both MTOR and AMPK. This dysregulation also is found in the aging liver [1,27,28]. In this connection, we found that AMPK and MTOR both were activated in senescent AML12 cells (Figure 5), suggesting that energy sensing had become dysregulated as evident by impaired oxidative phosphorylation (Figure 4a,b) and compensatory increase in glycolysis (Figure 3c,d).…”

“…consisting of marked increases in glycolysis, mitochondrial activity, and mitochondrial damage due to proton leakage [8,27,28]. After AML12 cells were given multiple sublethal H2O2 doses, we found they increased their cellular bioenergetics (Figure 3a,b) and showed greater reliance upon glycolysis under nutrient stress conditions.…”

“…Senescent cells secrete senescence-associated secretory proteins (SASP) such as IL6 and IL1b, and are thought to be responsible for creating a pro-inflammatory environment to neighbouring cells during aging-associated diseases [1,26,27]. We found that senescent AML12 cells showed higher expression of pro-inflammatory genes IL1b and IL6 (Figure 6a).…”

“…Senescent cells also had increased mitochondrial activity compared to control cells. However, this increased activity did not lead to more ATP production due to concomitant increases in basal uncoupling and proton leakage, which are hallmarks of senescent cells [1,25,27,29]. These findings thus explains the reason why there is increased AMP:ATP ratio leading to the AMPK activation often found in senescent cells [1,27,29].…”