A multitude of evidence suggests that metabolism is
A multitude of evidence suggests that metabolism is altered with age. In liver as well as in muscle tissue from old mice, glycolysis has been reported to be increased . Additionally, aging murine hearts exhibit an increase in proteins involved in glycolysis and oxidative stress-response [156,157]. Interestingly, glycolysis also increases in some animal models of heart failure , and augmented myocardial consumption of glucose has been reported in patients with idiopathic dilated cardiomyopathy . These results are in line with a reduction in oxygen utilization and ATP synthesis in aging rat ventricles . In flies, a decrease in ATP levels and in NADH/NAD+ and GSH/(GSH+GSSG) ratios was also found in muscle tissues, supporting a bioenergetic decline with age . However, it is well documented that transcription of genes related to glycolysis declines with age in Drosophila heart and muscle tissues [15,24,161]. Furthermore, Ma et al. provided metabolomic data from fly heads supporting a reduction in glycolysis . While the mechanistic underpinnings of energetic decline between certain animal models and discrete tissues might differ, it is possible that they converge and impact analogous downstream effectors. For instance, flies heterozygous for different subunits of the Polycomb Repressive Complex 2 (Pcl; Su(z)12), which are long-lived, have elevated ATP and cellular redox levels . Therefore, metabolomic studies on young vs. old fly hearts would be crucial to determine the conservation of mechanisms underlying the cardiac energetic imbalance that occurs with age. The strong connection between age- and obesity-related disorders implies that they may be controlled by similar or intersecting pathways. Accumulating evidence suggests that caloric restriction (CR) can increase longevity in yeast, worms, Ezatiostat structure flies, rats, and mice . Conversely, humans who are overweight or obese have a higher risk of mortality . This seems to be corroborated by experiments in which flies fed a HFD experienced severely shortened lifespans [144,164]. The nutrient sensor target of Rapamycin (TOR) is believed to be a key component in mediating the CR-induced increase in lifespan . TOR activation stimulates cell growth, increases lipid and protein synthesis (anabolism), and decreases autophagy (catabolism) . The TOR pathway is activated by insulin, insulin-like growth factors, and amino acids and inhibited in response to stress, such as energy depletion and caloric restriction. Thus, this pathway plays an essential role in orchestrating metabolic homeostasis. While complete depletion of TOR induced heart failure in mice , mild reduction may be cardioprotective . For example, mTORC1 inhibition attenuated load-induced cardiac hypertrophy  and reduced infarct size after ischemia by restoring cardiac autophagy in obese mice . These effects were proposed to be partially mediated by autophagy-induced removal of misfolded proteins and dysfunctional mitochondria. In flies, there is robust evidence indicating that HFD induces lipotoxic cardiomyopathy by activating the TOR pathway [30,31]. For instance, hypomorphic TOR mutant flies did not develop lipotoxic cardiomyopathy when fed HFD, since they have constitutively increased transcript levels of the adipose triglyceride lipase, ATGL (brummer in Drosophila), which prevented the flies from accumulating triglycerides . Additionally, heart-specific inhibition of TOR activity by overexpressing the downstream effector d4EBP also prevented the deleterious effects of HFD on heart function . Upon stress, cells accumulate Sestrins, a family of evolutionarily conserved antioxidant proteins, resulting in AMPK-dependent inhibition of TOR signaling. dSesn null flies displayed accumulation of triglycerides accompanying cardiac dysfunction, which could be rescued by inhibiting the TOR pathway with Rapamycin . Overall, these studies suggest that partial inhibition of TOR can improve metabolic balance by reducing triglyceride accumulation and, therefore, prevent the deleterious effects of HFD on heart performance. Conversely, TOR hypomorphs showed reduced physical activity levels, as assessed by a negative geotaxis assay , implying that each tissue may have a specific energy balance requirement. Therefore, different TOR activity levels might be required to counteract the deleterious effects of metabolic imbalance induced by obesity, stress, or aging, each posing a threat to healthy heart function.