Comparing the New and Existing Hypotheses on Energy Metabolism and Longevity

Abstract

In this issue of BioEssays, Chaudhari and Kipreos hypothesize that mitochondrial fusion promotes survival, especially in old animals, through the mechanism of maintaining energy metabolism. [1] Along with the substantial evidence from their own work on C. elegans and studies on other model animals, the logic of the authors' argument is clear: first, aging is closely associated with the mitochondria's well-being; second, nine of ten lifespan extension pathways in C. elegans are associated with elongation of mitochondria via fusion, and elongated mitochondria are more efficient in producing ATP. Interestingly, the 10th pathway upregulates alternate energy generating pathways; third, maintaining ATP levels and energy metabolism supports longevity.Practitioners in the relevant fields may have three questions about this hypothesis. Chaudhari and Kipreos well address them in the paper.First, the hypothesis suggests a positive correlation between enhanced energy metabolism and lifespan extension, which is seemingly opposite to the long-standing observation of the negative correlation between energy metabolism and lifespan. Across species, the animals with high mass-specific energy consumption live shorter. Many researchers believe that high energy production may lead to higher reactive oxygen species (ROS) production, which causes oxidative stress and shortens lifespan. Also, caloric restriction (CR) extends lifespan, but does not lower energy consumption greatly.As cited in Chaudhari and Kipreos, the results from Hou et al. [2,3] have suggested that cellular damage is insensitive to the change in total energy consumption. It is the energy allocation to damage repair (or maintenance in general) that largely influences the damage level and aging rate. In the case of CR, while it negligibly alters animals' metabolic rate, CR channels more energy to maintenance through suppressing biosynthesis. [3] Along this line, Chaudhari and Kipreos further elaborated on how energy allocated to maintenance would allow the cell to maintain repair and homeostatic mechanisms, such as proteostasis and mitochondrial biogenesis.Second, in the last two decades, the importance of mitochondrial proton leak (uncoupling) in cellular damage and aging has been highlighted by multiple researchers, e.g., Ref. [4]. At the first glance, the "uncoupling to survive hypothesis" may conflict with Chaudhari and Kipreos' hypothesis, because uncoupling causes a decrease in ATP production, but fusion increases ATP production.Analyzing the data from mice, [4] as well as the data from human cells in culture and yeast, Chaudhari and Kipreos give convincing argument that mild uncoupling, which extends lifespan, is correlated with greater mitochondrial respiration and higher ATP levels. They conclude that "the linkage between uncoupling and lifespan/healthspan is in the context of increased metabolic intensity." Thus, these two hypotheses are compatible.Third, Barja has championed the idea that the mitochondrial ROS production is the key to understanding how empiri...

Metabolic Regulation Effect and Potential Metabolic Biomarkers of Pre-Treated Delphinidin on Oxidative Damage Induced by Paraquat in A549 Cells

“…The PQ and Del treatments did not completely interrupt the energy supply process but rather replenished it via the glycolytic pathway to resist oxidative stress. The disturbance in the TCA cycle and pentose phosphate pathway induced by PQ led to a reduction in mitochondrial ATP synthesis, affecting energy generation [ 59 , 60 , 61 ]. However, the PQ treatment had no significant effect on glycometabolism, whereas the Del pretreatment upregulated or downregulated the abundance of several metabolites such as fructose, lactulose, and glucose.…”