On the complex relationship between energy expenditure and longevity: Reconciling the contradictory empirical results with a simple theoretical model

Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long-lived C. elegans vhl-1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. elegans by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy-intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals.

Section: An Emerging Paradigm: the Energy Maintenance Theory Of Agingmentioning

confidence: 99%

Section: Compatibility Of the Emta With Other Theories Of Agingmentioning

confidence: 99%

The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity

Chaudhari

Kipreos

2018

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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. 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. 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.

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mentioning

confidence: 94%

“…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.…”

mentioning

confidence: 94%

“…[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. [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. Chaudhari and Kipreos well address them in the paper.…”

mentioning

confidence: 99%

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Comparing the New and Existing Hypotheses on Energy Metabolism and Longevity

Hou

2018

Self Cite

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...

Is mitochondrial reactive oxygen species production proportional to oxygen consumption? A theoretical consideration

Hou

Metcalfe

Salin³

2021

Self Cite

It has been assumed that at the whole organismal level, the mitochondrial reactive oxygen species (ROS) production is proportional to the oxygen consumption. Recently, a number of researchers have challenged this assumption, based on the observation that the ROS production per unit oxygen consumed in the resting state of mitochondrial respiration is much higher than that in the active state. Here, we develop a simple model to investigate the validity of the assumption and the challenge of it. The model highlights the significance of the time budget that mitochondria operate in the different respiration states. The model suggests that under three physiologically possible conditions, the difference in ROS production per unit oxygen consumed between the respiration states does not upset the proportionality between the whole animal ROS production and oxygen consumption. The model also shows that mitochondrial uncoupling generally enhances the proportionality.