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

Abstract

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.

Keywords: C. elegans; energy metabolism; lifespan; mitochondria; mitochondrial fusion.

Figure 1.

The Energy Maintenance Theory of Aging (EMTA). Energy levels in animals broadly decrease during aging. Mechanisms that extend lifespan utilize different pathways to increase or maintain energy generation. In C. elegans, diverse longevity pathways increase mitochondrial fusion, as elongated mitochondria are more efficient at ATP synthesis than fragmented mitochondria. Mitophagy allows more efficient energy metabolism by removing damaged mitochondria. Mild uncoupling reduces ROS generation to allow increased rates of energy metabolism without excessive levels of damaging ROS. Caloric restriction promotes increased energy levels by increasing mitophagy, mitochondrial fusion, and increased expression of genes for glycolysis and other energy metabolism pathways. Mitochondrial biogenesis allows the generation of healthy mitochondria to promote energy metabolism. Inactivation of VHL (potentially through mild hypoxic conditions), increases the levels of HIF1A, which upregulates the expression of genes required for energy generation via glycolysis. The maintenance of energy generation in older animals allows energy-dependent repair and homeostatic mechanisms that reduce damage associated with cellular aging to increase lifespan. All of these pathways may not operate in every animal species. See text for details.