Changing ROS, NAD and AMP: A path to longevity via mitochondrial therapeutics.

Abstract

Lifespan of many organisms, from unicellular yeast to extremely complex human organism, strongly depends on the genetic background and environmental factors. Being among most influential target energy metabolism is affected by macronutrients, their caloric values, and peculiarities of catabolism. Mitochondria are central organelles that respond for energy metabolism in eukaryotic cells. Mitochondria generate reactive oxygen species (ROS), which are lifespan modifying metabolites and a kind of biological clock. Oxidized nicotinamide adenine dinucleotide (NAD⁺) and adenosine monophosphate (AMP) are important metabolic intermediates and molecules that trigger or inhibit several signaling pathways involved in gene silencing, nutrient allocation, and cell regeneration and programmed death. A part of NAD⁺ and AMP metabolism is tied to mitochondria. Using substances that able to target mitochondria, as well as allotopic expression of specific enzymes, are envisioned to be innovative approaches to prolong lifespan by modulation of ROS, NAD⁺, and AMP levels. Among substances, an anti-diabetic drug metformin is believed to increase NAD⁺ and AMP levels, indirectly influencing histone deacetylases, involved in gene silencing, and AMP-activated protein kinase, an energy sensor of cells. Mitochondrially targeted derivatives of ubiquinone were found to interact with ROS. A mitochondrially targeted non-proton-pumping NADH dehydrogenase may influence both ROS and NAD⁺ levels. Chapter describes putative how mitochondria-targeted drugs and NADH dehydrogenase extend lifespan, perspectives of creating drugs with similar properties and their usage as senotherapeutic pills are discussed in the chapter.