page_title: Mitochondrial theory of ageing
section_title: Mitochondrial metabolites
hierarchical_section_title: Mitochondrial theory of ageing / Molecular basis / Mitochondrial metabolites
caption_attribution_description: English: TCA cycle metabolites
context_page_description: The mitochondrial theory of aging has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of aging. It was formulated by J. Michel in 1980 and was developed in the works of A. V. Linnan. The second was proposed by A. N. Lobachev in 1978.
  Mitochondrial free radical theory of aging, MFRTA, proposes that free radicals produced by mitochondrial activity damage cellular components, leading to aging.
  Mitochondria are cell organelles which function to provide the cell with energy by producing ATP. During ATP production electrons can escape the mitochondrion and react with water, producing reactive oxygen species, ROS for short. ROS can damage macromolecules, including lipids, proteins and DNA, which is thought to facilitate the process of ageing.
  In the 1950s Denham Harman proposed the free radical theory of ageing, which he later expanded to the MFRTA.
  When studying the mutations in antioxidants, which remove ROS, results were inconsistent. However, it has been observed that overexpression of antioxidant enzymes in yeast, worms, flies and mice were shown to increase lifespan.
context_section_description: As the mitochondrial matrix is where the TCA cycle takes place, different metabolites are commonly confined to the mitochondria. Upon ageing, mitochondrial function declines, allowing escape of these metabolites, which can induce epigenetic changes, associated with ageing.
  Acetyl-coenzyme A (Acetyl-CoA) enters the TCA cycle in the mitochondrial matrix, and is oxidized in the process of energy production. Upon escaping the mitochondria and entering the nucleus, it can act as a substrate for histone acetylation. Histone acetylation is an epigenetic modification, which leads to gene activation. 
  At a young age, acetyl-CoA levels are higher in the nucleus and cytosol, and its transport to the nucleus can extend lifespan in worms.
  Nicotinamide Adenine Dinucleotide (NAD⁺) is produced in the mitochondria and upon escaping to the nucleus, can act as a substrate for sirtuins. Sirtuins are family of proteins, known to play a role in longevity. Cellular NAD⁺ levels have been shown to decrease with age.
caption: TCA cycle
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