Themitochondrial free radical theory of ageing (MFRTA) proposes thatfree radicals produced bymitochondrial activity damage cellular components, leading toageing.

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 ageing. It was formulated by J. Miquel and colleagues in 1980^[1] and was developed in the works of Linnane and coworkers (1989).^[2] The second was proposed by A. N. Lobachev in 1978.^[3]

Mitochondria arecellorganelles which function to provide the cell with energy by producingATP (adenosine triphosphate). During ATP productionelectrons can escape the mitochondrion and react with water, producingreactive oxygen species (ROS). ROS can damagemacromolecules, includinglipids,proteins, andDNA, which is thought to facilitate the process of ageing.

In the 1950sDenham Harman proposed thefree radical theory of ageing, which he later expanded to the MFRTA.

When studying themutations inantioxidants, which remove ROS, results were inconsistent. However, it has been observed thatoverexpression of antioxidant enzymes inyeast,worms,flies andmice were shown to increaselifespan.

Mitochondria are thought to be organelles that developed fromendocytosedbacteria which learned tocoexist insideancient cells. These bacteria maintained their own DNA, themitochondrial DNA (mtDNA), which codes for components of theelectron transport chain (ETC). The ETC is found in theinner mitochondrial membrane and functions to transferenergy derived from food into ATP molecules. The process is calledoxidative phosphorylation, because ATP is produced fromADP in a series ofredox reactions. Electrons are transferred through the ETC fromNADH andFADH₂ tooxygen,reducing oxygen to water.

ROS are highlyreactive, oxygen-containingchemical species, which includesuperoxide,hydrogen peroxide andhydroxyl radical. If thecomplexes of the ETC do not function properly, electrons can leak and react with water, forming ROS. Normally leakage is low and ROS is kept atphysiological levels, fulfilling roles insignaling andhomeostasis. In fact, their presence at low levels lead to increased life span, by activatingtranscription factors andmetabolic pathways involved inlongevity. At increased levels ROS causeoxidative damage by oxidizing macromolecules, such as lipids, proteins and DNA. This oxidative damage to macromolecules is thought to be the cause of ageing. Mitochondrial DNA is especially susceptible to oxidative damage, due to its proximity to the site of production of these species.^[4] Damaging of mitochondrial DNA causes mutations, which may lead to the production of ETC complexes that do not function properly. This results in an increase in ROS production, which then increases oxidative damage to macromolecules.

Themitochondrial unfolded protein response (UPR^mt) is turned on in response to mitochondrial stress. Mitochondrial stress occurs when theproton gradient across the inner mitochondrial membrane is dissipated, mtDNA is mutated, and/or ROS accumulates, which can lead tomisfolding and reduced function of mitochondrial proteins. Stress is sensed by thenucleus, wherechaperones andproteases areupregulated, which can correctfolding or remove damaged proteins, respectively.^[5] Decreases in protease levels are associated with ageing, as mitochondrial stress will remain and increase ROS levels.^[6] Such mitochondrial stress and dysfunction has been linked to variousage-associated diseases, includingcardiovascular diseases, andtype-2 diabetes.^[7]

As themitochondrial matrix is where theTCA cycle takes place, differentmetabolites are commonly confined to the mitochondria. Upon ageing, mitochondrial function declines, allowing escape of these metabolites; this can induceepigenetic changes^[8] associated with ageing.

Acetyl-coenzyme A (Acetyl-CoA) enters the TCA cycle in the mitochondrial matrix, and isoxidized in the process of energy production. Upon escaping the mitochondria and entering the nucleus, it can act as asubstrate forhistone acetylation.^[9] Histone acetylation is an epigenetic modification, which leads togene activation. At a young age, acetyl-CoA levels are higher in the nucleus andcytosol, and its transport to the nucleus can extendlifespan in worms.^[10][11]

Nicotinamide Adenine Dinucleotide (NAD⁺) is produced in the mitochondria and upon escaping to the nucleus, can act as a substrate forsirtuins.^[12] Sirtuins are a family of proteins known to play a role in longevity. Cellular NAD⁺ levels have been shown to decrease with age.^[13]

Damage-associated molecular patterns (DAMPs) are molecules that are released duringcell stress. Mitochondrial DNA is a DAMP, which is only present outside of the mitochondria if the mitochondria is damaged. Blood mitochondrial DNA levels become elevated with age, contributing toinflamm-ageing, a chronic state of inflammation characteristic of advanced age.^[14]

Mitochondrial DNA has been known to encode 13 proteins. Recently, other short protein coding sequences have been identified, and their products are referred to as mitochondria-derived peptides.^[15]

The mitochondrial-derived peptidehumanin has been shown to protect againstAlzheimer's disease, which is considered anage-associated disease.^[16]

MOTS-c has been shown to prevent age-associatedinsulin resistance, the main cause of type 2 diabetes.

Humanin and MOTS-c levels have been shown to decline with age, and their activity seems to increase longevity.^[17]

Almaida-Pagan and coworkers found that mitochondrialmembrane lipid composition changes with age, when studyingTurquoise killifish.^[18] The proportion ofmonounsaturated fatty acids and the overallphospholipid content decreased with age.

In 1956Denham Harman first postulated thefree radical theory of ageing, which he later modified to the mitochondrial free radical theory of ageing (MFRTA).^[19] He found ROS as the main cause of damage to macromolecules, known as "ageing". He later modified his theory after discovering that mitochondria were producing and being damaged by ROS, leading him to the conclusion that mitochondria determine ageing. In 1972, he published his theory in theJournal of the American Geriatrics Society.^[20]

It has been observed that mitochondrial function declines with age, and mitochondrial DNA mutation increases intissue cells in an age-dependent manner. This leads to an increase in ROS production and a potential decrease in the cell's ability to remove ROS. Most long-living animals have been shown to be more resistant to oxidative damage and have lower ROS production, linking ROS levels to lifespan.^{[21][22][23][24][25]} Overexpression ofantioxidants, which reduce ROS, has also been shown to increase lifespan.^[26][27] Multiple studies have linked mitochondria to the process of ageing, including abioinformatics analysis showing that amino acid composition of mitochondrial proteins correlates with longevity (long-living species are depleted incysteine andmethionine),^[28][29] as well as the discovery that disruption of ETC complexes can extend life inCaenorhabditis elegans^[30]Drosophila,^[31] and mice.^[32]

Evidence supporting the theory started to crumble in the early 2000s.Mice with reduced expression of the mitochondrial antioxidant,SOD2, accumulated oxidative damage and developedcancer, but did not age faster.^[33] Overexpression of antioxidants reduced cellular stress, but did not increase mouse life span.^[34][35] Thenaked mole-rat, which lives 10-times longer than normal mice, has been shown to tolerate higher levels of oxidative damage compared to other organisms of its size.^[36]

• Ageing
• Calorie Restriction
• Denham Harman
• Free radical theory of ageing
• Gerontology

• Ageing

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