Mitochondrial theory of ageing

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Mitochondria are thought to be organelles that developed from endocytosed bacteria which learned to coexist inside ancient cells. These bacteria maintained their own DNA, the mitochondrial DNA (mtDNA), which codes for components of the electron transport chain (ETC). The ETC is found in the inner mitochondrial membrane and functions to transfer energy derived from food into ATP molecules. The process is called oxidative phosphorylation, because ATP is produced from ADP in a series of redox reactions. Electrons are transferred through the ETC from NADH and FADH₂ to oxygen, reducing oxygen to water.

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ROS are highly reactive, oxygen-containing chemical species, which include superoxide, hydrogen peroxide and hydroxyl radical.

If the complexes of the ETC do not function properly, electrons can leak and react with water, forming ROS. Normally leakage is low and ROS is kept at physiological levels, fulfilling roles in signaling and homeostasis. In fact, their presence at low levels lead to increased life span, by activating transcription factors and metabolic pathways involved in longevity. At increased levels ROS cause oxidative 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.{{cite journal |last1=Kowald |last2=Kirkwood |title=Resolving the Enigma of the Clonal Expansion of mtDNA Deletions |journal=Genes (Basel) |date=2018 |volume=9 |issue=3 |page=126 |doi=10.3390/genes9030126|pmid=29495484 |pmc=5867847 |doi-access=free }} 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.

The mitochondrial unfolded protein response (UPR^mt) is turned on in response to mitochondrial stress. Mitochondrial stress occurs when the proton gradient across the inner mitochondrial membrane is dissipated, mtDNA is mutated, and/or ROS accumulates, which can lead to misfolding and reduced function of mitochondrial proteins. Stress is sensed by the nucleus, where chaperones and proteases are upregulated, which can correct folding or remove damaged proteins, respectively.{{cite journal |last1=Nargund|display-authors=etal|title=Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). |journal=Molecular Cell |date=2015 |volume=58 |issue=1 |pages=123–133 |doi=10.1016/j.molcel.2015.02.008|pmid=25773600|pmc=4385436 }} Decreases in protease levels are associated with ageing, as mitochondrial stress will remain and increase ROS levels.{{cite journal |last1=Bota|display-authors=etal|title=Downregulation of the human Lon protease impairs mitochondrial structure and function and causes cell death |journal=Free Radical Biology and Medicine |date=2005 |volume=38 |issue=1 |pages=665–677 |doi=10.1016/j.freeradbiomed.2004.11.017|url=https://escholarship.org/uc/item/3348s0gq |pmid=15683722|s2cid=32448357 }} Such mitochondrial stress and dysfunction has been linked to various age-associated diseases, including cardiovascular diseases, and type-2 diabetes.{{cite journal |last1=Kim |last2=Wei |last3=Sowers |title=Role of mitochondrial dysfunction in insulin resistance. |journal=Circulation Research |date=2008 |volume=102 |issue=4 |pages=401–414 |doi=10.1161/CIRCRESAHA.107.165472|pmid=18309108 |pmc=2963150 }}

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; this can induce epigenetic changes{{cite journal |last1=Frezza |title=Mitochondrial metabolites: undercover signalling molecules. |journal=Interface Focus |date=2017 |volume=7 |issue=2 |pages=20160100 |doi=10.1098/rsfs.2016.0100|pmid=28382199 |pmc=5311903 |doi-access=free }} associated with ageing.

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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.{{cite journal |last1=Menzies |last2=Zhang |last3=Katsuyaba |last4=Auwerx |title=Protein acetylation in metabolism - metabolites and cofactors. |journal=Nature Reviews Endocrinology |date=2016 |volume=12 |issue=1 |pages=43–60 |doi=10.1038/nrendo.2015.181|pmid=26503676 |s2cid=19151622 }} 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.{{cite journal |last1=Shi |last2=Tu |title=Acetyl-CoA and the regulation of metabolism: mechanisms and consequences |journal=Current Opinion in Cell Biology |date=2015 |volume=33 |pages=125–131 |doi=10.1016/j.ceb.2015.02.003|pmc=4380630 |pmid=25703630 }}{{cite journal |last1=Benayoun |last2=Pollina |last3=Brunet |title=Epigenetic regulation of ageing: linking environmental inputs to genomic stability. |journal= Nature Reviews Molecular Cell Biology|date=2015 |volume=16 |issue=1 |pages=593–610 |doi=10.1038/nrm4048|pmc=4736728 |pmid=26373265 }}

Nicotinamide Adenine Dinucleotide (NAD⁺) is produced in the mitochondria and upon escaping to the nucleus, can act as a substrate for sirtuins.{{cite journal |last1=Imai |last2=Guarente |title=It takes two to tango: NAD+ and sirtuins in aging/longevity control |journal=npj Aging and Mechanisms of Disease |date=2016 |volume=2 |pages=16017 |doi=10.1038/npjamd.2016.17|pmid=28721271 |pmc=5514996 }} Sirtuins are a family of proteins known to play a role in longevity. Cellular NAD⁺ levels have been shown to decrease with age.{{cite journal |last1=Schultz |last2=Sinclair |title=Why NAD(+) Declines during Aging: It's Destroyed. |journal=Cell Metabolism |date=2016 |volume=23 |issue=6 |pages=965–966 |doi=10.1016/j.cmet.2016.05.022 |pmid=27304496 |pmc=5088772}}

Damage-associated molecular patterns (DAMPs) are molecules that are released during cell 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 to inflamm-ageing, a chronic state of inflammation characteristic of advanced age.{{cite journal |last1=Pinti |display-authors=etal|title=Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for "inflamm-aging" |journal=European Journal of Immunology |date=2014 |volume=44 |issue=5 |pages=1552–1562 |doi=10.1002/eji.201343921|pmid=24470107|s2cid=5407086 |doi-access=free }}

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.{{cite journal |last1=Kim |display-authors=etal|title=Mitochondrially derived peptides as novel regulators of metabolism. |journal=The Journal of Physiology |date=2017 |volume=595 |issue=21 |pages=6613–6621 |doi=10.1113/JP274472 |pmid=28574175 |pmc=5663826}}

The mitochondrial-derived peptide humanin has been shown to protect against Alzheimer's disease, which is considered an age-associated disease.{{cite journal |last1=Kim |display-authors=etal|title=Mitochondrially derived peptides as novel regulators of metabolism. |journal=The Journal of Physiology |date=2017 |volume=595 |issue=21 |pages=6613–6621 |doi=10.1113/JP274472 |pmid=28574175 |pmc=5663826}}

MOTS-c has been shown to prevent age-associated insulin 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.{{cite journal |last1=Kim |display-authors=etal|title=Mitochondrially derived peptides as novel regulators of metabolism. |journal=Journal of Physiology |date=2017 |volume=595 |issue=21 |pages=6613–6621 |doi=10.1113/JP274472 |pmid=28574175 |pmc=5663826}}

Almaida-Pagan and coworkers found that mitochondrial membrane lipid composition changes with age, when studying Turquoise killifish.{{cite journal |last1=Almaida-Pagan |display-authors=etal|title=Age-related changes in mitochondrial membrane composition of Nothobranchius furzeri.: comparison with a longer-living Nothobranchius species |journal=Biogerontology |date=2019 |volume=20 |issue=1 |pages=83–92 |doi=10.1007/s10522-018-9778-0|pmid=30306289|s2cid=254287563 }} The proportion of monounsaturated fatty acids and the overall phospholipid content decreased with age.

In 1956 Denham Harman first postulated the free radical theory of ageing, which he later modified to the mitochondrial free radical theory of ageing (MFRTA).{{cite journal |last1=Harman |title=Aging: a theory based on free radical and radiation chemistry |journal=Journal of Gerontology |date=1956 |volume=11 |issue=3 |pages=298–300 |doi=10.1093/geronj/11.3.298 |pmid=13332224|hdl=2027/mdp.39015086547422 |hdl-access=free }} 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 the Journal of the American Geriatrics Society.{{cite journal |last1=Harman |title=A biologic clock: the mitochondria? |journal=Journal of the American Geriatrics Society |date=1972 |volume=20 |issue=4 |pages=145–147 |doi=10.1111/j.1532-5415.1972.tb00787.x |pmid=5016631|s2cid=396830 }}

It has been observed that mitochondrial function declines with age, and mitochondrial DNA mutation increases in tissue 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.{{cite journal |last1=Martin |display-authors=etal|title=Genetic analysis of ageing: role of oxidative damage and environmental stresses. |journal=Nature Genetics |date=1996 |volume=13 |issue=1 |pages=25–34 |doi=10.1038/ng0596-25|pmid=8673100|s2cid=9358797 }}{{cite journal |last1=Liang |display-authors=etal|title=Genetic mouse models of extended lifespan. |journal=Experimental Gerontology |date=2003 |volume=38 |issue=11–12 |pages=1353–1364 |doi=10.1016/j.exger.2003.10.019|pmid=14698816|s2cid=136263 }}{{cite journal |last1=Lambert |display-authors=etal|title=Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms. |journal=Aging Cell |date=2007 |volume=6 |issue=5 |pages=607–618 |doi=10.1111/j.1474-9726.2007.00312.x|pmid=17596208|s2cid=22676318 |doi-access=free }}{{cite journal |last1=Ungvari |display-authors=etal|title=Extreme longevity is associated with increased resistance to oxidative stress in Arctica islandica, the longest-living non-colonial animal. |journal=The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences |date=2011 |volume=66 |issue=7 |pages=741–750 |doi=10.1093/gerona/glr044|pmid=21486920|pmc=3143345|doi-access=free }}{{cite journal |last1=Barja |display-authors=etal|title=The mitochondrial free radical theory of aging. |journal=Progress in Molecular Biology and Translational Science |date=2014 |volume=127 |pages=1–27 |doi=10.1016/B978-0-12-394625-6.00001-5|pmid=25149212|isbn=9780123946256}} Overexpression of antioxidants, which reduce ROS, has also been shown to increase lifespan.{{cite journal |last1=Sun |display-authors=etal|title=Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. |journal=Genetics |date=2002 |volume=161 |issue=2 |pages=661–672 |doi=10.1093/genetics/161.2.661 |pmid=12072463|pmc=1462135}}{{cite journal |last1=Orr |last2=Sohal |title=Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. |journal=Science |date=1994 |volume=263 |issue=5150 |pages=1128–30 |doi=10.1126/science.8108730|pmid=8108730 |bibcode=1994Sci...263.1128O }}

Multiple studies have linked mitochondria to the process of ageing, including a bioinformatics analysis showing that amino acid composition of mitochondrial proteins correlates with longevity (long-living species are depleted in cysteine and methionine),{{cite journal |last1=Moosmann |last2=Behl |title=Mitochondrially encoded cysteine predicts animal lifespan |journal=Aging Cell |date=2008 |volume=7 |issue=1 |pages=32–46 |doi=10.1111/j.1474-9726.2007.00349.x|pmid=18028257 |doi-access=free }}{{cite journal |last1=Aledo |display-authors=etal|title=Mitochondrially encoded methionine is inversely related to longevity in mammals |journal=Aging Cell |date=2011 |volume=10 |issue=2|pages=198–207 |doi=10.1111/j.1474-9726.2010.00657.x |pmid=21108730|doi-access=free }} as well as the discovery that disruption of ETC complexes can extend life in Caenorhabditis elegans{{cite journal |last1=Rea |display-authors=etal|title=Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. |journal=PLOS Biology |date=2007 |volume=5 |issue=10 |page=e259 |doi=10.1371/journal.pbio.0050259|pmid=17914900|pmc=1994989|doi-access=free }} Drosophila,{{cite journal |last1=Copeland |display-authors=etal|title=Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. |journal=Current Biology |date=2009 |volume=19 |issue=19 |pages=1591–1598 |doi=10.1016/j.cub.2009.08.016|pmid=19747824|doi-access=free }} and mice. {{cite journal |last1=Liu |display-authors=etal|title=Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. |journal=Genes & Development |date=2005 |volume=19 |issue=20 |pages=2424–2434 |doi=10.1101/gad.1352905 |pmid=16195414 |pmc=1257397}}

Evidence supporting the theory started to crumble in the early 2000s.

Mice with reduced expression of the mitochondrial antioxidant, SOD2, accumulated oxidative damage and developed cancer, but did not age faster.{{cite journal |last1=Van Remmen |display-authors=etal|title=Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging |journal=Physiological Genomics |date=2003 |volume=16 |issue=1 |pages=29–37 |doi=10.1152/physiolgenomics.00122.2003|pmid=14679299|s2cid=9159294 }} Overexpression of antioxidants reduced cellular stress, but did not increase mouse life span.{{cite journal |last1=Huang |display-authors=etal|title=Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. |journal=The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences |date=2000 |volume=55 |issue=1 |pages=B5-9|pmid=10719757 |doi=10.1093/gerona/55.1.b5|doi-access=free }}{{cite journal |last1=Pérez |display-authors=etal|title=Is the oxidative stress theory of aging dead? |journal=Biochimica et Biophysica Acta (BBA) - General Subjects|date=2009 |volume=1790 |issue=10 |pages=1005–1014 |doi=10.1016/j.bbagen.2009.06.003|pmid=19524016|pmc=2789432}} The naked 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.{{cite journal |last1=Andziak |display-authors=etal|title=High oxidative damage levels in the longest-living rodent, the naked mole-rat |journal=Aging Cell |date=2006 |volume=5 |issue=6 |pages=463–471 |doi=10.1111/j.1474-9726.2006.00237.x|pmid=17054663|doi-access=free }}

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

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Category:Ageing