Mitochondrial theory of ageing

Last updated

The mitochondrial theory of ageing 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]

Contents

The mitochondrial free radical theory of ageing (MFRTA) proposes that free radicals produced by mitochondrial activity damage cellular components, leading to ageing.

Free radicals damage mitochondria, which, according to the mitochondrial free radical theory of ageing, leads to ageing. MFRTA2Dw001.png
Free radicals damage mitochondria, which, according to the mitochondrial free radical theory of ageing, leads to ageing.

Mitochondria are cell organelles which function to provide the cell with energy by producing ATP (adenosine triphosphate). 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.

Electron transport chain in the inner mitochondrial membrane ElectronTransportChainDw001.png
Electron transport chain in the inner mitochondrial membrane

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.

Molecular basis

Molecular contributors to ageing (reactive oxygen species, mitochondrial unfolded protein response, mitochondrial metabolites, damage-associated molecular patterns, mitochondrial-derived peptides, mitochondrial membrane) AgeingDw001.png
Molecular contributors to ageing (reactive oxygen species, mitochondrial unfolded protein response, mitochondrial metabolites, damage-associated molecular patterns, mitochondrial-derived peptides, mitochondrial membrane)

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 produce energy in the form of 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.

ROS

Reactive oxygen species and oxygen ROSDw001.png
Reactive oxygen species and oxygen

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. [4] Damaging of mitochondrial DNA causes mutations, leading to production of ETC complexes, which don’t function properly, increasing ROS production, increasing oxidative damage to macromolecules.

UPRmt

The mitochondrial unfolded protein response (UPRmt) 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. [5] Decrease in protease levels are associated with ageing, as mitochondrial stress will remain, maintaining high ROS levels. [6] Such mitochondrial stress and dysfunction has been linked to various age-associated diseases, including cardiovascular diseases, and type-2 diabetes. [7]

Mitochondrial metabolites

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, [8] associated with ageing.

TCA cycle TCAcycleDw001.png
TCA cycle

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. [9] 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. [10] [11]

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

DAMPs

Damage-associated molecular patterns (DAMPs) are molecules that are released during cell stress. Mitochondrial DNA is a DAMP, which only becomes available during mitochondrial damage. Blood mitochondrial DNA levels become elevated with age, contributing to inflamm-ageing, a chronic state of inflammation characteristic of advanced age. [14]

Mitochondrial-derived peptides

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 peptide, humanin has been shown to protect against Alzheimer’s disease, which is considered an age-associated disease. [16]

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. [17]

Mitochondrial membrane

Almaida-Pagan and coworkers found that mitochondrial membrane lipid composition changes with age, when studying Turquoise killifish. [18] The proportion of monounsaturated fatty acids and the overall phospholipid content decreased with age.

History

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). [19] He found ROS as the main cause of damage to macromolecules, known as “ageing”. He later modified his theory because he found 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. [20]

Evidence

It has been observed that with age, mitochondrial function declines and mitochondrial DNA mutation increases in tissue cells in an age-dependent manner. This leads to increase in ROS production and 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 of antioxidants, which function to remove ROS has also been shown to increase lifespan. [26] [27] Bioinformatics analysis showed that amino acid composition of mitochondrial proteins correlate with longevity (long-living species are depleted in cysteine and methionine), linking mitochondria to the process of ageing. [28] [29] By studying expression of certain genes in C. elegans , [30] Drosophila , [31] and mice [32] it was found that disruption of ETC complexes can extend life – linking mitochondrial function to the process of ageing.

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 live longer than normal life. [33] Overexpression of antioxidants reduced cellular stress, but did not increase mouse life span. [34] [35] The naked mole-rat, which lives 10-times longer than normal mice, has been shown to have higher levels of oxidative damage. [36]

See also

Related Research Articles

<span class="mw-page-title-main">Mitochondrion</span> Organelle in eukaryotic cells responsible for respiration

A mitochondrion is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.

<span class="mw-page-title-main">Superoxide dismutase</span> Class of enzymes

Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O−
2) radical into ordinary molecular oxygen (O2) and hydrogen peroxide (H
2O
2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive O−
2.

<span class="mw-page-title-main">Mitochondrial DNA</span> DNA located in mitochondria

Mitochondrial DNA is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DNA is only a small portion of the DNA in a eukaryotic cell; most of the DNA can be found in the cell nucleus and, in plants and algae, also in plastids such as chloroplasts.

<span class="mw-page-title-main">Senescence</span> Deterioration of function with age

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. The word senescence can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

Maximum life span is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the maximum amount of time that a member of a given species could survive between birth and death, provided circumstances that are optimal to that member's longevity.

The free radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">Biogerontology</span> Sub-field of gerontology

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick has said that the natural average lifespan for a human is around 92 years and, if humans do not invent new approaches to treat aging, they will be stuck with this lifespan. James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000. Many surveyed biogerontologists have predicted life expectancies of more than three centuries for people born after the year 2100. Other scientists, more controversially, suggest the possibility of unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age". The idea of this approach is to use presently available technology to extend lifespans of currently living humans long enough for future technological progress to resolve any remaining aging-related issues. This concept has been referred to as longevity escape velocity.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

<span class="mw-page-title-main">Michael Ristow</span> German medical researcher (born 1967)

Michael Ristow is a German medical researcher who has published influential articles on biochemical aspects of mitochondrial metabolism and particularly the possibly health-promoting role of reactive oxygen species in diseases like type 2 diabetes, obesity and cancer, as well as general aging due to a process called mitohormesis.

<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">SOD2</span> Enzyme

Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the SOD2 gene on chromosome 6. A related pseudogene has been identified on chromosome 1. Alternative splicing of this gene results in multiple transcript variants. This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer.

<span class="mw-page-title-main">MSRA (gene)</span> Protein-coding gene in the species Homo sapiens

Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene.

<span class="mw-page-title-main">Brain mitochondrial carrier protein 1</span> Protein-coding gene in the species Homo sapiens

Brain mitochondrial carrier protein 1 is a protein that in humans is encoded by the SLC25A14 gene.

Ageing is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In a broader sense, ageing can refer to single cells within an organism which have ceased dividing, or to the population of a species.

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

<span class="mw-page-title-main">Pathophysiology of Parkinson's disease</span> Medical condition

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

The disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 to conceptualize the essence of biological aging and its underlying mechanisms.

References

  1. ↑ Miquel, J.; Economos, A. C.; Fleming, J.; Johnson, J. E. (1980-01-01). "Mitochondrial role in cell aging". Experimental Gerontology. 15 (6): 575–591. doi:10.1016/0531-5565(80)90010-8. ISSN   0531-5565. PMID   7009178. S2CID   38511082.
  2. ↑ Linnane, AnthonyW; Ozawa, Takayuki; Marzuki, Sangkot; Tanaka, Masashi (1989-03-25). "Mitochondrial DNA Mutations as an Important Contributor to Ageing and Degenerative Diseases". The Lancet. 333 (8639): 642–645. doi:10.1016/S0140-6736(89)92145-4. ISSN   0140-6736. PMID   2564461. S2CID   11933110.
  3. ↑ Lobachev A.N. Role of mitochondrial processes in the development and aging of organism. Aging and cancer (PDF), Chemical abstracts. 1979 v. 91 N 25 91:208561v.Deposited Doc., VINITI 2172-78, 1978, p. 48
  4. ↑ Kowald; Kirkwood (2018). "Resolving the Enigma of the Clonal Expansion of mtDNA Deletions". Genes (Basel). 9 (3): 126. doi: 10.3390/genes9030126 . PMC   5867847 . PMID   29495484.
  5. ↑ Nargund; et al. (2015). "Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt)". Molecular Cell. 58 (1): 123–133. doi:10.1016/j.molcel.2015.02.008. PMC   4385436 . PMID   25773600.
  6. ↑ Bota; et al. (2005). "Downregulation of the human Lon protease impairs mitochondrial structure and function and causes cell death". Free Radical Biology and Medicine. 38 (1): 665–677. doi:10.1016/j.freeradbiomed.2004.11.017. PMID   15683722. S2CID   32448357.
  7. ↑ Kim; Wei; Sowers (2008). "Role of mitochondrial dysfunction in insulin resistance". Circulation Research. 102 (4): 401–414. doi:10.1161/CIRCRESAHA.107.165472. PMC   2963150 . PMID   18309108.
  8. ↑ Frezza (2017). "Mitochondrial metabolites: undercover signalling molecules". Interface Focus. 7 (2): 20160100. doi: 10.1098/rsfs.2016.0100 . PMC   5311903 . PMID   28382199.
  9. ↑ Menzies; Zhang; Katsuyaba; Auwerx (2016). "Protein acetylation in metabolism - metabolites and cofactors". Nature Reviews Endocrinology. 12 (1): 43–60. doi:10.1038/nrendo.2015.181. PMID   26503676. S2CID   19151622.
  10. ↑ Shi; Tu (2015). "Acetyl-CoA and the regulation of metabolism: mechanisms and consequences". Current Opinion in Cell Biology. 33: 125–131. doi:10.1016/j.ceb.2015.02.003. PMC   4380630 . PMID   25703630.
  11. ↑ Benayoun; Pollina; Brunet (2015). "Epigenetic regulation of ageing: linking environmental inputs to genomic stability". Nature Reviews Molecular Cell Biology. 16 (1): 593–610. doi:10.1038/nrm4048. PMC   4736728 . PMID   26373265.
  12. ↑ Imai; Guarente (2016). "It takes two to tango: NAD+ and sirtuins in aging/longevity control". npj Aging and Mechanisms of Disease. 2: 16017. doi:10.1038/npjamd.2016.17. PMC   5514996 . PMID   28721271.
  13. ↑ Schultz; Sinclair (2016). "Why NAD(+) Declines during Aging: It's Destroyed". Cell Metabolism. 23 (6): 965–966. doi:10.1016/j.cmet.2016.05.022. PMC   5088772 . PMID   27304496.
  14. ↑ Pinti; et al. (2014). "Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for "inflamm-aging"". European Journal of Immunology. 44 (5): 1552–1562. doi: 10.1002/eji.201343921 . PMID   24470107. S2CID   5407086.
  15. ↑ Kim; et al. (2017). "Mitochondrially derived peptides as novel regulators of metabolism". The Journal of Physiology. 595 (21): 6613–6621. doi:10.1113/JP274472. PMC   5663826 . PMID   28574175.
  16. ↑ Kim; et al. (2017). "Mitochondrially derived peptides as novel regulators of metabolism". The Journal of Physiology. 595 (21): 6613–6621. doi:10.1113/JP274472. PMC   5663826 . PMID   28574175.
  17. ↑ Kim; et al. (2017). "Mitochondrially derived peptides as novel regulators of metabolism". Journal of Physiology. 595 (21): 6613–6621. doi:10.1113/JP274472. PMC   5663826 . PMID   28574175.
  18. ↑ Almaida-Pagan; et al. (2019). "Age-related changes in mitochondrial membrane composition of Nothobranchius furzeri.: comparison with a longer-living Nothobranchius species". Biogerontology. 20 (1): 83–92. doi:10.1007/s10522-018-9778-0. PMID   30306289. S2CID   254287563.
  19. ↑ Harman (1956). "Aging: a theory based on free radical and radiation chemistry". Journal of Gerontology. 11 (3): 298–300. doi:10.1093/geronj/11.3.298. hdl: 2027/mdp.39015086547422 . PMID   13332224.
  20. ↑ Harman (1972). "A biologic clock: the mitochondria?". Journal of the American Geriatrics Society. 20 (4): 145–147. doi:10.1111/j.1532-5415.1972.tb00787.x. PMID   5016631. S2CID   396830.
  21. ↑ Martin; et al. (1996). "Genetic analysis of ageing: role of oxidative damage and environmental stresses". Nature Genetics. 13 (1): 25–34. doi:10.1038/ng0596-25. PMID   8673100. S2CID   9358797.
  22. ↑ Liang; et al. (2003). "Genetic mouse models of extended lifespan". Experimental Gerontology. 38 (11–12): 1353–1364. doi:10.1016/j.exger.2003.10.019. PMID   14698816. S2CID   136263.
  23. ↑ Lambert; et al. (2007). "Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms". Aging Cell. 6 (5): 607–618. doi: 10.1111/j.1474-9726.2007.00312.x . PMID   17596208. S2CID   22676318.
  24. ↑ Ungvari; et al. (2011). "Extreme longevity is associated with increased resistance to oxidative stress in Arctica islandica, the longest-living non-colonial animal". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 66 (7): 741–750. doi: 10.1093/gerona/glr044 . PMC   3143345 . PMID   21486920.
  25. ↑ Barja; et al. (2014). "The mitochondrial free radical theory of aging". Progress in Molecular Biology and Translational Science. 127: 1–27. doi:10.1016/B978-0-12-394625-6.00001-5. ISBN   9780123946256. PMID   25149212.
  26. ↑ Sun; et al. (2002). "Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster". Genetics. 161 (2): 661–672. doi:10.1093/genetics/161.2.661. PMC   1462135 . PMID   12072463.
  27. ↑ Orr; Sohal (1994). "Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster". Science. 263 (5150): 1128–30. Bibcode:1994Sci...263.1128O. doi:10.1126/science.8108730. PMID   8108730.
  28. ↑ Moosmann; Behl (2008). "Mitochondrially encoded cysteine predicts animal lifespan". Aging Cell. 7 (1): 32–46. doi: 10.1111/j.1474-9726.2007.00349.x . PMID   18028257.
  29. ↑ Aledo; et al. (2011). "Mitochondrially encoded methionine is inversely related to longevity in mammals". Aging Cell. 10 (2): 198–207. doi: 10.1111/j.1474-9726.2010.00657.x . PMID   21108730.
  30. ↑ Rea; et al. (2007). "Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans". PLOS Biology. 5 (10): e259. doi: 10.1371/journal.pbio.0050259 . PMC   1994989 . PMID   17914900.
  31. ↑ Copeland; et al. (2009). "Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain". Current Biology. 19 (19): 1591–1598. doi: 10.1016/j.cub.2009.08.016 . PMID   19747824.
  32. ↑ Liu; et al. (2005). "Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice". Genes & Development. 19 (20): 2424–2434. doi:10.1101/gad.1352905. PMC   1257397 . PMID   16195414.
  33. ↑ Van Remmen; et al. (2003). "Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging". Physiological Genomics. 16 (1): 29–37. doi:10.1152/physiolgenomics.00122.2003. PMID   14679299. S2CID   9159294.
  34. ↑ Huang; et al. (2000). "Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 55 (1): B5-9. doi: 10.1093/gerona/55.1.b5 . PMID   10719757.
  35. ↑ Pérez; et al. (2009). "Is the oxidative stress theory of aging dead?". Biochimica et Biophysica Acta (BBA) - General Subjects. 1790 (10): 1005–1014. doi:10.1016/j.bbagen.2009.06.003. PMC   2789432 . PMID   19524016.
  36. ↑ Andziak; et al. (2006). "High oxidative damage levels in the longest-living rodent, the naked mole-rat". Aging Cell. 5 (6): 463–471. doi: 10.1111/j.1474-9726.2006.00237.x . PMID   17054663.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.