A proposed refinement of the mitochondrial free radical theory of aging

Grey, Aubrey D.N.J. de

doi:10.1002/bies.950190211

Cited by 283 publications

(176 citation statements)

References 27 publications

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“…This possibility is supported by the occurrence of homoplasmic mtDNA mutations in neoplastic [65] and intestinal epithelial cells [66]. These cells are actively proliferating and, thus, cannot selectively accumulate mutated mitochondria, due to a decreased rate of elimination, as was suggested by de Grey in his survival of the slowest (SOS) hypothesis for postmitotic cells [67]. This is because cellular proliferation will result in the dilution of mutated mitochondria, preventing their accumulation.…”

Section: Mechanisms Of Mitochondrial Damagementioning

confidence: 91%

Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

263

210

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As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death.

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Section: Mechanisms Of Mitochondrial Damagementioning

confidence: 91%

Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

263

210

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“…Mitochondria specialize in the rapid oxidation of NADH and FADH through the ETC to produce ATP. The ETC is constituted by four complexes and the electron transfer from one complex to another is driven by the reduced forms of the ubiquinone (UQ) and cytochrome c (cyt c) [de Grey, 1999]. During this electron transfer, O 2 may be partially reduced, yielding ROS.…”

Section: Introductionmentioning

confidence: 99%

Melatonin, mitochondria, and cellular bioenergetics

Acuña-Castroviejo

Martı́n

Macías

et al. 2001

Journal of Pineal Research

384

313

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Aerobic cells use oxygen for the production of 90-95% of the total amount of ATP that they use. This amounts to about 40 kg ATP/day in an adult human. The synthesis of ATP via the mitochondrial respiratory chain is the result of electron transport across the electron transport chain coupled to oxidative phosphorylation. Although ideally all the oxygen should be reduced to water by a four-electron reduction reaction driven by the cytochrome oxidase, under normal conditions a small percentage of oxygen may be reduced by one, two, or three electrons only, yielding superoxide anion, hydrogen peroxide, and the hydroxyl radical, respectively. The main radical produced by mitochondria is superoxide anion and the intramitochondrial antioxidant systems should scavenge this radical to avoid oxidative damage, which leads to impaired ATP production.

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“…In addition, activated lymphocytes express the a-chain of the ILZreceptor (CD25) and the MHC classd1 related molecuIe HLA-DR. Lymphocytes bearing these surface motecules or activation markers 141 show enhanced sensitivity to apoptosis upon stimulation of these receptors. Accumulation of chronically activated lyrnphocytes seems to be one reason for Ihe higher susceptibility to apoptotic celt death probably leading 10 a lowered Ieukocyte number in aged individuals. In the present study, we evaluated the basal, spontaneous, activation-, and agent-induced apoptosis and ROS of native and activated peripheral human lymphocytes.…”

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confidence: 99%

Age-related changes of apoptotic cell death in human lymphocytes

Schindowski

Leutner

Müller

et al. 2000

Neurobiology of Aging

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Apoptosis seems to be involved in irnmunosenescence associated with aging. Moreover, in lymphocytes (PBL) of patients with Akheimer's disease, an increased susceptibirity to the apoprotic pathway has been described possibly due to impaired protection o f oxidative stress. Accordingly. it seemed to be of particular interest to investigate the contribution of normal aging to the susceptibility from human lymphocytes 20 programmed cell death. We coiild show that PBL from elderly individuals (>60 years) accumuIate apoptosing cells to a significant higher extent in spontaneous and activation-induced cell death compared to younger controls (<35 years). Treatment with the oxidative Stressor 2-deoxy-D-ribose or with agonistic-CD95-antibody pronounced this effect even more implicating a higher sensitivity to reactive oxygen species and a higher functionril CD95 expression, respectively. In addition, expression of the activation markerc HLA-DR and CD95 was significantly increased in CD3 "-cells of aged subjects, while expression of CD25 did not seem to be affected by age.Expression of Bcl-2 was increased in aging and comlated with the number o f apoptotic cells.Kqwordv. &in& Apoptosis: 1,yrnphocytes; Oxidativc stress; dctivation markers; Bcl-2 Programmed cell death (PCD) or apoptosis is of particular interest in aging, as it is thought X o play an irnportant role in various age-related degenerative diseases. Apoptosis of white bIood cells could be one reason for the decrease of the total number of leukocytes and the decrease of the immune response with aging related Z o Cancer, infections, and autoirnmune disorders [3]. Several changes in lymphocytes have been observed related to aging: diminished synthesis of g r o~h and survive factos 146,511, impaired intracellular calcium regulation [18], different surface malecule expression 1431, and defects of signal transdi~ction [36]. Some of these pathological changes are additionally altered in patients witl~ Alzheimer's disease (AD), but are not present in vascular dementia [13][14][15]171. In order to differentiate common and divergent mechanisms of an enhanced susceptibility of lymphocytes to apoptosis in aging and sporadic AD, we investigated in detail the molecular basis of enhanced apoptosis in aged human lymphocytes. Oxidative Stress increases with aging and ltads to enhanced cellular damage (e.g. Iipidperoxidation, protein oxidation, DNA damage (for review see ref.[IO]). In addition, reactive axygen species (ROS) can trigger cells to undergo pragrammed cell death and can act as second rnessenger by influencing transcription factors like NF-KB and AP-I. Increased oxidative stress and decreased ability to cope with ROS could ampliQ apoptotic cell death in aging lymphocytes. BcI-2 acts in an antioxidative and antiapoptotic way and can interfcre with the apoptotic pathway 17,471.One oF the best known and characterized surface receptors related to PCD in lymphocytes is ApollFas (CD95), a rnernber of the himor necrosis factor (W) superfamily. Stimulation of this recep...

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A proposed refinement of the mitochondrial free radical theory of aging

Cited by 283 publications

References 27 publications

Autophagy, organelles and ageing

Autophagy, organelles and ageing

Melatonin, mitochondria, and cellular bioenergetics

Age-related changes of apoptotic cell death in human lymphocytes

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