Aging: ROS or TOR

Blagosklonny, Mikhail V.

doi:10.4161/cc.7.21.6965

Cited by 356 publications

(313 citation statements)

References 114 publications

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“…The description of these results and their impact on the validity and the future of the theory is the main subject of recent reviews in the field [22][23][24][25].…”

Section: Recent Results That Are Incompatible With the Mfrtamentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

511

373

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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“…The description of these results and their impact on the validity and the future of the theory is the main subject of recent reviews in the field [22][23][24][25].…”

Section: Recent Results That Are Incompatible With the Mfrtamentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

511

373

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“…In broad terms, what Blagosklonny has done is to remove certain elements from the existing conceptual framework of biogerontology, add some new ideas, and rearrange the rest. The result is a radically new, coherent integrated theory that presents a very different big picture of aging (4)(5)(6).…”

Section: Aging As Quasi-programmed Hyperfunctionmentioning

confidence: 99%

“…In this essay, we explore one such new idea about the biology of aging that it is the result of continued activity (hyperfunction) during adulthood of pathways and processes that evolved to optimize development to adulthood. This idea argues that the resulting overgrowth causes pathologies that limit lifespan (4,5). We will first briefly outline the crisis in the oxidative damage theory, then describe the hyperfunction theory, and finally ask whether it could explain aging in one key model organism, the nematode Caenorhabditis elegans.…”

Section: Introductionmentioning

confidence: 99%

Alternative Perspectives on Aging inCaenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?

Gems

Guardia

2013

Antioxidants & Redox Signaling

155

122

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Significance: The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair, and turnover) protect against aging and increase lifespan. Recent Advances: However, recent tests of the oxidative damage theory, many using the short-lived nematode worm Caenorhabditis elegans, have often failed to support the theory. This motivates consideration of alternative models. One new theory, conceived by M.V. Blagosklonny, proposes that aging is caused by hyperfunction, that is, overactivity during adulthood of processes (particularly biosynthetic) that contribute to development and reproduction. Such hyperfunction can lead to hypertrophy-associated pathologies, which cause the age increase in death. Critical Issues: Here we assess whether the hyperfunction theory is at all consistent with what is known about C. elegans aging, and conclude that it is. In particular, during adulthood, C. elegans shows a number of changes that may reflect pathology and/or hyperfunction. Such changes seem to contribute to death, at least in some cases (e.g., yolk accumulation). Future Directions: Our assessment suggests that the hyperfunction theory is a plausible alternative to the molecular damage theory to explain aging in C. elegans. Antioxid. Redox Signal. 19, 321-329.

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“…The TOR-centered model of aging predicts that developmental programming continuation can, but does not always, incidentally increase ROS when ROS act as secondary messengers in regulatory pathways (Blagosklonny 2008). In the TOR-centered model, ROS do not cause aging or senescence; instead, quasi-development, mediated by TOR, causes aging-related diseases before ROS reaches lethal levels.…”

Section: Aging Hypothesesmentioning

confidence: 99%

“…During quasi-programmed development, TOR upregulates various cellular pathways (e.g., cell growth, autophagy, protein synthesis), eventually leading to organismal aging. The TOR-centered model of aging predicts that ROS act as secondary messengers in regulatory pathways, and ROS concentrations can therefore incidentally increase in cells with age (Blagosklonny 2008). Additional hypotheses propose decreasing proteome functionality or the reduction of telomeres with age as mechanistic causes of aging (Walton 1982;Pérez et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Age-related cellular changes in the long-lived bivalve A. islandica

Gruber

Wessels

Boynton

et al. 2015

AGE

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One of the biggest challenges to studying causes and effects of aging is identifying changes in cells that are related to senescence instead of simply the passing of chronological time. We investigated two populations of the longest living non-colonial metazoan, Arctica islandica, with lifespans that differed sixfolds. Of four investigated parameters (nucleic acid oxidation, protein oxidation, lipid oxidation, and protein instability), only nucleic acid oxidation increased with age and correlated with relative lifespan. Nucleic acid oxidation levels increased significantly faster and were significantly higher in the shorter-lived than the longer-lived population. In contrast, neither protein oxidation, lipid oxidation, nor protein stability changed over time. Protein resistance to unfolding stress when treated with urea was significantly lower overall in the shorter-lived population, and lipid peroxidation levels were higher in the longer-lived population. With the exception of nucleic acid oxidation, damage levels of A. islandica do not change with age, indicating excellent cellular maintenance in both populations. Since correlations between nucleic acid oxidation and age have also been shown previously in other organisms, and nucleic acid oxidation accumulation rate correlates with relative age in both investigated populations, nucleic acid oxidation may reflect intrinsic aging mechanisms. AGE (2015) 37: 90

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Aging: ROS or TOR

Cited by 356 publications

References 114 publications

Taking a “good” look at free radicals in the aging process

Taking a “good” look at free radicals in the aging process

Alternative Perspectives on Aging inCaenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?

Age-related cellular changes in the long-lived bivalve A. islandica

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