Early Mitochondrial Dysfunction in Long-lived Mclk1+/- Mice

Lapointe, Jérôme; Hekimi, Siegfried

doi:10.1074/jbc.m803287200

Cited by 199 publications

(214 citation statements)

References 68 publications

(58 reference statements)

Supporting

Mentioning

205

Contrasting

Unclassified

Order By: Relevance

“…In this way the mutations also delay the onset of the thresholds that lead to the run-away process and thus to a negative effect of ROS on the aging process. This could explain why both C. elegans and mouse mutants with elevated mitochondrial ROS generation [43,48] have low levels of overall ROS damage [51,58]. Similarly, the hypothesis also provides an explanation for why overexpression of antioxidant proteins or treatment with antioxidant drugs are unable to extend lifespan and rather cause cellular dysfunction [59] (Figure 1).…”

Section: The Gradual Ros Response Hypothesismentioning

confidence: 97%

“…Mclk1 +/− mice lack one copy of an enzyme that is necessary for the synthesis of the antioxidant and redox co-factor ubiquinone [47]. This leads to numerous metabolic changes but in particular to an increase in mitochondrial oxidative stress [48], which is deleterious under some experimental conditions [49]. Surprisingly these mutant mice not only live longer than wild-type siblings [50], they also show a much slower development of biomarkers of aging, including a slower loss of mitochondrial function [51].…”

Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

“…Mclk1 +/− mice sustain high mitochondrial oxidative stress but live longer than their wild type siblings [48,50]. High levels of oxidative damage have been observed in several tissues of very long-lived naked mole rats (NMRs) [56].…”

Section: Figure 2 High Ros Phenotypes That Affects Aging and Lifespamentioning

confidence: 99%

See 2 more Smart Citations

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

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

Self Cite

495

348

View full text Add to dashboard Cite

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 *

show abstract

Section: The Gradual Ros Response Hypothesismentioning

confidence: 97%

Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

See 1 more Smart Citation

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

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

Self Cite

495

348

View full text Add to dashboard Cite

show abstract

“…However, we have recently presented a new aging study with a large sample size in a mixed background which showed again that Mclk1 +/− mutants live significantly longer than controls [45]. To date, virtually all our findings resulting from the analysis of the phenotype of the long-lived Mclk1 +/− mice appear irreconcilable with the MFRTA [45,53]: 1) We found that mitochondria in young Mclk1 +/− mutant are dysfunctional despite normal levels of ubiquinone: for example they display slow electron transport, contain low levels of ATP, and sustain high oxidative stress. Yet these mice are long-lived and their altered function ultimately results in a significant attenuation of the rate of development of non-mitochondrial oxidative biomarkers of aging.…”

Section: From Incompatible To Irreconcilablementioning

confidence: 97%

When a theory of aging ages badly

Lapointe

Hekimi

2009

Cell. Mol. Life Sci.

Self Cite

223

150

View full text Add to dashboard Cite

According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species (ROS) during cellular respiration is THE cause of aging. However, although it is clear that oxidative damage increases during aging, the fundamental question regarding whether mitochondrial oxidative stress is in any way causal to the aging process remains unresolved. An increasing number of studies on long-lived vertebrate species, mutants and transgenic animals have seriously challenged the pervasive MFRTA. Here, we describe some of these new results, including those pertaining to the phenotype of the long-lived Mclk1 +/− mice, which appear irreconcilable with the MFRTA. Thus, we believe that it is reasonable to now consider the MFRTA as refuted and that it is time to use the insight gained by many years of testing this theory to develop new views as to the physiological causes of aging.

show abstract

“…Support for the gradual ROS response hypothesis of aging comes from different studies in which increased oxidative stress in mitochondria of young animals protects against agedependent loss of mitochondrial function [117] and, in some cases, increased longevity [118]. The discrepancies between the studies that correlate antioxidant administration to longevity can be approached taking account of this theory, so that it is not ROS accumulation that causes oxidative stress and consequent aging, but more an imbalance between the protective and toxic roles of ROS.…”

Section: Alternative Role Of Rosmentioning

confidence: 99%

MECHANISMS LINKING mtDNA DAMAGE AND AGING

Pickrell

Wang

Pinto

et al. 2013

Free Radical Biology and Medicine

View full text Add to dashboard Cite

In the last century, considerable efforts were made to understand the role of mtDNA mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the last few years, however, new elements have discredited this original theory. The major source of mitochondrial DNA mutations seems to come from replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms appears to occur by clonal expansion and are not caused by a reactive oxygen species-dependent vicious cycle.New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging, and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.

show abstract

Early Mitochondrial Dysfunction in Long-lived Mclk1+/- Mice

Cited by 199 publications

References 68 publications

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

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

When a theory of aging ages badly

MECHANISMS LINKING mtDNA DAMAGE AND AGING

Contact Info

Product

Resources

About