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Hypoxia and lifespan

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Hi ,
This study mentions that "Transient hypoxia extends lifespan through TOR signaling"
This other one mentions that

-impaired mitochondrial respiration extends the life span of yeast, C. elegans, Drosophila, and mice
-reduced mitochondrial respiration could lead to longevity in mammals and suggest the existence of evolutionary conserved underlying mechanisms.

What are your thoughts about that? Is there any volunteer to test intermittent hypoxia  (1) with cold exposure & CR+intermittent fasting ? :Dxyz

 

1) breathing pattern of of one of the  longest known living animals :whales according to this brochure

 

Tasbin

Edited by tasbin

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Tasbin,

 

Hmmm... Intriguing, but I'm leery about exploring hypoxia, or oxygen restriction (OR). The life extending effects of OR have only been observed in C. elegans. In fruit flies (drosophila), any changes in atmospheric pressure appears to reduce lifespan [1]:

 

 In the survivorship test, all changed atmospheric conditions caused a significant reduction in lifespan. The lifespan reduced more after hypoxia exposure than after hyperbaria exposure.

 

That evidence, coupled with the fact that Roy Walford attributed the Parkinsons-like illness that finally killed him to working in low oxygen conditions in the Biosphere II [2] makes me especially wary of messing with oxygen level.

 

That said, I think it plausible that holding one's breath in cold water for occasionally and for short periods of time might be potentially beneficial combination of CE and OR, and trigger the mammalian diving reflex, although the evidence (e.g. here and here) seems to point the other way, i.e. the risks of underwater breath holding appear to outweigh the potential benefits. Plus sleep apnea represents a form of intermittent oxygen deprivation, and it isn't thought to be beneficial, to put it mildly, although there is a lot more going on with sleep apnea than simple oxygen deprivation.

 

I'd love to see evidence that suggesting benefits of underwater breath holding, since I love cold, and swimming, and holding my breath underwater.

 

--Dean

 

-----------
[1] Arch Insect Biochem Physiol. 2015 Apr;88(4):222-34. doi: 10.1002/arch.21217. Epub
2014 Dec 22.
 
Effects of oxygen concentration and pressure on Drosophila melanogaster:
oxidative stress, mitochondrial activity, and survivorship.
 
Bosco G(1), Clamer M, Messulam E, Dare C, Yang Z, Zordan M, Reggiani C, Hu Q,
Megighian A.
 
Author information: 
(1)Department of Biomedical Science, University of Padua, Padua, Italy;
Hyperbaric Center Association Hyperbaric Technicians ATIP, Padua, Italy.
 
Organisms are known to be equipped with an adaptive plasticity as the phenotype
of traits in response to the imposed environmental challenges as they grow and
develop. In this study, the effects of extreme changes in oxygen availability and
atmospheric pressure on physiological phenotypes of Drosophila melanogaster were 
investigated to explore adaptation mechanisms. The changes in citrate synthase
activity (CSA), lifespan, and behavioral function in different atmospheric
conditions were evaluated. In the CAS test, hyperoxia significantly increased
CSA; both hypoxia and hyperbaric conditions caused a significant decrease in CSA.
In the survivorship test, all changed atmospheric conditions caused a significant
reduction in lifespan. The lifespan reduced more after hypoxia exposure than
after hyperbaria exposure. In behavioral function test, when mechanical agitation
was conducted, bang-sensitive flies showed a stereotypical sequence of initial
muscle spasm, paralysis, and recovery. The percentage of individuals that
displayed paralysis or seizure was measured on the following day and after 2
weeks from each exposure. The majority of flies showed seizure behavior 15 days
after exposure, especially after 3 h of exposure. The percentage of individuals
that did not undergo paralysis or seizure and was able to move in the vial, was
also tested. The number of flies that moved and raised the higher level of the
vial decreased after exposure. Animal's speed decreased significantly 15 days
after exposure to extreme environmental conditions. In summary, the alteration of
oxygen availability and atmospheric pressure may lead to significant changes in
mitochondria mass, lifespan, and behavioral function in D. melanogaster.
 
© 2014 Wiley Periodicals, Inc.
 
DOI: 10.1002/arch.21217 

 

PMID: 25529352
 
-----------
[2]  Mov Disord. 2004 Apr;19(4):465-9.
 
Atypical parkinsonism and motor neuron syndrome in a Biosphere 2 participant: a
possible complication of chronic hypoxia and carbon monoxide toxicity?
 
Lassinger BK(1), Kwak C, Walford RL, Jankovic J.
 
Author information: 
(1)Parkinson's Disease Center and Movement Disorders Clinic, Department of
Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
 
Exogenous toxins and chronic hypoxia have been implicated in the etiopathogenesis
of a variety of neurological disorders, but it is not always possible to
establish a cause-effect relationships. We describe a patient who presented with 
an unusual gait disorder and progressive motor neuron disease after residing for 
2 years within Biosphere 2, a scientifically engineered dome, tightly sealed to
allow miniscule exchange of air between its atmosphere and the earth's
atmosphere. We postulate that this unusual syndrome resulted from chronic hypoxia
possibly coupled with carbon monoxide and nitrous oxide exposure.
 
Copyright 2004 Movement Disorder Society
 
DOI: 10.1002/mds.20076 
PMID: 15077246

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Hi ,

This study mentions that "Transient hypoxia extends lifespan through TOR signaling"

This other one mentions that

-impaired mitochondrial respiration extends the life span of yeast, C. elegans, Drosophila, and mice

-reduced mitochondrial respiration could lead to longevity in mammals and suggest the existence of evolutionary conserved underlying mechanisms.

 

First, as I've said many times in the past (and now have an additional reason to emphasize), one should ignore studies on interventions in aging in nematode worms (C. elegans), fruitflies (Drosophila), and all other non-mammalian species: they just don't age or anti-age in remotely the same ways as mammals.

 

The claim that "impaired mitochondrial respiration extends the life span of ... mice" is false. A recent paper tried to argue this, eg, and none of it held up: If you look at the figure tabulating the lifespan findings, all of the findings of increased LS from boosting mtROS production are in yeast and invertebratess, and one cited example (administration of drugs that inhibit different Complexes of the mitochondrial electron transport chain) is known to cause severe pathology in mice: two of them (rotenone and MPP+) are dopaminergic neurotoxins used as standard ways to create Parkinson's-model mice, and indeed, MPP+ is actually the active downstream metabolite of MPTP, which is a well-established cause of a Parkinsonian disorder in humans.

 

The only mammalian finding cited in the table is mutations in MCLK1 (a gene required for CoQ10 biosynthesis) in mice, of which the authors actually say "Although mutations in MCLK1 in mice increase ROS levels, there is no definitive evidence that boosting ROS extends lifespan in mammals." This is a bit too non-definitive, in fact: indeed, elsewhere, they note that "Siegfried Hekimi's laboratory has shown that controlled disruption of Coenzyme Q (CoQ) biosynthesis, through knock-out of the Mclk1 gene, severely affects mitochondrial function and dramatically reduces lifespan," which they try to reconcile with their overall thesis by arguing that because

 

restoration of CoQ levels through administration of ... the natural precursor of CoQ) that is only able to partially rescue the mitochondrial phenotype completely rescued the shortened lifespan of Mclk1 mutant mice. This result is totally unexpected [!], as chronic mitochondrial dysfunction should cause the accumulation of irreversible damage and a shortened lifespan ... Hekimi's work suggests [38] that mitochondrial dysfunction per se does not cause ageing, as replacement of damaged mitochondria with functional mitochondria instantly restored a youthful phenotype.

 

But this summary ignores the fact that, despite what could accurately be characterized as mt dysfunction, these mice did not suffer any increase in mtROS generation nor any rise in oxidative stress or damage, but in fact (as the Hekimi paper notes), their mutation "significantly decreased H2O2 production in mouse heart mitochondria (Fig. 5a)", which they tie to the fact that CoQ10 "is closely involved in superoxide generation by the respiratory chain. Accordingly, these animals also suffered no increase in oxidative stress. So whatever else one thinks this indicates about the role of mitochondria in aging, it simply cannot be used to support the idea that "This defies the dominant paradigm that states that chronic mitochondrial dysfunction accelerates ageing," if by "the dominant paradigm" one means the thesis that accumulating damage from mtROS help drive the process.

 

Elsewhere in the paper, they claim that "heterozygous mutations in MCLK1 ... extends lifespan in mice": this ignores the fact that all the animals in the study — the controls, the mutants, and the CoQ-restored animals — were aberrantly short-lived — an all-too-common problem in lifespan studies claiming "extended lifespan" when what it really shows is one group of animals not living quite as miserably short a lifespan as another.

 

And, the authors themselves correctly note that "mutations in the mitochondrial polymerase (DNA polymerase γ) [which mutations increase the rate of accumulation of mitochondrial DNA mutations] has also been shown to accelerate ageing [39] through a reduction in mitochondrial function [40]". The pol-γ mice aren't actually good support for MiFRA, because most of the damage they suffer is done during embryonic development and affects stem cells, rather than by driving a lifelong increase in ROS generation and mtDNA mutations — but it certainly can't be used to support a claim that such an increase is compatible with normal or even increased lifespan. And for some reason, this finding is not mentioned in their Table, or elsewhere in the paper ...

 

David Carradine seemed unnaturally healthy for his age.  Now we know why.

In case I'm not the only one who didn't get the allusion ...

 

That reminds me of dry Douglas Adams quote: "It's not the fall that kills you; it's the sudden stop at the end..."

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This seems relevant in this thread.  This man has experienced quite a bit of hypoxia, granted for a goal other than longevity. Interestingly, he has also completed a 44-day fast.

 

Edited by drewab

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