Increased Generation of Mitochondrial Reactive Oxygen Species Tends to Slow Aging in Laboratory Species

The interactions between molecular damage in cells, repair system activity, the generation of reactive oxygen species (ROS) in mitochondria capable of causing damage, and individual or species longevity are far from simple. The free radical theory of aging and its variants were early and in hindsight overly simplistic views based on the observation that the presence of ROS and their signs of their damage increase with age. However, numerous methods of slowing aging in short-lived animals involve increases in the rate at which mitochondria produce reactive oxygen species. These molecules are signals as well as sources of damage, and an increase can cause repair systems to overcompensate, producing a net gain in cellular maintenance and reduction in overall levels of damage. It isn't just repair: many of the benefits of exercise are also keyed to temporary increases in ROS levels.

Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the ageing process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artefacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect ageing and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan.

A topic highly debated in the field is the role that mitochondrial ROS play in age related and non-age related pathological processes with a mitochondrial component. Are ROS a cause or a consequence of mitochondrial dysfunction? This is a very important question, which needs to be addressed, since it will affect the treatment of those pathologies. Considering all the available evidence, it is plausible to suggest that ROS can have both positive and negative roles depending on the type of the ROS, when, where and how much is produced. Therefore, we can talk about "Good" and "Bad" ROS. "Good" ROS being low reactivity ROS (i.e. superoxide or hydrogen peroxide) produced at specific places, at specific times and in moderate amounts and "Bad" ROS being highly reactive ROS (or low reactive ROS as hydrogen peroxide or superoxide produced at high concentrations) generated continuously and unspecifically. Experimental evidence suggests that boosting ROS production can contribute to the maintenance of cellular homeostasis and positively affect lifespan when induced correctly, whereas if produced in excess or in an unspecific way, they shorten survival and accelerate the onset of age-related disease.



Maybe it makes sense to understand this in terms of systems. To the extent that either intervention reducing or increasing ROS stimulates and strengthens the system that deals with oxidative stress then longevity is increased. Similarly with exercise both rest and activity increase strength because they both stimulate the system particularly in the context of each other.

Posted by: Chris at March 22nd, 2016 7:53 AM

The authors make a number of good points, particularly if one digs into the free full text, particularly regarding the role of regulated modulation of ROS production in cellular signaling. Still, they demonstrate the too-common over-reliance on and overextrapolation from findings from nonmammalian to mammalian species, and their wording in the abstract of the paper is sufficiently ambiguous as to have misled as perspicacious a commentator as Reason ;) into the headline "Increased Generation of Mitochondrial Reactive Oxygen Species Tends to Slow Aging in Laboratory Species."

Note that the abstract is at least careful enough to say "boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan," by which they here intend invertebrates such as yeast, nematodes, and fruitflies. But then they try to argue that this has some significance for mammalian aging, which is quite another matter, and which they try to support with some rather shoddy arguments.

If you look at the figure tabulating the lifespan findings, all of the findings of increased LS from boosting mtROS production are in such species, 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) [mutation of which increases 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 ...

Posted by: Michael at March 22nd, 2016 5:18 PM

Hi all! : )

I believe this reaches the mitohormesis effect of NRF2 translocating to the nucleus and activating SIRT1/DAF-16/Foxo3a (just like in CR) and ARE/EpRE Phase II detoxification enzymes. Some low-to-mild ROS stress can be good and act as hormesis signal by ROS signal (hormesis activating antioxidative enzymes in compensation to ROS oxidative 'still-healthy' dosed mild-stress). It is one reason why exercice increases ROS production, paradoxically, but improves health through NRF2 redox master switch that, upon increased stress translocates and, activates hundred of antioxidative enzymes (Antioxidative Response Element (ARE) and Electrophile Response Element (EpRE)).

Still, as mentioned, this is not viable for extreme MLSP. Increased mitoROS production will eventually tip the balance towards oxidative stress and an increased oxidized Redox milieu (mitochondrial glutathione, cellular glutathione, cytosolic, nuclear, extracellular glutathione and total glutathione pool will become oxidized). We have to understand that mitochondrial ROS by Complex I and III in the mitochondrial innermembrane in itself is not so important; it is the aftereffect (wave/shockwave) of it. Meaning destruction of mitochondrial DNA and, the mitochondrial membrane itself(which accelerates telomere loss in the nucleus, mitochondrias and telomeres act in concert), but most importantly, increased production of membrane peroxidation toxic residues that have an Order of magnitude effect on intrinsic aging; far more than anything so far. Replicative aging is greatly accelerated by this mechanism.

We can infer that because for example, Naked Mole Rats live 30+ years and lab mice live 3 years, a dramatic diffence, not talking about a mouse living 50% more but here this a mouse living 30 years (1000%). Innermembrane peroxidation is 10-fold in liver mice mtmembranes because it has 10-fold more peroxidizable-susceptible unsaturated dha Docosahexaenoic acid fatty acids in their phospholipids (mainly phosphatidylcholine and ph''ethanolamine). Dha, via lipid signaling, modulates mitochondrial ROS production, depending on membrane fluidity, anisotropy, PI, inner membrane potential (mV) and host of other reasons. But the most important reason, is that this extremely damaging fatty acid in itself, is 320-times more peroxidizable and humans have high antioxidant levels that protect against their own high DHA content. But, overall, humans have low DHA and total PI (peroxidizable index) in mammals (membrane fluidity/pacemaker hypothesis), it allows extreme lifespan when the Redox itself stop only what it can of the entire mitochondrial propagation 'products' from aldehydes (MDA-TBARS) from the lipid peroxidation of unsaturated fatty acid chains; which destroys mtDNA and telomeres too (these residues are far reaching and MLSP was demonstrated by the mitochondrial PI in select organs. For example, bowhead whales have lower DHA in the heart, lower metabolism, lower chemical reactions from reduced metabolism and lower heart mitoROS/lower peroxidation residues than human hearts, they also live to 211 years old). Mitochondrias can only do so much themselves and be protected by redox mtglutathione pool; it still does not stop mitoROS from destruction of membrane lipid unsaturated fatty acids, which contribute to massive destruction of mtDNA and extra-cellular matrix by amounts of aldehydes (which lead to formation of lipid age pigment, lipofuscin, AGEs, crosslinks, protein carbonyls, all closely related to aldehydes level, the major main instigator). It makes a whole lot of sense, mitochondrias create the cell ATP energy, destroy them and replace them all you can, this is a short-term fix, in the long-term mitochondrial failure will drive cell energy deficit, cell stalling/replicative/proliferation arrest and cell replicative aging acceleration. You need your mitochondrias to function optimally to allow cell survival and, for certain proliferation cells, cycling to continue. At least, in mammals, it's definitely the case and that is why we can corroborate mitochondrial protection/function will extreme longevity (evolution solved the riddle by altering mitochondrial inner membrane lipid composition and lipidome : instead of repairing damage or slowing it, it would avoid it altogether by removing it at the source in the quadrillions of mitochondrias (throuhg lipid modulation/change)). This is also why studies in mice are not the best longevity model for human translation. I sincerely hope they study more long-lived models (at least go with a NMR that lives 30 years, we have more in common by that fact, short-lived mammals effects don't translate well to long-lived ones, NMRs are quite long-lived, it may take longer to see the effects (scientists having to wait a long time in long-lived models) but it would be worth it too, to add to the mice. What good is studying a short-lived model if it is not compatible/translatable, seems almost like a waste of precious research time/energy; when they could concentrate on more long-lived resembling models. So many studies showed that translatability/compatibility failure is the number one reason why research on mice or other short-lived models is futile; unless they can create a mouse that reach NMR age, it's better to study NMRs themselves, they are, already, at that long-lived age, like us. Better to put more time, waiting after them, and getting real, applicable, to us results.

Posted by: CANanonymity at March 22nd, 2016 8:57 PM

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