Mitochondrial Antioxidants as a Contributing Cause of Naked Mole-Rat Longevity

Naked mole-rats exhibit exceptional longevity in comparison to other rodent species. They can live nine times longer than similarly sized mice, for example. There are no doubt a sizable number of distinct mechanisms that contribute to this difference in species life span, and the existence of mammals with widely divergent life spans acts as a natural laboratory for researchers interested in better understanding aging. If one species lives a much longer life than another, then using their differences in order to identify the more important aspects of cellular metabolism in the matter of aging may well be a faster approach than other strategies that aim to reverse engineer the workings of aging. Thus research groups have been energetically investigating the biochemistry of naked mole-rats for many years now.

Naked mole-rats are exceptionally resistant to cancer, to the point at which for all of the populations maintained across the years in laboratories and zoos, only a few cases of cancer have ever been reported. Of late the ability of naked mole-rats to suppress cancerous mutations and cancerous cells has become one of the primary areas of study when it comes to their metabolic peculiarities. Avoiding death by cancer probably isn't one of the most important contributions to naked mole-rat longevity, however.

Instead, it seems likely that at least some of the major determinants of longevity relate to mitochondrial function and cellular resistance to oxidative damage. The horde of mitochondria in every cell act as power plants, but also as a source of oxidative molecules. These are generated as a byproduct of the energetic chemical reactions needed to package up the adenosine triphosphate (ATP) used as fuel for cellular processes. The presence of too many oxidative molecules are harmful to cells, and mitochondria themselves can be damaged by oxidative molecules in ways that contribute to aging. The situation is far from simple, however: oxidative molecules are used as signals for cellular maintenance, and thus small or brief increases are in fact beneficial. Further, antioxidant processes in mitochondria act to clean up much of the exhaust of new oxidative molecules. This is a complex, dynamic system of oxidants and reactions to oxidants that does not lend itself to easy predictions of outcomes.

The membrane pacemaker hypothesis suggests that the important factor in all of this, when considering differences between species, is the composition of cell membranes, particularly those of mitochondria. Different cell membrane lipids are more or less vulnerable to oxidative reactions and consequent functional damage. Species like naked mole-rats, with very high levels of all of the markers of oxidative stress, yet few to no apparent consequences, are perhaps a good argument for the membrane pacemaker way of looking at things. Equally, the research here makes a different argument - that this is all about the degree to which mitochondria can direct their own antioxidant processes to consume oxidizing molecules, and naked mole-rats are much better at this than mice. It is known that raising levels of mitochondrial antioxidants, either via gene therapy or by delivering artificial antioxidants that localize to mitochondria, appears to slow aging in a number of different species. The question, as always, is the size of any specific contribution to the overall outcome.

The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses

Naked mole-rats (NMRs; Heterocephalus glaber, Rodentia) are mouse-sized eusocial mammals native to Eastern Africa that live in large subterranean colonies. Individuals of this species can live for longer than 30 years in laboratory conditions, and also exhibit a remarkably long health span; typical signs of senescence seen in old rodent are mostly absent in NMRs. Conversely, the common mouse (Mus musculus, Rodentia) lives less than 4 years and is highly susceptible to aging-related diseases and physiological decline. As a result, comparisons between these two species are considered to be a "gold standard" in mammalian studies of aging.

According to the oxidative stress theory of aging, senescence is caused by the gradual accumulation of oxidative damage to cells, inflicted by reactive oxygen species (ROS) of mitochondrial origin. However, previous comparative studies of NMR biology mostly provided evidence that contradicted this theory. For example, comparisons of isolated heart mitochondria found no difference in the rate of H2O2 efflux (i.e., the proportion of H2O2 not consumed by the mitochondrion before detection) between NMRs and mice. In addition, extensive oxidative damage and limited antioxidant capacity have been reported in the cytosol of NMR hepatocytes. Taken together, these findings led to the conclusion that the longevity of NMRs occurs independently of enhanced protection against oxidative damage, and this conclusion has been used repeatedly to refute the oxidative stress theory of aging.

More recently, however, the mitochondrial oxidative stress hypothesis of aging has gained empirical support; however, this hypothesis remains controversial, and has not yet been investigated in NMRs. This refined hypothesis stems from the fact that mitochondrial ROS are mostly released inside the mitochondrion (i.e., within the mitochondrial matrix), thereby directly exposing mitochondrial biomolecules to oxidative damage. According to the mitochondrial stress hypothesis, cellular senescence is primarily driven by loss of mitochondrial function with age. A central step toward testing this hypothesis would be to measure the balance between internal production and internal consumption of ROS within mitochondria themselves.

We have recently shown that traditional methodologies for detecting the rate of H2O2 formation from isolated mitochondria underestimate ROS generation because of the remarkable endogenous capacity of matrix antioxidants to consume H2O2. For example, this underestimation can reach 80% or more in rat skeletal muscle with certain respiratory substrates. Moreover, mitochondria can consume far more H2O2 than they generate; therefore, this capacity of mitochondria to consume H2O2 putatively represents a novel and widely underappreciated test of the mitochondrial oxidative stress theory of aging in of itself. We hypothesized that differences in the capacity of mitochondria to eliminate H2O2 might solve the apparent NMR oxidative stress/longevity-conundrum.

To test our hypothesis, we took advantage of antioxidant inhibition methods that we developed previously to measure H2O2 formation rates without the confounding influence of internal consumption. We also compared mitochondrial H2O2 clearance (i.e., maximal consumption) rates between these two species in functional isolated mitochondria. Our results support the mitochondrial oxidative stress hypothesis of aging via a mechanism that has not been previously demonstrated: NMRs and mice do not differ in their rate of H2O2 formation, but rather in the markedly greater capacity of NMR mitochondria to consume H2O2.


Glad to see research is being done on NMR. They are an important outlier, maybe the most important

Posted by: JohnD at February 23rd, 2019 10:20 AM

It would be interesting to s
Do the same experiments with human mitochondria.

Posted by: Cuberat at February 23rd, 2019 7:55 PM

So does his result support efforts to develop and use mitochondrially targeted anti oxidants, or does it support the SRF's attempts to express the thirteen protein coding mitochondrial genes in the nucleus? Or does it support both?

Posted by: Jimofoz at February 23rd, 2019 10:27 PM

Hi Jimofoz! Just a 2 cents.

I would say yes, the study more or less supports that conclusion; but more, yes. It's funny because many studies have foudn conflictual, ambiguous and contradictory results with antioxidants; albeit, mitochondrially targeted antioxidants/enzymes such as mt-CAT (catalase) or mt mn-SOD (manganese Super Oxide Dismustase to mitos), have yielded longevity extension results by simply quenching direct H2O2 from Super Oxide production at Complex I-III of mitochondrial inner membranes. Mice fed mitochondrial anti-oxidants saw improvement in function and reversal of fragility/frailty, and also a strong rejuvenating effect (for example, Ubiquinol, increase mice lifespan, made their gray coat back to dark, make their saggy skin becomes pulpous and 'young'/tight with more collagen, etc...; they live a bit longer but overall, no, did they not reach the age of a Nake Mole Rat either (35 years, in any case, these mice would still be alive after all these years - a total surprise and never heard of past 5 years of mouse life); they died on clock at 2-3 years, thus 'healthy aging' (if you are unhealthy, you will reap benefit, and if you are healthy, the benefits will be lesser/redundant) is what mitochondrial targeted antioxidants give mostly so far). To improve fitness and organ function, by better ATP production in mitos, mitochondrial antioxidant improve function and 'aging' to become 'healthy'..but the aging continues.

Now, there have been Many many studies on mitos, it's such a fascinating 'bacteria' (bacterial origin million years ago when bacterias and cells were two things; with time they symbiozed and mitos entered cells in a symbiose relationship (cell (hoster), mito (hosted/provides cell energy to live); thus a win win situation for both by teaming together (think of it like small fish that continuously harass big fish, yet the big fish do not eat is a symbiosis (big fish (protects small fish/gets 'cleaned in holes/some other favor/service by small fish/does not eat small fish as reward); small fish (is protected from other predator big fish/is not eaten/needs to clean big fish/do something in return for such protection)); Win win situation.

Mitos are very simple overall in function (ATP energy producer), yet very complex in their details of such and many layers. I'll try to give a brief run, studies showed that mitos ROS emission, mitos ROS quenching capacity (which is tantamount to this study here, quncher consuming), mito membrane integrity (membrane pacemaker theory, homeoviscous membrane theory) and mito redox are strong determinants of longevity. But, as time goes, we see there is More nuance to such theories and such reasoning (just like this study here, where they nuanced and said it's not mito ROS, it's mito antiox consumption to quench ROS as they say that the values have been drastically Undervalued/Underrepresented/ Undercalculated and hence why discrepancies and contradictions between studies; and why, people would say mito ROS have no decision in lifespan; it's not the mito ROS, it's the mito antioxidants system - mainly the mitochondrial redox (as they say in the study, between TRX (tioredoxin) and GSH (glutathione); but not just that; mitochondrial CAT, SOD, Ascorbate, etc). One study had showed that TRX and GSH/GSH:GSSG/thiol pools determine redox milieu; even in mitochondrias - that, in order to have 'reduced/sustained' level of ROS at Complex I-II-III, there must be quenching - Continuously.
And, that's exactly what they found. TRX and GSH 'balance themselves out' to obtain a correct 'low ROS basal emission' and to protect the mitochondrial membranes.

like in the membrane pacemaker theory or the Peroxidizability Index determines how 'strong' the membranes are depending on the type of phospholipid fatty acids in them; this another added element of longevous animals. By having more sturdy/unsusceptible fatty acids, lipid peroxidation chains are greatly diminished which means dramatic reduction of surrounding macro-damage and DNA fragmenting/lesions/deletions/mutations. Including mitochondiral DNA and nuclear DNA.

Studies on extreme long lived animals have been conflictual; from one side, low peroxidizability index does indeed increase lifespan, dramatically; but from the other side (other studies), it seems that function can find 'work arounds'; and as such, why for example, the brain has higher peroxidizability index - yet we live very long. Still, there was a connection where high DHA/EPA meant higher peroxidation on brain mito membranes and htus accelerated aging - but , in the inverse, it improved brain health/cognition, by improving membrane fluidity/fast kinetic speed (less viscous by polyunsaturation fluidizing effect, acting 'like water' instead of 'thick viscous saturated fatty acids' (like palmitic acid or stearic acid that create water impermeability/wall but are slow and compact/bad for fast signaling). Still, if these Omega-3 should peroxidize so easily ours brain mito membranes, we would be dead..but we are not...evolution found ways to circumvent this problem.
Such as, improving Redox in long live mammals (better quenching/more consuption of ROS as this study shows), reordering of membrane composition towards low peroxidizability and minimal levels/exposure of Omega-3 'just enough' to function. And, not onlt that, it also changed the composition of certain elements in the membranes, such as adding 'vynil-ether' linkage, which drastically reduce ROS susceptibility and lipid peroxidation. This was demonstrated in extremely long live A.Islandica (from Iceland) quhogs clams that live 500 years. The mantle/foot pedal mitos in their cells showed that, indeed, they have higher plasma logens, more vynil ether linkages, More Redox in Total (total thiol pool to keep mitomilieu 'reduced' instead of oxidized), that they preserve the redox Far longer than other quahogs that live 1 century. They preserve they proteins, thiols, chaperones, intact, undamaged/not unfolded/but neat and no aggregation. They also found a lower Peroxidizability Index in these long live clams; again, demonstrating it's the combinations of many things that allow such extreme lifespan; not one thing.
Not only that, it ties to epigenetics (yes), one study showed that the redox and epigenetics are in constant communication (both feed of each other and regulate each other); but this study demonstrated that with age, epigenetic drift creates redox loss - demonstrating that epigenetic clock is a Big contributor of this mitochondrial redox control of mito ROS/Antiox env. Mitochondrial DNA also has a large say; it was demonstrated taht there is an inverse correlation (and to a certain degree, causation), between mitochondrial lesions formation (8-oxodG)/DNA frags SSBs and MLSP (Maximum Lifespan Potential) in the heart/brain/liver of many mammals ranging from 1 year to a 100 years lifespan.
Thus, it shows that indeed, mitos are extremely important (there quadrillions of mitos in body..that 's a lot...and if they fail, it's catastrophic; imagine a zillion mitos failing, ATP production becomes devoid, the cell is energy starved and Senescence entry or apoptosis/mPTP (mostly) happens then 'mass apoptosis' 'mass senescence'; which means at higher level, organ arrest/cause whole organs system dysfunction/death if essential organ starts working below function 'life sustaining' threshold).

I even read studies that refute that and say :'No, we don't see Antthing about mito antioxidants, they do nothing...and do not save you beyond basic 'sort of' quenching nothing more', like I read a few studies that said : ''No difference in mammal antioxidant system accross different fact, there is LESS antioxidant in certain longer lived animals..why? because they don't need them (they live long already...something must be working - something Else); Indeed, it's why when they looked at parrots vs pigeon vs quail, they saw barely no difference in mitos...sometimes the longest live animal was the least it really muddied the whole thing. It would make sense taht the longest animal would Not need More Protection...they live long no need for more..and it is sort of what they saw : '' Naked Mole rats had much higher damage and no more antioxidative activty..than mice/mice had Strong antioxidant activity to offset the rapid degradation and dysfunction - hence, mice lived short lives''.'s not just 'antioxidant' question, it's 'qualitative' question 'functional question' and many other factors why you muight see an animal live longer yet have less antioxidant activity.

One thing is certain though, in all the longest animal - over time - the redox needed to be maintained, demonstrating that indeed the mitochondrial redox theory and antioxidant theory are true, just very mudded and conflictual. Naked mole rats had much less Omega-3 than mice, same thing for humans; thus much less peroxidizable membranes in mitos (more sturdy/less susceptible to the ravages of ROS and less production of chain lipid perodixdation end products (MDA, TBARS, CML, protein carbonyls, ALEs (Advanced Lipodixation End products)). But, not only that, the naked mole rat preserved its redox much much longer (20 yaers at least until they saw protein carbonyls/oxidize protein sulfur thiols in its mitos/cells), while the mouse's became very oxidized and completely out of whack - accelerating 'epigenetic aging' (as there is mutual talk between epigenome - redox, as said, epigenetic drifting causes redox homeostasis loss - and vice versa). Hence, mouse become dysfunctional very quickly (that's because of their 'master plan': breed fast/a lot/live quick/die young/replace population of specie...humans it's in the inverse specie evolutive master plan (low birthing/no need for more kids all live long/long life/live slow/grow slow/'late puberty' (13 years old vs 1 year mouse)/delayed sexual senescence (menarch/menopause/andropause by delayed endocrinal development)/populate slowly since no one dies/all live ultra-long compared to mouse/more protection/more somatic tissue repair resources/(epi)genetic longevity)).

So to conclude, I would say, that yes, it is worth it; but don't expect mitoquinone/quinol/ubiquinol to ubiquinonize you to eternal life. Mitochondrial antioxidants improve Health, especially, I used them (I have atherosclerosis, I took some for a long while, from everthing like quinols, food antixoidants...astaxanthin, zeaxanthins, cryptoxanthins, astragalus, DHA/EPA, quercetin, resveratrol you name it/I did it and many other mitochondrial membrane entering elements); none of that cured anything but only very mildly stopped symptoms (but it takes a whole lot more than that and it's Long/very long to come back from near death), it did reduce my LDL-ox concentrationa and increased my blood ORAC/TAC (Oxide Radical Capacity/Total Antioxidant Capacity) which means imrpove LDL oxidation lag (meaning your LDL will stay unoxidized longer and 'consume' all these mitochondrial antioxidants before ROS starts to elevate dramaticaly in atherosclerotic lesions and by failing macrophage ROS themselves). Still, in the end, it was not that that helped me, it was cutting the cause, the LDL itself in much too high amount and bad low ratio (HDL:LDL). This allowed to restors correct macrophage function, switch from Liver LDL specie to HDL specie production gene switch (liver receptor-X/reduction of cholesterases for LDL and competing for HDL) and stop macrophage invasion/ROS production to stabilize/remove plaques and avoid clot formation later from unstable plaques rupturing in artery.

Just a 2 cents.

Posted by: CANanonymity at February 24th, 2019 2:12 AM

PS: I should have been more specific to your question, yes, its supports Both: use [of] mitochondrially targeted anti oxidants And - it support [of] the SRF's attempts to express the thirteen protein coding mitochondrial genes in the nucleus.

Posted by: CANanonymity at February 24th, 2019 2:52 AM

CANanonymity, as usual, you're amazing. Do you/did you take MitoQ, and if so, what dose? I've been taking the low, manufacturer recommended dose since early 2017.

Posted by: NY2LA at February 24th, 2019 8:40 PM

Hi NY2LA! Thank you for that. No, I did not, not that specific one; but I took variants of it (like regular CoQ10 (ubiquinone) but also the better unoxidized version ubiquinol; and, it's true, it is quite powerful and goes straight to the mitos (it's no wonder, mitochondrial Complex III of mito ETC is called 'ubiquinol-cytochrome c reductase complex' (or complex III for short). It restores correct electron flow in the ETC (electron transport chain) in the inner membrane and reduces electron leakage during state 3/4 respiration electron flow; it is an electron donor; ubiquinone is less electron-dense; while ubiquinol is electron-rich and better electron-donor (ubiquinol is more expensive then regular Coq10 ubiquinone); that's because the former is oxidized (electrons lost/stolen by ROS) while the latter isn't (is in 'reduced' intact form)). Mouse that were fed both version, saw much more improvement by ubiquinol than regular oxidized coq10; makes sense, much more electron donation from unoxidized ubiquinol (this electron-dense donating makes up for the much higher electron leakage in short-lived animals, which accelerates diseases/even 'premature' aging by faulty mitos' ETC production of ATP). MitoQ is a fat-soluble version of CoQ10 that seems to yield very good results at improving health/diseases; by being more bioavailable/absorbed due to fat solubility/integration in fatty mitochondrial memebranes (thus quench ROS and donate electrons 'at the heart' of the mito ETC). Here is an excerp about somone taking MitoQ:

''I am diabetic as well as CAD in early stages (no stenosis). Have taken all sorts of coQ10 with essentially no noticeable change. Tried MitoQ and after 4 days felt 10-15 years younger. Blood sugar a1c dropped 10 points, loads of energy, liver handling alcohol like when I was in 30's, BP also lower. Best supplement I have ever taken in my 79 years. Can't say that about any other. Alpha lipoic acid and Omega 7 run a distant second and third.''

This is very impressive (I believe this it does not look bogus) (and as he says, only very few antioxidant reach that, such as Alpha lipoic acid (A powerful one), and mysterious omegas-7 (palmitoleic acid, essentially these reorder phospholipid fatty acids composition of mitochondrial membranes towards 'anti-inflammtion signaling' and improved kinetic of a saturated fat (palmitic acid + oleic acid (monounsaturate) -> palmitoleic acid; it's been shown that oleic acid improves function by reducing membrane peroxidizability susceptibility and creates a 'anti-inflammation' signal (vs Omega6 which in high dose increase 'inflammation' signalling such as ARA/arachidonic acid (found in arachides/nuts/ peanuts); and it's Even More strong with palm oil/palmitic acid thrown in (a saturated compact fat - but now more fluidized/faster/lighter but still very sturdy, when combined with oleic acid properties of (mono)unsaturates fatty acids; and why, omega-7 have great benefits))). My father has the same as him, type II diabetes and he took alpha lipoic acid and other mitochondrial antixoidant, they helped, but I think the one that helped the most was metformin (a t2d prescribed supplement (with side effects) from blood glucose control; and he sort went on it/went off of finally come back on it because glucose control is a thing you must do Continuously when you are diabetic; otherwise, once off the pills, the glucose can go wack again and that'S what happened for him). So, whether you take coq10, mitoq or ubiquinol, there are far more positives to taking some (albeit it's the most cheap supplement, it's in the highest priced supplement, but for a reason, it works (especially MitoQ and Ubiquinol) when a lot of everything else does not (do much)).

Posted by: CANanonymity at February 24th, 2019 10:09 PM

Per annual carotid and vertebral ultrasound screening through my general practitioner, my stenosis has mildly progressed from 10 to 20 percent range to 15 to 25 percent since before I started MitoQ in early 2017. I want to get it down to zero. Meanwhile, per Human Longevity, Inc., my calcium score is zero as of March 2018.

Posted by: NY2LA at February 25th, 2019 2:20 AM

I was alerted to the possibility of using MitoQ from this blog in late 2014. That supplement is my all time favorite. I have tried countless (CoQ10, Curcumin, Turmeric, Glucosamine, Lithium etc etc) but never found anything that brings consistent increase to energy levels, heat tolerance until MitoQ.

It is very pricey so I cycle it in and out, I never Went higher than 25mg (5x5mg pills) but wow that gives some boost. I expect it to be classified as a doping agent sooner or later.

Hopefully the producers will increase pill size to 50mg/pill.

Doubt it will save me from Death but it certainly makes Life more enjoyable.

Posted by: arren brandt at February 25th, 2019 3:10 AM

MitoQ is good sh--, especially if you have a fatty acid oxidation disorder. But getting more & more expensive. PQQ, also good sh--. Still wondering if PQQ needs to be cycled.

My big puzzle of the moment is why doesn't CoQ10 do more for Parkinson's Disease patients?

Posted by: CD at February 25th, 2019 2:10 PM

@arren brandt
>MitoQ... I expect it to be classified as a doping agent sooner or later.
I would expect young athletes to already have close to optimal mito metabolism , so no direct performance enhancement here. Probably can be used as for improved recovery after long periods of extreme energy use. Still it might be interesting to see how does it apply to young people. Well, I would be curious to see independent peer-reviewed study on how it works in aged humans too...

Posted by: cuberat at February 25th, 2019 4:53 PM

Now that a couple companies (like mitolab) have finally made skq1 available in the United States, I've switched from mitoq to that. I also take .5 mg if methylene blue in water each morning.

Posted by: August at February 26th, 2019 7:03 PM

#CANanonymity you said "Still, in the end, it was not that that helped me, it was cutting the cause, the LDL itself in much too high amount and bad low ratio (HDL:LDL)."
What did you do for this? Statins?

Posted by: August at November 15th, 2019 4:04 AM
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