Naked Mole Rats as the Outlier Species, Thriving with High Oxidative Stress

Rising levels of oxidative stress occur with aging. This term describes the presence of excessive numbers of oxidative molecules, reacting with surrounding molecular machinery to cause breakage and cellular dysfunction. It is significant enough in aging for the free radical theory of aging to have arisen some decades ago, postulating that oxidative damage was the cause of aging. Alas, matters are not that simple. Persistently raised levels of oxidative stress are a downstream consequence of deeper causes, such as mitochondrial dysfunction, chronic inflammation, cellular senescence, and the like. Further, oxidative molecules do in fact serve a necessary and useful role in healthy cellular metabolism. They act as signals to spur cellular maintenance, for example, and thus small or temporary increases in oxidative stress tend to be beneficial. This is one of the mechanisms by which exercise produces health benefits.

Naked mole rats are a strange species, an outlier among rodents. They are eusocial, like some insects. They live nine times longer than similarly sized rodent species, and show few signs of aging across most of that life span. They exhibit high levels of oxidative stress, but appear near completely immune to the consequences that would appear in rats or mice given the same flood of oxidative molecules. They show the presence of senescent cells, but appear largely unaffected by that as well, which is interesting given the very prominent role played by the harmful, inflammatory secretions of senescent cells in the aging and age-related diseases of mice. Finally, naked mole rats are near immune to cancer.

Needless to say, researchers are quite interested in learning how exactly of all this is possible. Might any of the findings result in biotechnologies that can be applied to humans, to shut down cancer, or resist aging? No-one knows. My suspicion is that it will take a while to find out, and there is a good chance that altering humans to be more like naked mole rats is not a near term project - something for the latter half of the century, not the next few decades. I would say we are better off trying to repair the metabolism we have rather than building a better one, given the present state of biotechnology. It is a much more plausible goal.

The Naked Mole Rat: A Unique Example of Positive Oxidative Stress

More than 60 years ago, it was first proposed that aging could be attributed to the deleterious effects of free radicals produced as natural by-products of aerobic metabolism. The free radical theory of aging (FRTA) is based on the hypothesis that dysfunctions observed during aging and a range of age-associated pathologies are due to the accumulation of oxidative damage to biological macromolecules (e.g., DNA damage, lipid peroxidation, and nonrepairable protein oxidation) by reactive oxygen and nitrogen species. A more precise version of the free radical theory of aging, called the mitochondrial free radical theory of aging (MFRTA), specifies that mitochondria are the main sources of reactive oxygen species (ROS) generation and are also the targets of deleterious effects: oxidative damages to mitochondrial DNA, mitochondrial proteins, or phospholipids are assumed to directly cause aging.

Naked mole rats (Heterocephalus glaber), first described in 1842, are the longest living rodents known. Several studies have investigated the production of free radicals and oxidative damages in the naked mole rat, and the results are puzzling. Despite remarkably long lives, some tissues of the naked mole rat, such as arteries, produce higher amounts of ROS (from cytoplasmic and mitochondrial sources) as compared to these tissues from the short-lived mouse. Importantly, the arteries of naked mole rats are highly resistant to the pro-apoptotic effects of ROS in vitro, whereas those of the mouse are not.

Furthermore, several studies have shown that naked mole rats have high levels of oxidative damages to macromolecules from a young age. Interestingly, these levels of damages are maintained over a 20-year period without increase. One hypothesis is that further damages are attenuated by an efficient repair system. A limit of these studies is that only damages to macromolecules were investigated: mitochondrial DNA damage has not been studied in naked mole rat tissues. Hence, further studies using this unique animal model are needed as it would be very informative to compare ROS-producing systems from cellular and mitochondrial sources and oxidative damage in nuclear, cytoplasmic, and mitochondrial targets in long-lived naked mole rat and short-lived rodents.

Many, but not all, features of the naked mole rat defy the free radical theories of aging. However, there is a recent extension of the theory, called the membrane pacemaker theory of aging, which holds true in the naked mole rat. This theory predicts that membrane fatty acid composition has an influence on lipid peroxidation and consequently may be an important determinant of aging and lifespan. Indeed, a study showed that naked mole rat membranes from different tissues contain more fatty acids resistant to peroxidation than do membranes from mice. Thus, the cellular membrane composition of the naked mole rat could partially explain their exceptional longevity. Still, the "naked mole rat exception" raises the question of whether or not ROS (cytoplasmic and mitochondrial) are responsible for aging.

Comments

Hi there ! Just a 2 cents.

NMRs are eternally elusive. But not so much anymore, they are now 'naked' as we know their secrets. I explained before that there are several reason why NMRs can outlive mice by nearly 10 times...

''Thus, the cellular membrane composition of the naked mole rat could partially explain their exceptional longevity. Still, the "naked mole rat exception" raises the question of whether or not ROS (cytoplasmic and mitochondrial) are responsible for aging. ''

Exactly, partially, explains it. ROS themselves, technically, no. Excess ROS -> Health threshold loss (apotosis/senenscence/inflammation/diseases). Excess ROS is not a form of aging, it is a form detruction irrespective of what goes in methylome. You see this with mouse vs pigeon heart...pigeon producing less H2O2 units/per O2 vs mouse..in mitochondrial H2O2 emission rate. Pigeon lives 35 years, mouse 3 eyars... just like NMRs..a rought 10 times..pigeon heart lower membrane pacemaker PI (peroxidizability index) - this makes Much less Peroxidation End products (the ALEs variety) and protein carbonyls, CML/MDA/TBARS lipoperoxidation chains that 'fry' the mtDNA. In doing so, this causes disturbances, up in the nucleus, in the chromosomes down to the methylome and alter the redox. Telomeres shorten (of course), and the whole thing becomes unstable. ROS are signaletic and helpful in that sense, but too much of something, is just as bad as none. It's why ROS are needed for NRF2- phase II redox detoxification activation - it goes to detoxify all the crap that happens around the mitochondria (mitochondrial redox is crucial (for cell homeostasis and detoxification of its own lipoperodixation chains at Complexes)...and NMRs maintain it, like humans, like pigeon ...
unlike, mice). The mitochondrial DNA damage is high in NMRs which is paradoxal...but, that is where, teh redox, epigenetic elements come in and can nullify, some of that, including the membrane lipid reordering caused by evolution selection pressure in mitolipidome genes/enzymes/proteins (namely the desaturases and elongases enzymes which cause lipid reodering towards lowered susceptibility to lipoperoxidation of the long-chain PUFA (ARA/DHA/EPA) Omega-6/3 fatty acids in PE and PC mitophospholipids).

But, one study, showed that despite NMRs having higher oxidative stress load than mice, they keep their proteins intact/no protein carbonylation/unfolding...keep a reduced redox and low PI; all this makes up for the high ROS rate they may have in certain tissues. Thus, just another game plan that works.

Just a 2 cents.

Posted by: CANanonymity at March 24th, 2019 5:43 AM

Some studies have shown that the Naked Mole Rats have a different composition for their cellular membranes:

https://www.ncbi.nlm.nih.gov/pubmed/18029129

How can we get our cellular membranes to look more like theirs? Can a change of diet or supplements help?

Posted by: san at March 24th, 2019 8:42 PM

Hi san! Thank you for asking. Just a 2 cents.

Yes. There are several ways but it would not make us have 'as drastical' effect as that that happened in other animals; the reasons is because, currently, the human Already has Very Low Peroxidizability Indeix..so, lowering it even more is dangerous -for humans...you might say, then why does other animals have it Lower than us and Liver longer, shouldn't they be dead?

That is because we have different master plans/blue prints, we share genetics but our programs are differents (master plan/purpose in life/for specie survival). For example, it was demonstrated that reduced ARA (20:4) arachidonic acid, helpd to reduce inflammation for this acid is involved in prostanglandins formation and other inflammatory molecules; it also acts ont he immune system (inflammatory cytokines IL-6/INF-g), it's a long subject to explain rapidly but I try to make it short.
The composition of membranes is iportant because it dictates many things like metabolism/mitochondrial kitentics and such...plus, it also, determines level of 'susceptbility' (sorry my typos..), to lipid perodixation of the longest-chain fatty acids (like OMega3, DHA (22:6) EPA (20:5)), these fatty acidshave great benefits (for example your brain needs it, Omega-3 boost brain power...except..at a cost..it increases Susceptibility of membranes to lipoperoxidation - thus 2-faced/doubled-edge..like most anything in the body; there is always a (anti)compensatory/inverse/'dark twin'/'good twin'...somewhere, yes, just like 2-Face in comic book Spiderman; or like a 'good voice' and the a 'devil voice'; it'S a balance.

Naked Mole Rats have less DHA in their membranes, a huge contributor of lipid peroxidation - DHA - itself gets peroxidized and releases a cascade of molecules that create macro-molecular damage and destroy the mtDNA (really close-by), it demonstrates 8-oxodG mitolesions and deletions (literally, chunks, of mtDNA gone; thus 'holes' if you will) also.

Naked Mole Rats don't have a brain developped as much as a human (albeit there's is developped..but the human as longer period of development..but humand and naked mole rat have long neoteny period/brain plasticising...they are just 'late' to become adults for sexal reproduction - thus late puberty, late puberty means postponing the evolution survival of species purpose (make kids for specie continuity - if no kids no specie...if less kids...then each animal/human Must live Much longer to make up for low/late birthing; keeping the specie number intact. Mice, it'S the inverse. short life, many pups, real quick, rinse and repeat)).

Naked Mole Rats and Humans have 'just enough' DHA/EPA/PUFAs To 'function' well...studies have demonstrated that children/adults that had lackings in nutrition (nutrition deficiencies/malnutrition/undernutrition..not overnutrition), has 'disturbances' in their cellular mitochondrial membranes; mainly, at the DHA/EPA/ARA...and the saturated fatty acids, such as, Palmitic acid (16:0), Stearic Acid (18:0),...they even saw increase or decrease (Varying..) of Oleic Acid (18:1) a Monounsaturated fatty acid...they also saw decrease of cardiolipin and linoleic acid (18:2), the lowest/smaller PUFA, and the most protecting one, because it is the shortest carbon chain - PUFA (poly-unsaturated fatty acid 18:*2*, 2 double bonds/kinks; poly; 18:*1*, Mono-unsaturated, 1 kink);
20:4, 20:5, 22:6 Long-chain polyunsaturates (with 4-6 kinks - much more 'places' to attack, much more susceptible than short-chain polys and monos; or saturates). They also the increase of weird fatty acids, like Mead acid etc (20:3)...they saw reduction of 18:3 (LinoLenic acid), a precusor of Omega-3 Long-chain (out of 18:3, elongase increase it to 18:5/18:6 desaturases increase these to 20:5, 22:6 DHA/EPA). So there were changes in the lipid composition of these undernourrished children..many were suffereing and unhealthy or dying even...

The point I am trying to say is that this 'lipid composition' is Very Tightly Regulated..and small changes to it can yield pretty serious changes..for example, it was demonstrated that people suffering of Marfan Syndrome have much lower levels of DHA/EPA...in mitochondrial membranes, in fact they have a Lower PI then healthy people, so their cells have LESS lipoperoxidation than healthier people whom have HIGHER lipoperoxidation; demonstrating, that these fatty acids - are crucial - for function, if your 'delipidate' you can cause utter chaos as mitos will bbecome completely dysfunctional and ATP production devoid.

With that said, you can do something, for example, through food, you consume certain fatty oils that may alter the membrane..if you eat Omega-3 fish oil..you will increase the content in yoru membranes, it will improve your brain health/sharp thinkinh...BUT...it will increase lipid peroxidation, thus, it will only cause you to 'healthy aging'..which means you will keep health...age..and then die later, say 95 or something (for example).

Jeanne Calment she ate Lots of Dark Chocolate and ate a sh*ton of olive oil (and survived it ironically), she 'reordered' her membrane towards 'less peroxidation' - she obtained more Monounsaturates (from olive oil, mostly oleic acid 18:1 (oleic/olives-found fatty acid, present in everything)). She also ate dark cocoa chocolate, has tons of resveratrol from cocoa bean and drinking red wine, she ate the 'butter' part of chocolate (along with cocoa liquor), the butter part is the fatty part of chocolate - it's saturated/very with 16:0, but mostly 18:0 (stearic acid), thus she increased a bit a least the level of 'saturates' in her membranes - saturates are Extremely Resistant to lipoperoxidation phenomenon (no kinks/ROS can't attack -> 18:*0*), up to 320x most resistant than long-chain PUFAs - thus extremely sturdy - no damage - no lipid peroxidation chain. In that sense, that's a good thing, except one thing, saturates cause many problems mostly cardiovascluar prob like Atherosclerosis (I have it), CVD, etc...they, much like cholesterol LDL, cloggs arteries and create problems there (they are akin to Trans-Fats..the deadliest oness...or Hydrogenated Fats, very toxic), certain trans-fast are helpful very few (like CLA, to lose weight, a fat in milk of cows).
I ate dark chocolate, I ate olive oil (extra virgin, cold pressed, organic, from Greece), I drank red wine & pure grape guice...it did not stop anything. Atherosclerosis came, because I did not cut the culprit, all the crap food (cholesterol juink...eating burgers, eggs (here I was thinking, eggs will same me...(no), 'eggs&bacon..had that a lot...''waky waky - eggs & baky..except there is no more waky waky you're dead). popcorn (at movies, ladden in butter...), probably all the cheese fat and butter fat i put on corn...oh an corn syrup... recipe for death). These elements stave off things a bit...but, it is part of comprehensive change of all diet..if you do that then yes you improve mitochondrial lipid peroxidation and you might even Increase the PI (peroxidizablity Index) in your membranes, it sounds bad (and it is because it 'ages you') but it's better because you are alive -so your health is maintained. This fatty acids all specific signaling function in membranes, most of them are needed in acareful balance to make 'function', unbalace too much - creates dysfunction. and More lipidperoxidation. So, despite, these fatty acids Contributing to your aging (since they are the Culprits of Lipid Peroxidation when they are peroxidized by ROS at Complexes- they are the Source/Targets that upon 'attacked' by ROS - damage 'the rest' in a cascade of Lipid Perodixation End Products (ALEs), these far reaching residues damage everything.

On, the inverse, you Need Them - at the same time...talk about a dual/paradoxal..we want to do Withtout them..but we can't..evolution outwitted us once more. You need them because of their crucial signaling and kinetic functions in mitos; remove them and then..that's it dysfunction (as seen with people with Marfan Syndrome or Delipidation syndromes or people undernourrished/low Omega-3 -> low IQ/brain poor/brain mito membrane 'delipidated' -neuron need fast fluid/kinetic - High-chain Omega-3 provide that..except they age/peroxidation - ''d*mn if you do, d*mn if you don't'').

Just a 2 cents.

PS: It is Better to increase the Omega-3 level naturally and make 'natural healthy aging' rather than suffer of frailty or undernourishment or delipidation...you might have less lipoperoxidation, but the dysfunction will be Much more consequential on your health...Thus...you need them, and thus, the bestest answer of the 'worse' is that taking some is better than not taking. Children with low Omega-3 brain suffer mentally and can have low scores in school/lower IQ...same thing with centenarians, those with low levels are demential or show brain degeneration..demonstrating that evolution 'put us in a rut' and what other animals that have Very Little DHA/EPA...and live very long lives -Does Not work for us (humans), thus, non-translatable to humans (unless severe life/health defects).

Posted by: CANanonymity at March 25th, 2019 12:00 AM

Sorry for offtop

CANanonymity , Thanks for your answers.
You have a deep knowledge of aging issue. Tell me, please, what is your background? PHD ?

Posted by: Kianysh at March 25th, 2019 11:58 AM

Hi Kianysh! Thank you too. No, I wish ;)...simply self-taught (ok it was long...for 10 years I reserached and 'filtered' the entire nhi medical papers (50,000); it almost like an obsession (the reasoning, is my illness (ahterosclerosis) forced me to question my time left here; I wanted to survive (and I love biogerontology(was going to be in that field...decided otherwise, but the love of science never left); I had to learn about my disease, what my mom died (cancer), how much I am at risk..etc; so like a wake up call - to get informed, in doing so, the long-lost love of science cam back, almost to infatuation level - but when you are on death bed, you better be otherwise won,t survive, you have to want to Live/Survive).

Posted by: CANanonymity at March 25th, 2019 7:14 PM

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