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Negligible Senescence and Exceptional Genome Maintenance in Naked Mole-Rats

Studies of the comparative biology of aging involve mapping the genetics and cellular biochemistry of exceptionally long-lived species in search of significant differences, when compared with both humans and shorter-lived species. The hope is that findings may inform human medical research, and at best could lead to new directions for the development of therapies to address aspects of aging. Species of interest include whales, for longevity and exceptional cancer resistance given their size, elephants, also for unusual cancer resistance, and naked mole-rats, which live far longer than similarly sized rodent species, and are near immune to cancer.

Today I'll point out a couple of recent papers from research groups investigating the naked mole-rat. It has for a while now been generally accepted that naked mole-rats are negligibly senescent. This is a blanket and in practice fairly loosely applied term indicating that members of a species show little signs of aging across most of a life span (for some definition of "little" and "most"), with a sudden and short decline at the end. This is very unlike the human life course, which takes the form of an exponential decline that starts comparatively early, in the middle of life.

Aging in this context has a precise definition: it is the rise in mortality rate over time due to intrinsic causes, the accumulation of cell and tissue damage resulting from the normal operation of cellular metabolism. If mortality rate remains roughly static over time in a population, then its individuals are not aging - which can in principle be the case at any mortality rate, high or low, but agelessness coupled with a high mortality rate seems more of a curiosity than a useful phenomenon, where it does occur. The naked mole-rats exhibit the low mortality option, of course. The first paper below provides evidence to back up the assertion that naked mole-rats don't just seem negligibly senescent, but actually are negligibly senescent.

The second paper looks at stochastic mutation rates across the life span, one of the many areas of biochemistry that researchers believe is important to aging. Mutation incidence is also a determinant of cancer risk - cancer is a numbers game, with every mutation that occurs having a tiny chance to be of a type that can give rise to an unrestrained, cancerous cell. Everything connected to aging looks better in a naked mole-rat, and that includes low mutation rates and highly effective DNA repair. Clearly some of those measures are secondary to the root cause reasons as to why the species ages so lightly until the very end of life - they can't all be root causes.

DNA maintenance may fall into either category, though the present consensus places it a meaningful contributor to the declines of aging. However, it remains the case that definitively determining the relative importance of specific contributions to the outcomes of aging is a challenge. These questions will probably remain open until biotechnology is applied to block or eliminate various likely mechanisms in naked mole-rats, or recreate those same mechanisms in mice, in order to observe the outcome. Theorizing and mapping can only take us so far at the present time.

Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age

The naked mole-rat is a strictly subterranean, mouse-sized rodent and is one of only two known eusocial mammals. The longest-lived rodent, it is recognized as an animal model of biogerontological interest, with a maximal lifespan of more than 30 years in our captive care. This maximum lifespan is five-fold greater than predicted allometrically for a 40g rodent. Beyond lifespan, the physiological declines that accompany advancing age in most mammals fail to manifest in naked mole-rats. Breeding females show no menopause, retaining high fertility even at ages past 30 years. Neurogenesis is also prolonged and may continue for at least two decades, and over a similar time course, no significant changes in cardiac function, body composition, bone quality, and metabolism are evident. Age-associated chronic diseases such as cancer are also rare. Within the cell, proteasome function, as well as mitochondrial mass, gene expression, and protein expression are maintained with age.

The concepts of mortality and physiological decline associated with aging can be connected within the mathematical framework of the Gompertz-Makeham law of mortality. Mortality hazard increases exponentially with age, presumably due to intrinsic age-related physiological declines. While naked mole-rats are already noted as exceptionally long-lived, this status relies on small-sample-based estimates, leaving much uncertainty as to how exceptional their longevity may truly be and how they differ from other mammals with respect to the Gompertz-Makeham aging framework. Here, we compiled a large, historical dataset of naked mole-rat lifespans using records kept throughout the ~35 year maintenance of our collection. With over 3000 data points, we constructed survival curves and performed analyses of age-specific hazard. In these analyses, this mouse-sized rodent exhibited no increase in mortality hazard, that is, no Gompertzian aging, across its full, as-yet-observed, multi-decade lifespan. This life-history trend is unprecedented for mammals.

Genome Stability Maintenance in Naked Mole-Rat

DNA damage caused by environmental stress and normal metabolic processes occur daily at a frequency raging from 1,000 to 1 x 10^6 per living cell. As a result, only 0.00017% of the human genome consisting of 3 x 10^9 base pairs is damaged, but lesions in essential genes, such as the genes that code for tumor-suppressor proteins, can significantly disturb cellular function. The efficient DNA repair mechanisms that counteract DNA damage accumulation substantially contribute to genome stability maintenance, which is one of the crucial cellular functions. Accumulation of DNA lesions and mutations increases the risk of cancer and is related to aging.

Only a few experimental studies have focused on the search for a correlation between the activity of DNA repair systems and maximum lifespan. The complexity of these studies and their controversial findings may stem from both the imperfect methods used for activity assessment and improper selection of model systems. The naked mole-rat (NMR) is one of the most promising models used to study genome maintenance systems, including effective repair of DNA damage. The lifespan of the NMR can reach 32 years, ten times longer than that of the mouse. For most of its lifespan (at least 80%), this animal shows no signs of aging and retains the ability to reproduce. It possesses a very efficient mechanism of resistance to cancer, including cancer induced by different stressors.

The naked mole-rat draws the heightened attention of researchers who study the molecular basis of lengthy lifespan and cancer resistance. Despite the fact that the naked mole-rat lives under genotoxic stress conditions (oxidative, etc.), the main characteristics of its genome and proteome are a high stability and effective functioning. Replicative senescence in the somatic cells of naked mole-rats is missing, while an additional p53/pRb-dependent mechanism of early contact inhibition has been revealed in its fibroblasts, which controls cell proliferation and its mechanism of ARF-dependent aging. The unique traits of phenotypic and molecular adaptations found in the naked mole-rat speak to a high stability and effective functioning of the molecular machinery that counteract damage accumulation in its genome.

Comments

Hi, great article. Just a 2 cent.

I think that NMRs are ironic like that, that they would be Negligibly senescent or pretty much
Non-senescent is at odds with the fact that they die at 35 years MLSP. But, they are 'negligibly' in that sense - Because they reach 35 years. But, We, humans might be (sort of or not) Negligibly Senescent - Too. Although, we suffer a longer period of senescence perhaps because we are more sturdy or the senescence element in humans, is mostly reserved for diseases/health (spontaenous/oncogenic senescences) - while the Real senescence element in humans is the Replicative Senescence, because it takes a very long time to happen (an entire life) and we excellent DNA repair, just like a Naked-Mole Rat, in fact, we have Better repair the NMRs; In that sense, humans are More Negligibly Senescent than NMRs. What that problem is with us, is that cancer/mutations get the best of us because we don't have the clever tricks the NMRs adapted (such as hypoxia-adapted p53/cell contact inhibition/stromal barriers by high long-chain hyaluronan in their ECM/peculiar immune system); our tricks are not as good - But, we accumulate things So Slowly, Even Slower than NMRs that we Outlive the NMRs; by nearly 4-fold (35 vs 122 years old MLSPs).

Plus another thing, just like NMRs, we share protracted developmental growth/brain plasticising/'adult onset' and sexual puberty (NMRs are sexually amorph except for that one Alpha male who gets the entire females count for himself including the 'queen NMR'; all other males are beta and asexual. This demonstrates sex/IGF/growth at convergence between DNA repair resources vs Sexual Reproduction Resources allocation). Mice live 2 years because they are hypersexual and hyperreproducing, this is costly (short-life/lots of sex; no sex/longer life; sexual senescence can be slowed if the aging is slowed too but there is a Trade-Off between DNA/longevity genes vs Sexual/Hormones/IGF/GHs/axis resources).

Probably the most important point, why they would Negligibly Senescent is because they retain Redox, like us. Without Redox, they would never be negligible senescent. It's impossible, redox controls/works in tandem with Proteasome/Autophagy Mecanisms/Proteostasis/Folding of Unfolded Proteins by CHaperones/glucose control/telomere protection..etc.. etc...
It was demonstrated - Over Time - that NMRs maintain 1.5x more thiol pools than mice and kept it 'reduced' not oxidized; just like humans too. PLus, mices crucial proteins become oxidized/aggregated in less than 2 years; while NMRs have No Changes whatsoever for at least - 20 years - again, like humans. What is behind that, the redox. With that also, are nDNA repair, telomere repair, mtDNA repair, mitochondrial IMM/OMM repair. The question that begs :
Is repair more important or is protection against damage ? The answer is the latter, because repair is 2nd/Secondary thing, Once the damage has been done. Avoiding Damage (by better redox protection) supplants repairing it any time (catch-up/mop-up game where repair systems fail (repairing) with age). NMRs studies tell us a lot, it would be great if they studied longer lived animals that ressemble us more, both in longevity and size, than a rodent.

Just a 2 cent.

Posted by: CANanonymity at January 26th, 2018 11:11 PM

So this is what Calico is doing...

Posted by: Antonio at January 27th, 2018 3:15 AM

I'd have to say if this is what the mainstream is after they are preparing quite the hell for everyone in old age because - and let me directly quote a significantly better researched paper here :

"In our colony (Figure 1A), for example, the oldest individual (Figure 1B) is a male caught from the wild in June 1980; like other very old animals, he has recently become markedly sarcopenic"

"Older individuals show a substantial decline in articular cartilage thickness of the femoral and tibial condyles and in the patella (Figure 1G,H).Surprisingly, this decrease in cartilage thickness is not accompanied by significant age-related changes in calcified cartilage thickness, subchondral bone thickness, or chondrocyte number. The appearance of osteophytes (small bone protrusions), severe loss of cartilage, and cell cloning in the anterior region of the medial condyle of a 26-year-old individual suggests that old animals may naturally be afflicted with osteoarthritis"

"Older animals may also have pronounced deposits of hepatocellular pigments, which often present as a combination of iron, lipofuscin, and sometimes bile and show signs
of hepatocellular degeneration, with large misshapened, multinucleated cells"

https://academic.oup.com/ilarjournal/article/52/1/41/648968

It goes on in this manner... negligibly senescent? Not really. Humans have a similar health trajectory. Maybe slightly less square, but come on.

How can you define what old age is for an animal well known for it's inability to feel pain anyway?
Even if they could talk there would be little they could tell you about what it feels to be a senile mole rat.

Posted by: Anonymoose at January 27th, 2018 5:41 AM

Yet more support that DNA damage is a cause of aging and that it is relevant during the normal lifespan. Such studies are good for the greater knowledge in the field even if some people don't understand their value.

Posted by: Steve Hill at January 27th, 2018 7:03 AM

I agree that a strong DNA damage repair system and a strong redox system are important components of a long lifespan. What is missing here is what role does getting rid of metabolic waste products through autophagy, getting rid of aging molecules in their old blood, etc. have to do with their and our human long life spans. It seems to me these questions are not yet answered in a meaningful way in the research studies. For the old blood, is it a matter of declining kidneys, liver, spleen?

Posted by: Biotechy at January 27th, 2018 7:58 AM

PS: Related to the blood of NMR's is that humans are told to drink 8 glasses of water a day to maintain health, but as far as I know, the NMR does not drink much water, if at all, and must have very thick blood as a result. So how are the old rats able to get rid of their aging blood particles like CCL11, CCL2, CCL12, B2M, etc., that are elevated in old blood. They don't seem to have a strong flushing system?

Posted by: Biotechy at January 27th, 2018 8:32 AM

@Steve Hill

Help me out here with this... so... does this kinda support the NAD/NMN tech that Sinclair is working on? I like Dave, he seems like a nice guy and I can't fault his motives. But if this is what I think it is... NAD+ is quite possibly the leading candidate to commercialization...

Posted by: Mark Borbely at January 27th, 2018 10:43 AM

Methuselah Foundation (MF) recieved $ 1 mill from Pineapple Fund.

Posted by: Norse at January 27th, 2018 11:31 AM

I don't understand how NMRs can have a maximum lifespan of 35 years and still be considered as negligible in aging? Of what do they die then if not of old age?

Posted by: Arthur at January 27th, 2018 12:15 PM

@Antonio : Gracias ! I had last heared about the SRF's funding earlier this month, where only one donation from the Pineapple Fund had been mentionned.

An informative video about the state of philanthropy applied to rejuvenation-minded institutions. So glad it made Aubrey feel rewarded for all his hard work, whose message is now starting to reach the masses.

Posted by: Spede at January 27th, 2018 12:22 PM

Wow that's such great news! Can't believe how much money SENS have got in recently! I wonder if Aubrey will give us an update on what lines of work he is going to put the extra money into?

Posted by: Mark at January 27th, 2018 2:41 PM

That's a good question Mark. My complete guess is that most several scientific & educational projects already running in parallel will benefit from this funding, though probably not equally and that's where it'd be interesting to know which one will be funded in priority.

And maybe launch a few more projects will be launched on top of that.

Posted by: Spede at January 27th, 2018 3:09 PM

Good find, Antonio.

I'm quoting the most relevant part of his short answer below :

"It means very little for our DIRECTIONS, but it's huge for the rate at which we will be able to move in those directions. [...] At SRF we will be expanding existing programs and initiating new ones - all within the same seven-strand framework that has defined SENS since the beginning."

So there will indeed be new projects which will be funded and started, in addition to the existing ones. That's nice.

Posted by: Spede at January 27th, 2018 3:48 PM

@Steve Hill - I don't know if some evidence of DNA damage being important is something to crow about as there is currently no proposed means to fix it (just NAD+ to slow it down a little as far as I am aware).

I suppose you could remove it from blood stem cells during a safe immune system reboot. But still leaves it building up in a lot of other places.

Posted by: Jim at January 27th, 2018 9:08 PM

@Jim George Church is scratch building Genomes, you think once he does this we wont be able to repair our damaged genomes? Come on man.....

Posted by: Steve Hill at January 28th, 2018 11:52 AM

This paper does appear to show that Naked Mole Rats have no maximum lifespan, i.e. no mortality term that rises with age. (Or if they do, it's too small to be detected within the timescales of the records used within this paper). That is a pretty big deal.

Posted by: Mark at January 29th, 2018 5:23 AM

@Mark

Hi Mark ! Just a 2 cent. I think that is a fallacy, NMRs have a sort of MLSP, mortality may not rise with age, but in a very short span of time their mortality rises. This means high morbidity compression (like living perfectly in great health for 99 years, and dying the next day on your 100 birthday; the day before everthing went perfect, the next day you're gone). In that sense they are 'less' senescent (or a bit negligibly senescent). For they maintain health for entire life and drop dead one day in 'sudden death' when all was well the previous day.

Just a 2 cent.

PS: others have pointed that NMRs have shown certain oxidative damage and are definately not 'healthy' (Inside) and are 'hanging on'; this means they too experience some degrees of damage with age but it's not enough to halt them/stop them from living; it's minimal and they have Very High Pain Tolerance Thresholds; this is a combination for a hardy animal that 'keeps on trucking despite so (other animals would be dead, not it)'.

The fact is their redox, at a certain point, also becomes oxidized and shows that it starts to have difficulty continuing on; but there is at least a 20 years period before that happens (oxidized/aggregated proteins have 2 decades before showing, and lipofuscin now is more present at this later age; this means 'later (in a decade or so)' the proteasome will fail; amd once that happens, it's game over); thus from 20 years and on, then they enter a downhill slope to their death at 35 or so.

It would have been great to see a naked mole rat live to 100+ years, it could be possible but the fact that many don't go much beyond 35 tells me there is more to it then they having 'no limit/no Maximum lifespan); perhaps certain elements of their body have replicative potential upwards of 100 years but that has not been shown so far. Thus, since their redox does start to fail and do accumulate oxidative DNA damage/damaged ECM/oxidized thiols...it means that their telomeres are shrinking and they too enter replicative senescence (now rodent telomeres are very long, but that does not matter, what matters is how fast they go down; NMR have solid repair systems, but not as good as those of humans, thus we can speculate that their telomeres drop faster or they maintain their telomeres, but die of somethnig else than replicative senescence, like spontaneous senescence (DNA damage) affecting health, there may be still lots of replicative potential but the stress puts the health to a critical point where the animal dies - despite having still 'longer life' available (more replicative rounds left) - if it was not stressed); just as they do in mices' whom have long telomeres that become dysfunctional and die rapidly; they could live much longer, like NMRs, but their redox becomes oxidized rapidly and then it is spontaneous senescence (stress-induced senescence that alters health in a compromising way (the animal dies suddenly 'mid-life' because health complication), but is independent from cell cycling/replicative senescence (the maximum the specie can get))) or oncogenic senescence(they die of cancer))).
NMRs do not die of oncogenic senescence (cancer) because of their cell cancer-inhibition tricks.

Just speculating :), 2 cent.

Posted by: CANanonymity at January 29th, 2018 5:35 PM

That's the problem CANanonymity, this is just speculation - the papers I've read make some statements about such and such mechanisms by which NMRs live a long time: redox and telomere maintenance, DNA repair, etc., etc., but I've never been very convinced by their explanations. What was good about the Calico paper is that it didn't try and find any reasons - they just looked at survival - and what they found was that for the most part, mortality didn't rise with age. That mortality might be quite high compared to a young human, after all NMRs don't live that long in the wild, but the fact is that it doesn't go up. If this is true it means they don't age. It doesn't matter if they are not that healthy, so long as they don't get less healthy, they are not aging. Do I believe this is true? I'm not sure. I expect if we study them for long enough we'll find they do age, but they are certainly a very interesting study.

ps - NMRs have approximately human length telomeres, but they are maintained very well; all NMR cell have active telomerase (yet their cancer is still very low - truly impressive).

Posted by: Mark at January 30th, 2018 3:08 AM

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