Giant Mole-Rats Exhibit Greater Gene Expression Stability with Aging than Rats

A number of African mole-rat species live significantly longer than similar-sized rodents, and show very little age-related decline until very late life. Where examined in detail, their biochemistry is an odd mix. In some respects they exhibit the usual signs of damage and dysfunction associated with mammalian aging, such as raised oxidative stress and the presence of senescent cells, but don't appear all that affected by it. Elsewhere they exhibit clearly superior mechanisms, such as improved protein quality control, a layered set of anti-cancer mechanisms that provide near immunity to cancer, and - the topic of this paper - a well preserved pattern of gene expression. This latter case may be something of a tautology: dysregulation of gene expression, or changes in gene expression that are reactions to underlying damage, are a downstream consequence of the causes of aging. When an organism ages more slowly, or exhibits only a lesser degree of aging until very late life, then one would naturally expect gene expression patterns to remain more stable over time.

Compared to short-lived mammals, long-lived mammals have repeatedly been shown to exhibit fewer age-associated changes in numerous physiological parameters related to the functional decline during aging. Recent RNA-seq studies have suggested that much of the remarkable lifespan diversity among mammals is based on interspecies differences in gene expression. However, those studies focused on identifying particular genes and pathways that are differentially expressed between species with divergent longevities. Whether short-lived and long-lived species differ at the transcript level with respect to their amount of differentially expressed genes (DEGs) during aging (hereinafter referred to as "gene expression stability") has, to the best of our knowledge, not been explored yet.

Here, we examined age associated transcriptome changes in two similarly sized rodent species with different longevities: the laboratory rat (Rattus norvegicus), which has a maximum lifespan of 3.8 years, and the giant mole-rat (Fukomys mechowii), which has a maximum lifespan of more than 20 years. In giant mole-rats, longevity is significantly correlated with the reproductive status. Breeding animals outlive non-breeders by far. In the current study, we examined only non-breeding males. Male non-breeding giant mole-rats have a maximum lifespan of approximately 10 years and an average lifespan of approximately 6 years, still clearly exceeding the life expectancy of the laboratory rat.

For both species, we performed RNA-seq on tissue samples from five organs (blood, heart, kidney, liver, and skin; hereinafter called simply tissues) of young and elderly adults. The tissues were collected from young and elderly cohorts of laboratory rats (0.5 and 2.0 years) and giant mole-rats (young: approximately 1.5 years at average; elderly: approximately 6.8 years at average). For each species, we determined DEGs between the two respective time points and searched for enriched functional categories.

Our findings show that giant mole-rats exhibit higher gene expression stability during aging than rats. Although well-known aging signatures were detected in all tissue types of rats, they were found in only one tissue type of giant mole-rats. Furthermore, many differentially expressed genes that were found in both species were regulated in opposite directions during aging. This suggests that expression changes which cause aging in short-lived species are counteracted in long-lived species. Taken together, we conclude that expression stability in giant mole rats (and potentially in African mole-rats in general) may be one key factor for their long and healthy life.



@Reason, in fact all this looks like that they do not age more slowly because of they generate less primary damage but merely because they more resistant to primary damage

Posted by: Ariel at January 1st, 2019 11:12 AM

Maybe someone could partially resolve this tautology by measuring gene expression stability before and after removing damage such as senescent cells. If the gene expression stability goes up that would show that it is at less partially secondary damage rather than primary damage.

Posted by: Jim at January 1st, 2019 9:28 PM

Hi there! Just a 2 cents.

In my mind, this is an indicator that the giant mole rats preserve chromosomal packing (retard DNA uncoiling, retard production of progerin, retard loss of histone H3 (important for chromosomal stability and mainy genes such SIR/DAF which are H3 controlled), through gene silencing by epigenetic transcription silence. They thus preserve a epigenetic signature that of much younger and hence, genetic stability as they say. Because, with age, the epigenome is doorway entry to the inflammasome unsilencing (thus, epigenetic activation of the inflammatory program, which contributes to disease arrival); but, not just that it contributes to the emptying of the methylome (loss of 5-methylcytosine levels, shown as global DNA methylation loss in CpG-empty islands (which are the main element that become deactivated while the CpG-rich islands become 'unsilenced', hence the inflammation program), which means 'aging' (epigenetically). The giant mole rat is simply keeping a silenced epigenome, just like a child's, while the mouse is obtaining fast 'changes', 'transforming it' (aging it, it 'matures' much quicker and then it reproduces heavily, all taking heavy toll as its DNA repair resources are nearly nill), and thus it dies quick. It was also demonstrated that the redox is lost as transcriptional drifting happens, as such it becomes oxidized (oxidative stress) or overreduced ('reducive stress' when the milieu is Too reduced and ROS are so low/near gone that signaling is compromised; this activates apoptosis cascade; while oxidative stress creates oxidation of thiols which means destruction of macromolecules by ROS/oxidized end products/carbonyls/GSSG/MDA/AGEs/etc); so, the animal's organs become compromised and health can decline. But, I still believe there is a difficult blurred line we have not determined, which is that the damages if removed will absolutely 'de-age' you, via a reversal of methylome; and it has been shown that indeed, the DNA epigenetic clock can bounce back somewhat after damage reduction, but I have doubts (the epigenome landscape will become 'silenced' again but the signature has already 'changed', it's Too Late, the signature is permanent and permanently changing 'to age you'); in the sense that, unless you do iPSCs reprogramming, forget about it that cell is Aged, has Aged, has a specific Signature/remember phenotype and no matter if damaged removed, has an end - independently from damages. Reprogramming is Very Special, because it is More that just damage removal, it is Signature Reversal; our cells remember their age, don't forget and that is the problem. The saying that damage removal keeps an organism 'healthy' forever forgets the 'signing' thing ('codes' if you will that cells always remember and why reprogrammation erase them; and allow centenarian cells (that know themselves as such) to become age 0 once reprogrammed. Just a 2 cents.

@Jim Hi Jim! I would say that the gene expression changes after senescent cell removal; though it depends on what we are talking about. The sole fact of senescent removal/p16 cells will reduces certain inflammatory genes activity (p16,p53,p21, IL-6, TNF...) with their SASP gone.

@Ariel Hi Ariel! Mice lose approx. 5000bp (5kb)/year in their telomeres (healthy humans lose 50bp/year, while HGPS people lose 500bp/year), it's why they die quickly yet they have telomeres in the order of 40kb but they show rapid loss; but telomeres are separate from DNA epigenetic age; though working in tandem at the same time (as was shown with telomerase creating accelerated epigenetic aging whenever called in to repair/elongate telomeres; antagonistic pleiotropic enzyme; it,s funny and ironic because reprogrammed iPSCs have not only reversed cell age but Also elongated telomeres set 'anew' just like the tall telomeres of a child, so it is True age reversal (Yet, clearly, Elongating Telomeres is a Negative Aging element only meant to improve fitness and push cancer away; reprogramming is capable of erasing the signature of the cell While increasing telomeres/removing damages too; which telomerase cannot do, it was conceived as a negative ager to counterbalance the improved fitness (my take is that reprogramming is capable by different means, including telomerase itself or ALT and other ways (Ku-67), to increase telomere length and render telomerase as 'silenced' on epigenome, but only working 'on the telomeres' to lenghten them; while, in regular aging, it has this Double Role of health improver - and - aging activator). IT's also why certain tress like Great Basin Bristle Cone Pine have very high telomerase activity but in cyclical bouts; these trees live 5000 years; high-exposure-in-limited-bouts-that-seldom-occur-telomerase is able to increase telomeres/preserving fitness while ensuring minimal epigenomic 'contact'; fitness loss = frailty = death; fitness maintenance = aging acceleration via continuous telomerase activation = death advancement; fitness mainteance over Very Long Time (slow-mo, by rare 'telomerase boost' in limited cyclical bouts) = slowed aging = death retardation); with that said telomeres are tabs for health, while epigenetic clock for age signature). Giant mole rats lose a little bit more telomeres/year than humans, maybe around a 100-250 or so (live max at third of humans), dogs lose about 250-500 bp, they live as long as HGPS people (-/+ 15 years). In HGPS people studies it was demonstrated that they produced far more progerin, quickly/quantitatively and had protein clumping/aggregation (which laters causes Azh's). Mice that are progeric produce high amount of progerin like HGPS people, while regular mouse still produce a ton more/quicker than giant-mole rats/NMRs.

Posted by: CANanonymity at January 2nd, 2019 2:32 AM

PS: Happy New Year! Sorry for the length. Wishing to add that studies found that in yougn people/young animals they could see that damages can be uncoupled from aging (damages -> health, aging -> clock), a young person/animal could/would die if it's health threshold was surpassed as it became ill/frail/diseased - yet, was young. By the DNA methyl clock, this young animal was much younger, and died even so (of damages/inflammation caused, which exacerbated the senescence/apoptosis pathways; leading to premature death). Meaning, that animal, was (now) dead), and was Younger, than an older Alive animal. By signature, That older animal was Truly Older and More Aged, than that younger ill-dead animal; yet, that old animal was still alive - not forever because that clock was older than that yougner animal; one day it would run out of time and that old person would die 'of age'/reached the clock limit -they did not die of suddent premature 'health' decline in their younger age.

This is why the difficulty to prove that damages are truly causal to aging as mean it (AGING/getting old and then dying 'of age/of time cumulation by living long life'), but rather are parallel to age/decrease health (fitness), but their 'say' on 'aging' is less so than the clocks whom have this superceding word on 'longevity' maximal of animal; because they are rather gaurdians of the age signature tabs. It's really freaky that a young person, dead, would be 'yougner' than an older person - alive (I mean, it's obvious, they are younger, can't be any more obvious; they are young, so it shows, on their clock; so, they are, obviously, younger). Simply, because that young person never Reached their Full Potential/Theoritical Maximum (Aging Signature Limit, which that old person is Much Closer to for they lived a much longer life, so far and thus, cumul of many tabs on the clock. That young person, low cumul, they died of damage/inflammation - independently, from 'singuature aging' that happens over a full life until maximal lifespan is reached. (It's why that young person did not show epigenetic advancement in certain tissues. Who knew that tissues can 'die young 'as young' themselves'; it shows how much we 'think' we know how aging works, but we don'T). The cells can 'exit' the cell cycle prematurely and senescence spontaneously or apoptose like that; these cells are, by DNA epigenetic clock, still young (studies in laboratory showed that cells can have spontaenous senecence, replicative senescence, oncogeneic senescence, apotosis, necrosis. The studies were ambiguously trying to say that these things can Uncoupled from aging as we know it, and that spontaneous senescence or replicative senescence can happen - with very little DNA epigenetic advancement - Independeltly).

While cancer is a True epigenetic aging advancer, it was demonstrated in tumors that epigenetic clock of the cancerous tissues were 'aged' by the clock; this means that cancer tries to 'weaken' the body, and 'age it - Truely' by changing its signature towards much older tissues that are dysfunctional 'aged' and prone to errors/mutations (epigenome shows drastic hypermethylation of CpG rich islands which means cancer overtaking); so if that young person died of cancer, than whatever tissues that were touched by cancer had epigenetic age advancement; but many of of his/her other tissues are much younger than that Older person's same tissue, whom it is still alive. That Old person kept 'health' in check and never went below health threshold (of course with age that person'S health declined somewhat but never enough to kill him/her), but that person is more aged and would reach the 'limit' on the clock (around 120 years old). Analogy, 5 states, state 1 baby, state 2 child, state 3 teen, state 4 adult, state 5 elder.
The body cannot stay forever as state 5 - but it Can stay as state 3 or 4, because there is state 5 after it before death (it would simply 'restart' the state 3, state 4, state 5, you cannot stay in one state forever, you always 'age' because of this signature system thus, you will go to the next state, again; the trick is going back enough states so that you are as far as possible from 5th one; which is what LEV is tryinh to do). Why can it not stay as state 5 forever ? Because of tabs and tabs Keep on Accumulating, every day, every hour, every sec; because all cells have this 'self-tabs-remembering' system that collects this data if you will; all the time). Reprogrammation removes signature tabs and puts back to state 1 or 0. iPSCs show that exactly.

Posted by: CANanonymity at January 2nd, 2019 3:31 AM

PPS: Last thing (truly, sorry for the wallpost but it's NEw yEaR's!, and it's 4 in the morning (losin my marbles)!!) I believe that since we could technically reach LEV, by these states (1 to 5 analogy), it would mean, (most likely and evidently), one of two things: the body would grow but that would depend on which state we would go back to. If we would go back to state 3 (teen) repetitively, we would accelerate growth and make 'gigantic' humans (just like people whom measure 7 feet tall, or 8 feet tall, it would not be surprising to see humans reach 10-15 feet tall over many centuries, just like ageless Tall Trees (baobab, pines, sequoia, etc...measure many feet tall and live 1000 years old, very slow growth but always growing up). Just like Greenland sharks, these sharks live 500 years, and measure up to 25 feet long; they are extremely slow growing, but they reach immense size over the centuries; jsut like ageless trees. Now, if I compare it to quahog clams taht are tiny, and live 500 years, they are 'still' and very little growing - this would happen to humans - if they went back to state 4 continuously and then state 5 arrived; 1 state behind would allow to cancel 'gigantism'. Because in adult age, the human body have 'grown up' and the metabolism slows down with age in the mid-life, slowed growth. Thus, 1 state behind, would allow us to keep our size because the growth would be to a near stand still - just like in quhogs that barely grow a couple more millimeters over 5 centuries. Because, cellularity would be 'Expansion' and 'growth' so we would technically grow & grow & grow!BIG like huge trees. Giants over soo hundreds upon hundreds of years/near eternal life, what is important is how fast and how long. If we can nullify our growth to near-0 than we could stay 5 to 6 feet tall always; in other words, it would Ages (thousands of years) for us to reach 8 feet tall...just 3 feet more. And to think that we would 'shrink' again if we would go a = little bit in the state 5 but just a little bit; because if we brush state 5 we brush with death; too dangerous must go back one state at least to make sure 1 state 'in front' as protection and being '2-states away from death' at all time. The possibility that we would grow forever means we would Need to go to state 5 to 'Shrink' again just like elderly people whom lose BMD and become short stature/skeletal loss. But, taht would be a danger and assumed risk where the state 5 would be so brief to not be dangerous to you, so you get back to state 4 again after shriking in state 5. I guess we would need to do 'Alternativ Current', like go back to 'end' of 4, do 5 a little bit of time, go to back to 'end' of 4, do 5 a little bit of time, repeated like that; then we go back to 3 or 'Start' of we end up shrinking (by 'dipping' in the 5) while never continuing in the state 5, which would lead to death after it, if we did.

Posted by: CANanonymity at January 2nd, 2019 4:57 AM

PPPS: And, just to flip this around, when we look at centenarians; they show levels of damage to people that are much younger than themselves. So, this is where the dissociation of health/damage and aging/clock. Those centenarians, that have less damage, are in better shape - but, they will die on clock, around 120s-130s tops; demonstrating that the clock was the element in that long life, as a limiting factor and showing damages are not the 'decider/ager'; the clock is/the signature tabulation is. That young person, died 'young' and was Much Younger (by the clock) then that centenarian; in that case, that young person's damages kill them (health decline - not aging; that person died in young state - by his/her clock). Showing damages are contributory to health decline but, in my mind, not true decider of age (as can be seen on the clock, when comparing a 'young dead' person vs a centenarian - soon dead 'of age'; they just kept 'low damage' levels = healthy = long life; they had solid genetic and epigenetic 'silencing'; but these CEntenarians Clock Still kept tabs, and soon it is over, for them too once the clock says so - not 'damages'; damages are why there are more 'senile' centenarians vs 'healthy' centenarains = BOTH are centenarians and reached so; demonstrating disocciation/uncoupling of damages/health vs aging/longevity/clock). That is what I think : ) ...(Just a (very long) 2 cents. :) Sorry.

Posted by: CANanonymity at January 2nd, 2019 5:46 AM

@Jim, of course, change in gene expression is a secondary type of damage because this is a reaction to that damage . This is only meaningful explanation. However, this does not imply that after removing that damage all gene expression will be back because epigenetic profiles may not reverse automatically -- some chance that they are put in reverse by reprogramming.

Posted by: Ariel at January 2nd, 2019 9:59 AM

In my view damage is the entropy that (potentially) knocks the system from its youthful homeostasis; epigenetic stability is the resilience in the face of that entropy. Even a young animal can be killed if entropy is too high, or an old person can endure so long as entropy is kept low enough.

Posted by: Mark at January 7th, 2019 9:32 AM
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