Greater Expression of Mitochondrial Base Excision Repair Enzymes in Longer-Lived Mammalian Species
The hundreds of mitochondria present in every cell are critical to cell function. As the descendants of ancient symbiotic bacteria, mitochondria have their own remnant DNA, separate from the chromosomal genomic DNA present in the cell nucleus. Both sorts of DNA suffer similar forms of mutational damage and are attended by broadly similar repair mechanisms, but nuclear DNA is by far the better protected and maintained of the two. Some forms of mitochondrial DNA mutation, particularly the deletion of genes important to the electron transport chain, are thought to confer both dysfunction and competitive advantages to mitochondria, leading to a cell overtaken by broken mitochondria, exporting toxic reactive molecules into surrounding tissue. This may be important in aging, and in support of that proposition, researchers here find that longer lived mammalian species have a greater capacity for some forms of mitochondrial DNA repair.
Is the DNA repair of endogenous damage higher in long-lived animals? When base excision repair (BER) of genomic DNA was measured in four organs including heart and brain it was found not significantly changed or even decreased (instead of increased) in longer-lived caloric restricted mice. Moreover, comparative studies in brain and liver of 15 mammalian and avian species have shown that repair of genomic DNA endogenous oxidative damage by BER in nuclear fractions does not correlate with longevity or, more frequently, is lower (instead of higher) in tissues of long-lived mammals when compared to short-lived ones.
BER plays an important role in repairing oxidative damage to DNA, but these results might indicate that genomic (almost all nuclear) BER does not play a key role in longevity extension. The negative correlation of genomic DNA BER with longevity is analogous to what was previously found for the endogenous total cellular antioxidant enzymes CuZn SOD, catalase, glutathione peroxidase, and glutathione reductase, as well as reduced glutathione, which most generally negatively correlate, and in some cases do not significantly correlate with longevity in mammals and vertebrates.
The likely evolutionary explanation for this is that the mitochondrial ROS production rate (mitROSp) is also lower in long-lived than in short-lived animals. Since the mitochondria of long-lived animal species produce less H2O2 to the cytosol, they would also need less total cell endogenous antioxidants and less nuclear DNA repair systems. Endogenous total cell antioxidants and DNA repair enzymes are transitorily induced, when needed, to come back again to low levels when episodic increases in oxidative stress have been overcome. In this way, cells save much energy, which otherwise would be invested in the protein synthesis needed to continuously maintain high levels of cellular antioxidants and nuclear DNA repair enzymes when they are not needed at such high levels.
That is the situation concerning BER in nuclear DNA, but what occurs in the case of mitochondrial BER (mitBER)? MitBER had never been measured in species with different longevities, and we hypothesized that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus recently measured activities and/or protein levels of various mitBER enzymes including DNA glycosylases, NTHL1 and NEIL2, and APE endonuclease in mitochondrial liver and heart fractions from eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between mitBER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitDNA of long-lived species, not observed for nuclear DNA, can be due to the combination of a low rate of damage generation (low mitROSp) and a high level of mitDNA repair (by mitBER) in these slowly aging animals.
Hi there! Just a 2 cents. TL DR : it's a biggie.
DNA repair of DSBs, be it mitochondrial BER or nuclear BER, seems an avenue that though we corroborate that indeed DNA damage (and its repair needed), especially, in mitochondrias is consequential to the lifespan, the therapies/strategies that have been done to increase DNA repair have been lacking in result. Equalling (oftenly) to about calorie restriction or rapamycin/metformin or methionine restriction...in terms of effect. Which is to say 15-25% average and maximum lifespan extension. Not much more than 50% that is also. Of course that is impressive (I mean 50% would be 50 years extra in long-living humans). But, as we all know, the effects are always smaller in - humans (already optimized and pathways-redundant/already-used&benefiting-of-pathways(redundancy)). We live long because Already use these repairs - that is why we live long(er). Therefore, they are already used and perhaps, maximally/optimally?, used. Thus, can't be used (much) More Of - because already used and maximally.
Well, I mean, they could be used more - and we should live Even Longer...but therapies/studies/strategies that have boosted DNA repair have had mixed bag results....nothing huge. Again, about CR/exercise effect - 20-30% lifespan extension.
That is what I worry, is that we can't Boost DNA damage repair in Mitochondria -and- Nucleus...
all that much more..than it is already is in our body right now (if aging slowly-to reach 100 years old). It's almost like : we boosted DNA repair (like BER/NER...in mitos and nucleus) so you can get an extra 20-30 years lifespan...- but you will not live longer than Jeanne Calment - Neither; as in, you will live to 122 OR Less - Despite Doing This DNA repair - Extra.
As such, it just means, a mostly, Average Lifespan boost - and the Maximum Lifespan Potential is Pretty Much set in stone - Solid...and DNA repair boosting therapies don't make you go above it (or all that much) - Rather, they assure you -Can(now)- Reach the Maximum. But you won't go Above the maximum - or very little. As said, because, the results were less than stellar.
In essence, it is like saying : ''you will age slower...but not As Slow as someone Supercentenarian - Living to reach 122. You will, mostly, end before that but (by DNA repair therapies) you are much more assured - of Reaching 'Nearly' 122 - but won't go above it''.
Someone reaching 122 is aging Even Slower...than even 'adding' a DNA repair therapy to someone aging faster/regular.
And, for very Slow Agers (like supercentenarians)...DNA repair may end up Very Redundant... (as in they are already Extremely DNA repair efficient), hence not all that much effect.
It's the old studies of Progeria Mouse vs Wild type mouse...the progeria mouse (that ages in acceleration) sees a Big Boost of dna repair...while the wild-type mouse (that ages slower) sees a smaller boost...now let's put a Nake Mole Rat...it would get almost 0 boost..because it lives 10x longer - Already - than the longest lived mouse.
Redundancy. That's the killer. When we can't even beat what we already have/use in our body. Because it's Already optimized 'at best'...right now - without any therapy.
This means, that it is people that have progeria/age fast...that will gain a Lot. But people that live Long (like supercentenarians..and their offsprings..which was showed that age Slower Already than the rest of the 'control/faster aging' average population), they won't get all that much from DNA repair boost. Well, at least, from the ones that have been done So Far.
It means it is Insufficient - it needs to be Stronger DNA repair...in mitos/nucleus..but that's what I fear...we can't make it Stronger/Faster/Better/More - than that (so far).
Also.
A new epigenetic aging study by Horvath showed that (it seems ?) Aging and Maximum Lifespan are 2 things, and not necessarily the same. Which seems very surprising.
In the study, they studied 150+ mammals of longevities from 2 years (mouse) to 211 years (bowhead whales), they concluded that genes (in the CpG islands of epigenome) methylated were not the same between aging and maximum lifespan. Meaning, to Reach maximum lifespan, you needed some genes/methylation patterns - that were not there in 'aging'. Now, I am not too sure about this, but it could mean that the aging (they meant) is just the 'average aging/lifespan', and to reach Maximum (Specie) Lifespan you must have that epi 'genetic boost'...if not, you won't reach Maximum (predefined in humans (120)), you will live an 'average lifespan'. Which, that is, anything Below 122 and most likely not much more than 90-100, but higher than 60 or so (60-90).
I think there is a flaw though in this. Which is that it is not so much these genes that are needed to reach maximum lifespan - it's the RATE of aging, that is the sole biggest determinant if you reach Maximum Lifespan. We know that the rate of aging is not always 'constant'...but studies showed that, in long-lived people (and applicable to all animals), there are 3 Main Phases.
0-20 (puberty) - fastest aging - 'Growth/body 'growing up'/fast metabolism
20-90 (plateauing) - very slowed aging - slowed growth/no growing up/steady/slow metabolism
90-120 (death) - faster aging - damage cumul takings its toll/stochastic end/function incompatible
This 3 phases, is present in all animals - it can be 'fasten' or 'slowed'. In mouse, they reach pubery extremely fast and then they plateau..and then die. All this happens in 2-3 years.
In humans, it happens in 120 years. While in progeria HGPS humans, it happens in 15 years.
It means that all animals have the same 100%...level (death). A mouse reaches 100% in 2 years. While a human reaches 100% in 120 and a HGPS human reaches 100% in 15.
It's the same 100%. That 100% is the 'Threshold' for function. 0% is the full epigenome (at the start)/its landscape configuration. While 100% is the emptied/dysfunctional epigenome (inversed configuration).
A studi in 1980s had shown that mouse lost epigenomic methylcontent 100x faster than humans. A cow (that lives 25 years or so), lost is about 5-10 times faster...a horse (that lives 30-50 years), lost it about 2-3 times faster than a human. A perfect correlation to maximum lifespan in mammals. Not just correlation - Causation. This is a proof that it is the Rate of aging that determines the Maximum Lifespan of animal. And though we may see that Maximum lifespan potential (requires?) some specific genes or configuration...it is still the rate (of aging) right now, that is biggest factor of Wether or Not you reach 122. It is why I said, that if we can't make Better Partial Reprogramming, of epiclock age (because right now the best is 30 years reversal), and if we can't Repeat It (on and on) then it 'diminishes' in effect ('Diminishing Returns'), and the effect is Temporary (epigenomic reprogramming effect - lasts very short time, thus needs constant repeating), then ...it means that Rate/Speed of aging is mostly the only biggest Strongest Effecting enough element to Reach MLSP and Go Above It.
New studies have said that the biggest effector of Maximum Lifespan (besides NER/BER DNA damage repair) is the Chromosomal Organization.
Chromosome Organization seems to have a Dramatic Effect on lifesapn, and it makes sense because epigenome/methylation are intertwined to the the Chromosomal Organization. I think there is even a Mitochondrial Aspect to this, than just the Nuclear Chromosomes. It's still the DNA Chromosome domain. Chromosomes are the nDNA. While in Mitos it is Circular mtDNA.
Since, if there are mitochondrial DNA deletion -> ATP loss/ATP dysfunction production (ETC/Electron Transport Chain dysfunction (electron/proton leakage in mitochondrial membrane respiration chain)/OXPHOS and TCA dysfunction, mitos can't make ATP correctly (->mito pathologies/Mitopathies)). But, the Bigger one, is the Chromosomal Organization/Arrangement.
Chromatin Organization.
Disorganized/Diarranged/Disarrayed 'havoc in' Chromosomes -> Faster Aging.
HGPS/WS/Down's/Trisomy21 -> Failures of Chromosomal Organization/Arrangment -> Progeria.
Tight Coupling/Tight-Tight/Coiling/Condensation and Conformation/Organization -> Slow Aging.
''At these sites, long-lived species exhibit a lower rate of change in DNAm [DNA methylation], while short-lived species exhibit faster increases in DNAm. How those changes contribute to longevity is not entirely clear, but our results suggest several key transcriptional regulators are involved and modulate the rate at which DNAm changes between short and long-lived species.''
They are also saying that Faster methylation may cause faster aging because of faster acquiry of 'changes' in epigenome; while slow aging is 'accrues' slower the methylation...in my view it means that certain landscape 'pockets' (CpGs/genes) get activated/desactivated with time..and that is what causes faster aging...the faster this change the faster you age. Thus, this comes back to the 'epigenetic Silencing/transcription silencing'...keeping a genome silenced in areas that relate to aging..because with age we become 'unsilenced' and genes (and their transcription) that need to be - become, by then and contribute to 'aging'. If they are silenced, they do not contribute to aging. The short-lived animals acquire methylation at 'negative/deleterious' places (changing the epilandscape) towards aging/inflammation.Transcription has been shown to Increase with age and there is inverse correlation between longevity and gene transcription.
''Consequently, we carried out a meta-analysis that correlated methylation at individual CpG sites with age across species to identify age DMPs. At these sites, long-lived species exhibit a lower rate of change in DNAm, while short-lived species exhibit faster increases in DNAm. How those changes contribute to longevity is not entirely clear, but our results suggest several key transcriptional regulators are involved and modulate the rate at which DNAm changes between short and long-lived species.''
Long lived species had Less DNA methylation changes, and is why they live longer...they don't Need/(Have to) change...they keep it silenced and don't need higher methylation - it is Already methylated Enough (it is why the DNA methylation rate - is Lower - in Long-Lived animals, than short-lived animals). Short-lived animals but do 'Double Time'...work twice, thrice...etc...the time to Compensate the accelerated loss. Hence, higher DNA methylation rate in short-lived ones. But, long-lived ones, Still, need methylation, it's just better preserved already than short-lived ones. Hence, no need for more. While short-lived ones, lose it, really fast, and need some to 'Curb' the loss (compensation).
''Specifically, the
overlap between top 1000 CpG sites from both chronological age EWAS and generic
EWAS meta-analysis consists of mere 21 CpG sites, which implies a slight statistical
depletion, against the null hypothesis of selecting 1000 CpGs from background at random
(hypergeometric test p-value=0.0093, odds ratio=0.60). This suggests that maximum
lifespan is largely associated with a stable methylation state of the implicated CpGs, with
little change with age throughout the life course of an animal.''
''An important observation that surfaced in this study pertains to the differences
between ***epigenetic maximum lifespan and epigenetic aging***. Only 21 CpGs out of the top
1k most significant lifespan related CpGs overlap with the set of top 1k most age-related
CpGs. The fact that fewer than expected CpGs overlap (p-value = 0.0093, odds
ratio=0.60) reflects in part the statistical approach used to identify lifespan-related CpGs.
While there are ***apparent differences between aging and maximum lifespan*** at the level
of CpGs, there is complementarity at the level of chromatin states. ''
''Interestingly, lifespan-related CpGs in these
chromatin states exhibit ***lower methylation levels in long-lived species*** than in short lived
ones. In other words, ***it would take longer for these regions to become methylated in longlived
species since the basal methylation levels of these regions are lower***. This might be
the reason behind their slower physiological rate of aging and longer life. Based on these
findings we hypothesize that ***chromatin organization plays a pivotal role in determining
species lifespan***. Thus, ***interventions that enhance chromatin organization and
maintenance may increase epigenetic maximum lifespan*** which is consistent with
epigenetic aging theories''
Right now, I don't know of (any really) therapies that increase Chromatin Organization - besides HGPS Hutchison Gilford Progeria Syndrome therapies that slow down chromosomal disorganization by stopping mutant lamin/progerin formation - and Correctly Reorganizes the chromatin organization (and is why HGPS is then reversed - but only to the Regular Organization (the one, that people with no HGPS have). I mean even DNA BER/NER in mitos or nucleus will improve Chromosomal Organization (since DNA damage Causes Disorganization of chromatin), when repaired it slows/reverses the disorganization. But, so far, DNA damage repair as been Not Enough to counter the disorganization...that leaves us the RATE of aging and the RATE of Disorganization. That's the speed of aging. In humans, it is 100x times less (to 100% loss) vs a mouse, mouse live 1-2 years..thus age 100x faster than a 120 years old human. That, is the future, is how to reduce the rate of aging, ..I mean we want Reversal of Aging Rejuvenation...back to 20 years old body and repeat it...but so far, it seems it may not be possible (diminishing returns each reversal), as such it would leave us with having 'to slow' aging..the rate of aging; which so far as been weak and bad (Calorie restriction and other 'metabolistic therapies' that try to slow aging rate). It means we have to Improve the Slowing. If we can't improve Reversing or Repairing.
Just a 2 cents.
Epigenetic predictors of maximum lifespan and other life history traits in mammals
https://www.biorxiv.org/content/10.1101/2021.05.16.444078v1.full.pdf
https://www.sciencedirect.com/science/article/abs/pii/S1044579X99901347
https://www.cell.com/biophysj/pdfExtended/S0006-3495(17)30911-6
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103954
https://www.biorxiv.org/content/10.1101/2021.01.18.426733v1.full
https://www.nature.com/articles/s41467-021-21900-2
https://www.nature.com/articles/s41559-019-0913-3
''This suggests that maximum
lifespan is largely associated with a stable methylation state of the implicated CpGs, with
little change with age throughout the life course of an animal.''
If it is a stable state...that gives this Maximum Lifespan...then interventions that would try to make us go Above Maximum Lifespan would fail...if the animal - Would - reach the Maximum (as in, they are maintaining this 'stable (methylation) state'...and thus, Will Reach the Maximum). What happens if These Specific Animals...obtain a therapy...it would be Redundant/Effectless. Since, they will reach the Maximum - Already. It is not an assurance that it would be Additive - for them...as in they would go above the Maximum.
Thus, only Shorter-Lived, animals would - now - Reach the Maximum with the intervention..(again this is the 'progeria mouse' (getting big boost) vs 'normal mouse' (getting not boost). The fast agers - get a boost - because they are aging fast. The Slow Agers...don't get a boost, because they are Already slow in aging.
If it so...(redundant and slow agers don't get Any More Boost...) then..it means that interventions that try to increase lifespan - In Slow Agers - will not yield any or little result. Because they are Already 'Lined Up/Aligned' to Reach the Maximum (since they age slow already). Thus, again, redundancy (..again).
I hope I am wrong and that is it Additive to whatever rate of aging...but I'm not so sure when they say a 'stable state' is (already) maintained to reach Maximum lifespan. Reversal of aging would have to be better (than Partial Temporay Reprogramming of epiclock) because we would hit that Maximum Wall/Limit Barrier (as in, you already have this methylation state -> therefore you will reach the maximum - and End/die - at the maximum; not go over it/above it).
Like an 'assurance' to reach the max...now you are 'assured'..but you won'T go beyond it neither.
If it so.. then that leaves us to the Rate of aging. That would be the sole one that could go Above the Maximum - because it Does...when an animal ages faster (lives 2 years..and another one lives 122 years); that's the rate/speed of aging. So far, it has been lackluster with metabolism tinkering therapies that give 20% or so lifespan extension - in effect - the slow aging less than 20%..that's Dismal. I am talking Multiple X-Times/Folds slower aging; a mouse ages 10 times faster (that's 1000%****) than naked mole rat, 50-100times faster than a human (10000%).
A bowhead whales ages 2 times slower (200%) than a human...and clam/greenland shark age
5 times slower (500%) than a human (it loses epigenomic content five times slower - 5 times slower 'disorganization of chromatin'). And, thus reaches 500 years.
@CANanonymity
I cannot talk about the maximul lifespan but for ages after 50 (if not 40) we, mediocre humans, have a lot of mito repair issues. It almost looks like the mito repair just stops working after certain age. So if we can boost it we can easily get a few years of health span. Probably not something that will push us beyond 130 but making 60s the new 50s (and possibly shifting age-associated morbidity by a decade up to 100 y.o. )
Hi Cuberat! Thank you for that. Just a 2 cents. (and some random thoughts)
Yes, absolutely, mito repair is consequential, and affects health for sure....
But, if that is 'all there is to it' in the next decade(s) or so...then, that is very worrying.
''Nothing to worry about...we just die, lie expected...so don't worry (you will die and so everyone else''. I am supposed to be not worried.
Because, it would mean, we Just can look forward to 'healthy/average lifespan' extension.
that's about it.
And forget about living beyond 120-130 years Max/MLSP or so; because that MLSP is quite 'hard specie longevity maximal limit'. If Rejuvenation can't reverse Enough or be Robust enough to reverse things (repair the damage fast enough and reverse the epigenetic clock age (via partial epireprogramming).
That is why I am saying, it leaves us with having to slow our 'basal' aging rate (the speed/rate of aging - right now as you are alive). This is the Metabolism therapies (calorie restriction, etc..) and they always give very low/dismal result (20% extension). Hey...
I don't want to sound 'needy' about aging (ok I know I sound like that..)...but, when you face death/aging - you Have to Be Needy and Harsh....
because death/aging IS harsh. It's forever when it happens.
It's no joke.
But, out there, it seems it is and sometimes I feel people are 'whatever/forgetaboutit'/not waking up to Realizing that if we don't Aim Higher and Ask Higher...we won't Get There....ever - in the next 50-100 years...
like...in our Lifetime. No to sound pessimistic, negative, unhopeful or 'alarmed'..but we need to be a bit alarmed about it...aging does not wait...it continues ..until our end, when time runs out.
And the rich billionaires need to wake up that they may not believe this and think it's all balloney and hopeless (and in a sense they are a bit right), but we all their money...they should burn some of it to 'give the best shot'...if they keep their money (because they think lifespan extension is futile hopeless attempt), then that'S really bad...because they don't Need all this money...what they Need - is their Life.
Just a 2 cents.
PS: To just accept (defeat) and say: ''we resolve ourselves/just accept that 20% is the Very Best...we'll ever get...and forget about LEV or eternal life or even living 150...it's one big dream illusion (All Along - we were fooling ourselves - it was not happening in our lifetime)''.
I also wonder if AdG realizes that indeed it may not be possible to make any LEV in his lifetime (most likely, he did, because he did know it has a high chance of never happening).
PPS: I've said it, Horvath said it and thousands of people 1000s of years in the past said it: ''Defeating Aging (and death (of aging) is the Holy Grail''. It's not easy to get it, that much seems clear, and perhaps it may be too hard - if impossible.
I hope not.
PPPS: That is why, I say, that the Rate of aging may end up the very Only thing the Truly can go above our maximum as specie. To me - it's like unconceiveable - that we should 'accept we die at 120 or less'....it's like Giving up on Life. It's Utter utter uttteerr failure of biology/biogerontology.....alllll this work (for nothin?)
And just accepting death.
It can/is conceivable...but I Don'T want to conceive it...I like being/staying hardheaded/stubborn about it (especially when you faced death Before (like me, had atherosclerosis..it was enough, don't want that to happen again) & 'not accepting' that we just can'T live beyong 122 years max.
If I had 500 Trillion Dollars - and this entire sum of money would be required - to defeat aging - I would BURN IT./spend it all..immediately and be poor again/penniless; because, at least, I would now have defeated aging (no, there is no assurance...but if it had a solid chance, then it would be worth it). That would be worth more than ALL the riches in life - life is the most expensive thing Ever. (And I know govs or certain rich people...don't think that...they can 'measuer your life - value you' in terms of $$$ dollars...and that's wrong because there is no price$ to a life (yet, they made one/make one (especally, long ago, with slavery and 'selling humans/people - for money' (slavery); thus, they put a price(tag) on your life; it's the same when you go 'buy a dog or cat'..the cat or dog..is not worth 400$...or 300..or 600$...it has no price. But people put a price on that animal...gov does same thing...on your head - and your life. We saw that with COVID19...gov does not care..can put a price on your life and decide you are not worth much 'kept alive' (vs the rest of the population kept alive); 1 person vs the whole population dillemma; who's life is more important, more lives more important than 1 life...but how important is that 1 life...for gov...not important. just 1 loss.). IF you are That One person, you would have a different opinion. Because, Your, 1 sole life would depend on it.
PPPPS: I have my reservations too about mitochondrial studies...I mean, they show potential..mitochondrias might end up much stronger an effect...but will they make us reach about MLSP...as you said, it's quite doubtful...because of the rest (the nuclear DNA rest). Thus, mitochondrial tinkering could help 'health span' boosting...a nice thing...but SO so so so so disappointing in term of living Much Much longer, it still sam darn thing...live uup to 120 hard limit. We should be Very Impressed(?). That worries me, deeply. Because then you think to yourself : ''Oh..........so, no, it's not happening, we won't live above 120...that's just a big miracle - a very very - Big IF/Maybe''.
And I know some people are like : ''whattt? I mean living 10 years more is a Miracle, aren't you happy? or somethin......you expect us to live like clam for 400 years...are you crazy? never happening. we will live 10 year more and contend yourself with that..,,,....'be happy..and die happy'''....
PPPPPS: That'S the problem, contending ourselves with that/just accepting 'crumbs' is not ok (to just accept that like it's 'very good/and everything is A-OK/Fine'), it will mean our Assured end - 100% Guaranteed. ''Don't ask for the moon''...yet that's what we need...because it is a (far flung) 'moon shot'...to defeat aging. We landed on the moon...now we need to land on the figurative moon of aging and destroy that moon once and for all (solve aging and death of aging; for good).