Werner Syndrome is Strongly Mediated by Mitochondrial Dysfunction
Researchers here report that NAD+ upregulation to improve mitochondrial function, via supplementation with nicotinamide riboside and nicotinamide mononucleotide, does a decent job of rescuing the life span of flies and worms with the genetic mutation that causes Werner syndrome. It is not quite all the way restored to match wild-type animals, but close. Werner syndrome is a DNA repair deficiency condition in which patients exhibit, at the high level, what appears to be accelerated aging: early onset of a range of age-related conditions, early mortality. It is not, however, accelerated aging. Natural aging stems from rising levels of molecular and cellular damage, but damage of a particular blend of varieties. Werner syndrome is one specific class of damage, stochastic nuclear DNA damage, elevated to a very large degree. There are important differences, and it is never all that clear as to whether we can apply lessons learned in DNA deficiency conditions to normal aging - it depends greatly on the fine details in each case.
The most interesting point here is that, in at least short-lived species such as flies and worms, the harm done by this particular DNA repair deficiency is to a large degree mediated by an early collapse in mitochondrial function. It remains to be see whether this is also true in mammals: the literature might lead us to expect that high levels of stochastic mutational damage to nuclear DNA could be causing all sorts of other harms. Mitochondria are the power plants of the cell, responsible for packaging the chemical energy store molecule ATP needed to power cellular operations. NAD+ is vital to mitochondrial operation, and its levels decline with age, alongside mitochondrial function. Artificially boosting NAD+ levels has been shown to restore the ability of mitochondria to function in a more youthful fashion, but as yet there is only the one small clinical trial to show health benefits in older humans.
Can we take this paper as evidence for mitochondrial decline to be very important in normal aging? That would be the question. If I were speculatively joining pieces of the jigsaw puzzle, I would take this study, and put it next to the recent finding that suggests double strand breaks in nuclear DNA will cause epigenetic drift of the sort observed in aging. So the more of this sort of DNA damage, more epigentic change. Problems with mitochondria are perhaps proximately caused by changing levels of specific proteins, such as those necessary for the process of fission. Too little fission results in ever larger mitochondria that are not easily cleared out by the maintenance processes of mitophagy when they become worn and damaged. Protein levels are, of course, under epigenetic control. Perhaps this all fits together, but it still needs a lot of work to shore up the relevant evidence; it should be treated as speculative.
NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
We report that Werner syndrome (WS) is associated with a significant mitochondrial dysfunction, mainly manifested as defective mitophagy. This is reflected in lower NAD+ levels across species from worms to humans. NAD+ supplementation improves mitochondrial function and other age-related metabolic outcomes. Mitochondrial disease can manifest itself in multiple clinical outcomes amongst which neurodegeneration and impaired metabolism are common. Some features of WS may be explained by genomic instability due to mutation in the gene encoding the Werner protein (WRN), an important DNA helicase/exonuclease involved in DNA repair, telomere and heterochromatin maintenance, and cancer regulation. However, the relationship between WRN mutations and the syndrome's severe dysregulation of energy metabolism is unclear.
Mitochondrial quality and function decline with age, contributing to insulin resistance and metabolic diseases in the elderly. Mitochondrial quality control is regulated by biogenesis and mitophagy. Mitophagy involves the targeting of damaged mitochondria to the lysosomes wherein the mitochondrial constituents are degraded and recycled. Defective mitophagy is prominent in aging and age-predisposed disorders, including metabolic diseases and neurodegeneration. However, the role of mitophagy in WS has not been investigated.
The metabolic molecule nicotinamide adenine dinucleotide (NAD+) is emerging as a fundamental regulator of mitochondrial homeostasis, genome stability, neuroprotection, healthy aging, and longevity. Interestingly, genetic and/or pharmacological upregulation of intracellular NAD+ levels protects against obesity and type 2 diabetes in rodents, and against age-related diseases and neurodegenerative diseases such as Alzheimer's disease.
We therefore examined whether mitochondrial dysfunction and NAD+ depletion occur in WS, and if so, how it contributes to the molecular pathology in WS. We report that NAD+ depletion is a major driver of the severe metabolic dysfunction in WS through dysregulation of mitochondrial homeostasis. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.
Hi there! Just a 2 cents,
(AD) Alzheimer's Disease (my uncle died of that at 74, in 6 months he could not remember anything (could not remember his daughter&son (my cousins), his name, the last thing he said 5 seconds ago, the need to go to the bathroom, and then stopped eating/remembering to eat).
(NR) Nicotinamide Riboside (increases intracellular NAD+ levels) just like taking NAD+ supplement; or B3/Niacin/Niacinamide/Nicotinic acid (I use to take lots B3/Niacin to increase intraNAD levels; but high levels of this can cause liver failure (it happened with people who consumed too high levels of B3 for a year and then one year later, they have liver pain/liver failure/need liver transplant because it's too late for liver to regenerate; a jaundice is first manifestation).
'' Since AD patients show increased oxidative stress compared with healthy individuals (52), we investigated the oxidative DNA damage using AD patient fibroblasts (AG07374) and fibroblasts from age-matched controls (AG09857). 8-Hydroxy-2′-deoxyguanosine (8-oxo-dG) is one of the most abundant oxidative DNA lesions (53). Human AD fibroblasts treated with 1 mM NR for 24 h showed a 50% reduction of 8-oxo-dG levels as measured by ELISA (Fig. 4E). ******Mitochondrial reactive oxygen species (ROS) production was also measured using the MitoSOX probe. NR treatment of AD fibroblasts resulted in decreased levels of mitochondrial ROS compared with vehicle-treated cells (Fig. 4F)*******. Combined, our results show that NR decreases oxidative damage in human AD fibroblasts.''
8-oxodG in mitochondrial DNA and nuclear DNA is both causal to aging in mammals (it is the same thing as telomeric DNA DSBs and yH2AX TAF/SAHF foci in nDNA). Albeit, studies on mammals only saw a MLSP inverse correlation in mtDNA (meaning 8-oxodG in mammals organs' cells' mitochondrial DNA is inversely correlated to their maximum lifespan; not in nuclear DNA though. This was verified in the heart and liver of mammals from mouse to elephant; and only mitochondrial DNA 8-oxodG lesions were inversely linear to maximum specie lifespan in these organs). There is a correlation between 8-oxodG and nuclear telomere DNA foci yH2AX 53PB1. They are rise about equally; in the mitochondria DNA and in the nucleus/telomere DNA.
It is important to mention that NR/NAD+ supplementation was able to restore NAD ratio - and Reduced Mitochondrial ROS. In the mitos, precisely. This is most important point.
Another study did the same thing; but if autophagy was abrogated, there was Not a reduction of mitochondrial ROS; This means autophagy is important to remove effete/giant mitos/senescent mito that produce ROS - as increased burden. Thus mitophagy/autophagy is abled to reduce Total Mitochondrial Burden - Simply, because it removes the crap/junk out (that contribues to total mitochondrial ROS emission). This, demonstrates that it is not Autophagy that makes extreme lifespan, it only Enables it; without it, it's not possible (because our lysosomes would be clogged and dead mitos would accumulate and contribue to total mtROS burden).
Rather, it is the Mitochondrial ROS - PER - mitochondria that is causal to lifespan. The Total ROS Burden can be Relieved by Autophagy, once it removes dysfunctional mitochondria. THEN. the ROS levels reduce/come back down to Normal.
But. as said, it is not autopagy itsself that is Causal to the casacade of Nuclear DNA damage (Telomeric DNA DSBs/TAF (yHA2X)/SAFH/mitochondrial DNA/nDNA 8-oxodGs lesions and mtDNA Deletions) - it is Mayhem that is happening In the Mitochondria - each mitochondria - which each (by ETC leakage/Complex I ROS) - produce ROS; the largest cause of all descending damages. Let's remember - ROS - are necessary for senescence entry; not conditional, you need them; that's because they cause the cascade of damages in mitochondrais And in the nucleus - and making epigenetic changes later/equalling epiclock advancement (global Methylation loss of methylome/loss of cystosines/methyls which means decompaction of chromosomes in nuclear DNA).
1. https://www.pnas.org/content/115/8/E1876
PS: In this study here, (WS) Werner Syndrome is rescued partly by NAD because there is mitochondrial reduction of mitoROS emission. If that did not happen there would be No change to NAD in WS accelerated aging. As shown, when autophagy is blocked and there is no 'total ROS mitojunk burden'/No mtROS reduction, and no life elongation neither. A study had showed that humans have Elevation of ROS - with age; not just stagnation; but elevation of rate of mitochondrial ROS as they age. This Contributes to elevation/accumulation of nuclear telomeric DNA foci/DNA DSBs and thus, epigenetic changes/advancement (aging). Werner Syndrome people also have higher number of short telomeres in total telomeres count; thus they age faster (since mammals with the least amount of short telomeres live the longest); also, their rate of 'telomere attrition'; speed of telomere shortening is faster than regular humans. They live up to 50-60 years old; so I wager their telomere attrition rate is about 75-100 bp/year while healthy people is 50 bp/year avg; and fast progeria HGPS people they lose 500 bp/year in telomeric DNA; they live 15 years. Mice lose 5000 bp/year, they live 3 years. The rate of telomere shortening is staved-off by NR/NAD+ - Because - there is reduction of mtROS in the mitos -> the contributor to TAF/telomere DNA foci/DSBs and the Rate of telomere shortening; and accumulation of number of Short Telomeres. Downstream/after, it means slower epigenetic aging/changes/drifting and preservation of methylome longer (slowing of epiclock changes acquiry (in other words the epigenome remains silent/methylated (gene silencing (at least, for the inflammatory genes, the ones are activated in a vicious circle and contribue to inflammation/health degradation as mitochondrias tell telomere to 'send out' a continuous DDR signal (DNA Damage Response) at telomeres, especially, this signal prevalent in very Short telomeres))).
Mitochondrial ROS are regulated, specially, by the Redox state (NAD/NADH; GSH/GSSG; Cys/Cyss; ThioRedoxin, Thiols and other (non)enzymatic defenses (GST, GPX, PRX, ecSOD, mnSOD, mtSOD, CAT, SIR, DAF, FOXO; basically, everything, that NRF2 activates when there is oxidative stress for 'oxidative stress Resistance'); it is why antioxidant like MitoQ or Ubiquinone( Vit. E) help to quench mitochondrial ETC Complex I-III ROS and have boosted the health of animals/including their average longevity; and some, maximal lifespan. Not always, it's because it's a complex interplay between mitoROS, telomere foci/DNA DSBs and epigenomic changes.
PPS: For anyone wondering : (''Haven't we talked about this before...I feel we are running in circles...we tried to defeat ROS..we can't/antioxidant are useless and do notthing to stave ROS/or do but not much lifespan extension...it is a vicious circle of us doing the run-around in 'merry circles' we go....this, aging''.
Indeed. That's because the body is pure yin-yan; it's a balance, so it's like a (balanced) circle; and even more, a vicious circle. Hence, we feel back 'To Square 1' of the fun'circle 'rat maze'. It's only if we Attack All Sites, at the Same Time, that we defeat aging (not just mitos, not just teloemres, not just epigenome, ...)
It's good to see Reason catching up with the science an pointing the finger at an altered balance of fission and fusion as causal in mitochondrial aging, rather than Aubrey's 20 year old thesis on mitochondrial mutations.
Clearly the line runs from epigenetic alterations in the nucleus to mitochondrial decay and from there to everywhere in the cell. If this is true then repairing mitochondria will increase median lifespan but probably not affect the maximum, which will still be limited by changes in gene expression initiated in the nucleus.
Hi Mark! Just a 2 cents.
The mitochondrial mutations theory is still ambiguous; but we really see that mitochondria are the most center/starting point in the chain (like the weakest link; and not just weakest - Starting link/Upstream of everything downstream); studies that have looked at mitochondrial mutations have said that Certain mutations are actually aging the animal; very specific ones; while others seemed to be of no (or less) consequences (unconsequential in terms of aging). These mutations would deleterious to the mitochondrial function by causing 'mitochondrial DNA deletions'; basically, this caused, litteraly 'chunks' of mitochondrial DNA 'erased' from the mitochondrial DNA. These mtDNA deletions would cause havoc in the mitos - they are not capable of doing OXPHOS (Oxidative Phosphorylation) correctly anymore; the deletions caused dysfunction in the ETC (Electron Transport Chain) at the mitochondrial Complex I to IV; this means Very high production and leakage of ROS - due to loss of electron during electron transport. The mitos can't do 'respiration/state3/state4' correctly; the effect of this is that the cell energy ATP levels (produced by mitochondrias) drop catastrophically (to a level not enough to support cell function; causing senescence or apoptosis). People with certain mitochondrial disease (like MELAS) are not always having accelerated aging - because, their mitochondrial pathologies are not affecting enough to create damage/TAF/SAHF/or sufficient mitoROS; thus their actual speed of aging doesn't change - yet, these people can serious health problems/organ defects. The mutation is cleared then their health comes back to normal - but there is no difference on their average lifespan/Maximum lifespan - with or without these mitochondrial mutations. Because, as said, Only Certain mitochondrial/nuclear mutations affect speed of aging. Mitochondrial DNA (Base Pairs) Deletions are one these that can affect speed of aging and/or health (because there is litterally loss of mitochondrial DNA in the mitos; it it'S erased, the mitos are completely dysfunctional/can't do OXPHOS/ATP production; this would dramatically raise mitoROS at Complex I-III and cause aging advancement by accumulation of telomeric foci (yH2AX/8-oxo-dG/DNA Double-Strand Breaks), faster telomere shortening rate and accumulation of short telomeres (which later, would cause epigenetic advancement; since telomeres and epigenome talk to each other; telomere DDR is a signal and epigenome hearing it (will activate inflammatory genes in return))).
Just a 2 cents.
PS: And, we all forget that mitoROS also contribute to very large amounts of lipid peroxides/hydroperoxides; which, they, create ALEs/TBARS/MDA down the line. Not only that, AGEs/Amadori 'end products'; carbonylated proteins/unfolded proteins/oxidized thiols (GSSG), isoprostanes, and the list goes on - ALL (and 'thanks to/from) - mitochondrias producing ROS.
It's why studies that checked animals saw that the longest mammals had the lowest concentration of PUFAs (PolyUnsaturated Fatty Acids) in their mitochondrial phospholipids membranes. That's because PUFAs (like DHA/EPA Omega-3) are Highly peroxidizable bt their carbon length chain and number of double-bonds/kinks (DHA 22:6; EPA 20:5; ARA 20:4); in humans Omegas-3 are rich in the brain mito membranes' phospholipids; and, are needed for brain function because these highly unsaturated fatty acids cause 'membrane fluidization' thus; a faster more 'watery' membrane/better for neurons that send fast firing impulses (if we didn't have long-chain/high double-bonds/kinks Omega-3s we would be 'slow-mo'/retarded/mentally vegetable); because the neurons would be just too slow to 'make thoughts/think fast'/send impulses. The downshoot of this is that how mitochondrial membraes are 'susceptible' to Attack by ROS (from...the same mitos). ROS destroy PUFAs, and in doing so; PUFAs become 'peroxidized'; and then it is a cataclysmic chain 'lipid peroxidation' that happens near the mitochondrial DNA; 'frying it'. Causing TBARS (Thiobarbituric Acid Reactive Species (same as thio/barbiturates drugs that kill you from toxic lipid peroxidation)/MDA (MalonDiAldehydes), 4-HNE, Acrolein, really nasty sh...that wreaks havoc and causes, farther, nuclear DNA DSBs in nucleus/telomeres; and in mitos cause Mitochondrial DNA 8-oxo-dG lesions and then, entire Deletions of mtDNA chunk/'content' altogether. It is said that mitochondrias are 10-times more susceptible to oxidative stress ROS; simply, because, they themselves, are the Very Source of it.
Not only that, 10-times more suspectible to Membrane Lipid Peroxidization chains from these same mtROS.
It is not a surprise that the longest mammals had Strong Reordering of their Mitochondrial Membrane Phospholid Fatty Acids Composition. Mainly a reduction of DHA PUFA for Omega-6 Linoic acid (18:2; much less chain lengh/less double-bons...less places for ROS to Attack; thus, less Susceptible) and MUFAs (MonoUnsaturated Fatty Acids; like Oleic Acid (18:1; only 1 kink....is very low subsceptibility; thus ROS just can't attack it; mammals that live the longest have reordering towards this unsusceptible fatty acids in their IMM (Inner Mitochondrial Membrane)); and yes, this in return causes less end products of lipid peroxidation; thus, less destruction of macro molecules/macro-molecular damage. And, less DNA damage too (by less DNA frags/DSBs in telomeres).
Animals that live longer and have higher percentage of Long Chain Omega-3 PUFA in their brain and other organs - are paradoxical; because they would/should be dead from the peroxidation of these PUFAs; but, in their case, like for example humans; evolution found a way to make it work Despite the Increase Peroxidation caused of them - it increased Quenching/Consumption of ROS in the mitos as a compensation (via Redox/Antioxidant Systems) against increased ROS-lipid peroxidation.
''We hypothesized that, rather than differences in ROS generation, the ****capacity of mitochondria to *consume ROS* might distinguish long-lived species from short-lived species***. To test this hypothesis, we compared mitochondrial production and consumption of hydrogen peroxide (H2O2; as a proxy of overall ROS metabolism) between NMR and mouse skeletal muscle and heart. We found that ****the two species had comparable rates of mitochondrial H2O2 generation in both tissues; however, the capacity of mitochondria to consume ROS was markedly greater in NMRs****. Specifically, maximal observed consumption rates were approximately ****two and fivefold greater in NMRs than in mice, for skeletal muscle and heart, respectively***''
2. The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses
https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12916
Certainly aging goes through mitochondria and they are central to the process. But their maintenance is controlled from the nuclear genome. Many papers show this, and many other papers show mitochondrial fission is sufficient to reduce the DNA loops to the smallest possible size, show up any faults in their DNA manifest as loss of membrane potential, and eliminate them via mitophagy. For some reason this process is downregulated with age, most probably via epigenetic changes. Or maybe cells with worse mitophagy are selected with age. But it is controlled from the nucleus and therefore I wouldn't say mitochondria are 'driving' the process.
PS: Yes, just a 2 cents, mitophagy is very important/like autophagy (and why, oftenly, lifespan elongation studies don't work anymore - if autophagy/mitophagy is blocked; like Calorie Restriction...relying on autophagy (to clear junk) as a component of the lifespan elongation. But, that's where I am not sure...because autophagy is important (for example, Brown bats live 40 years and have better chaperoning (to the autophagosome/lysosome)/chaperones (HSPs), and thus better 'folded' proteins; they have a functioning autophagy/mitophagy and clean/unclogged; thus a lower total mitochondrial ROS burdern (from all the Junk that is cleared by auto/mitophagy). As such, studies that increased autophagy/mitophagy made a lifespan elongation but not a dramatic one/the way mitochondrial changes do. I think because it is the nuclear changes that cause the advancemetn of aging - and ROS - in the mitos contribue to that; to a Large extent. More so, than simply stuff cloggin the lysosome. I'm not saying the Junk burden is not consequential; it is; but, if we are to talk about Extreme Lifespan; autophagy increase does not do that on itself - I suspect that the Enormous amount of mitochondria in total - are the most largest contributor to aging (which downstream cause telomere foci/epigenetic advancement/and yes, lysosome clogged/dead mitos neending mitophagy); we have a zillion mitos; their total is what counts here (and is why evolution 'reordered' the lipid composition in Each mitochondria - so that Each mitochondrai would contributing Less damage - Each (by each having reduced ROS emission from the minute process of breathing oxygen..causing Reactive Oxygen Species that oxidize everything), High (unquenched) ROS = senescence entry. The mitochondrial membrane potential is necessary for H+proton motice force and create ATP in mitos; the downside is high potential = high ROS; it Must be Consumed (as shown in study above); or else mitos produce .O2/H2O2/ROS that will destroy their membranes; All in Total contributing to these lipid peroxidation chain in mitos. And, thus, as said why evolution put selection pressure on lipid genes/mitochondrial lipidome reordering. And why mammals that live 100-200 years have Lower Peroxidizability Index in mitos - or - they have Higher Consumption of mtROS to Compensate (for ex. in the brain with High Peroxidation). The riddle is finding 'where' we can Attack to affect downstream in the most impact/weight; I think at mitos we are difficulty because the Amount/necessity to quench the entire mitos is quite huge; and as shown in humans; their mitochondrial ROS emission rises with age (does not stay same; which will contribute to More damage at nuclear DNA/telomere (DDR)/causing epigenetic drifting).
Just a 2 cents.
Yes, but if damage to mitochondrial membranes really mattered then mitochondrial antioxidants should stop aging, but they only extend median lifespan and do nothing to max (to my knowledge). And if ROS escaping the mitochondria and damaging the nuclear DNA was what is driving aging, then similarly, large quantities of antioxidants should work for lifespan, but they don't.
I think that with upregulated mitophagy, or other such things like mitochondrial antioxidants , or things like methylene blue that make the ETC more efficient, we should be able to stop mtROS from rising with age of the cell (line) - to the point at which the nucleus instructs the mitochondria to break down. You see this with cells in a serum with nicotinamide - increase in mitochondrial turnover, reduction in mitochondrial mass, slight increase in ROS in the short term but arrested rise in ROS in the long term - and the cell line can survive longer - until the telomeres get short, and then bang, ROS rises really fast and the cells all die. In vivo the story might be different, but it goes to show that mitochondria are the slaves not the masters of the cell.
PPS:
The nicotinamide/NAD+ example is a good one indeed; but, as you said, nicotinamide, which restores NAD/NADH levels is able to stop this ROS elevation - only for a while; albeit, it definitely abates this elevation (for example, in fibroblast, instead of the usual dramatic increase of ROS in the last 20 population doublings (PDs) (out of 60 PDs/replicative senescence); it makes a soft rise in DCF ROS signal, and the cells can do about 120 population doublings and then, at 120 PDs, enters replicative senescence). Thus, there is a double-replicative lifespan elongation my nicotinamide (at least, in fibroblast...but this was tested in keratinocyes and other cells; it was basically the same results; not always double; but at least 15-20 PDs extra in any cell because it staved-off/abated the Rise of ROS with cell population doublings). Precisely, Mitochondrial ROS. Because it is the largest contributor to telomere foci (mtROS -> mtDNA foci, nDNA/TTAGGG foci (mtROS = Telomere DDR)). When the telomeres shrink they cause activation of epigenes responsible for replicative arrest; in continous cell cycling, it is the
p21 gene. While in spontaneous 'premature senescence', it is p53. p21 arrives to 'make the cell enter 'replicative senescence'; while p53 makes the cell enter 'premature senescence' (is different than 'passaged/replicative senescence'); it is also different from Proteasome-block induced senescence (both proteasome blockage or 'sponteanous premature senescence' cause a same p53 activation); while 'replicative senescence' causes a 'latent' 'late' p21 accumulation that is near-irreversible (except by ROS quenching or by remethylating it); (p53 and p16 are activated too but they are not the elements for replicative senescence entry; it's unconditional p21 (WAF1/CIP21); this specific tumor suppressing gene causes Massive accumulation of ROS in mitos and is specifically for replicative senescence. Once the cells enter replicative senescence, p21 stops immediately; demonstrating it is the 'enabler' cause (the real cause are the ROS; but the enabler is p21; because when it comes, it makes ROS rise Sharply). It makes sense, much like p21, p16..or even better; TNF-alpha (Tumor Necrosis Factor); is works as a tumor necrotic element to destroy cancers before they form/it's a safeguard mechanism against cancer invasion (by killing you - it kills the cancer cells...kind of like chemotherapy or radiation...it kills tumors...except it kills your healthy cells too, at the same time; because of these ROS bursts caused by these tumor suppressor genes making the mitos produce more ROS; killing Cancer With ROS - and killing you in the process). A futile attempt/vicious circle. In other words 'Fight Fire with Fire'...you still burn/die in flames no matter if destroys the fire (cancer). That's what happen to my mother and my gf; both died of cancer and both did chemotherapy; and both it was useless (and Contributed to their death, because chemo makes ROS, too much = More Senescence). For evolution, get cancer = kill self/destroy self (compromise specie survival) = ROS Burst (via Tumor Suppressing Genes) = must Stop Senescence/Cancer formation to preserve specie survival/eliminate 'bad weed' from genepool (no transfer of 'cancer heredity to children').
Maximal Lifespan, just a 2c, is determined how quick to replicative senescence of cells; and that is determined, most upstream, by mitochondrial ROS and by arrival of p21. Once p21, arrives, ROS signal multiplies (DCF ROS signal can be 8-10fold higher once p21 is fullpin), and once, that happens, it is replicative senescence entry. All along of this; telomeres will Dramatically reduce - at that specific point (of cell/mito ROS rising and of p21 showing up); the speed of nucleus chromosomal telomere shortening will accelerate right there; and the number of foci (yH2AX/8oxodG) will accumulate at telomere (causing DDR and DNA Double/Single Strand Breaks/Frags))) in telomeres - because ROS (of mitos/p21 demethylation) - will cause that. While, in the epigenome, it will be sustained demethylation of that p21 gene; in other words 'full activation' ('derepression/Unsilenced gene (by loss of its methyl) becoming demethylated'); On top of that the DNAmethyltransferase will suddenly reduce in Activity - which will reduce methylation; causing this derepression of this post-translational activation p21 gene (in epigenome). This will cause Instrinsic Aging (in the sense we mean it; just like progeria, but slightly bit different...but all in all the same thing; faster telomere shortening, accumulation of telomere foci, DSBs, accumulation of lipofuscin and especially, of Progerin/Lamin-a (this accumulates in progeria fast-aging Hutchison-Gilford Progeria Syndrome people/Werner Syndrome/Trisomy 21/Down Syndrome...and Also in regular healthy humans (albeit slower; but still detectable levels of progerin in healthy cells too)); When telomeres are lengthned by telomerase - progerin stops accumulating/likewise for lipofuscin (lysosome becomes empty).
When you abrogate p21 or you consume mitochondrial elevation of ROS; you stop progerin and also lipofuscin; this happens inside immortalized/infinitely dividing cells (like cancer cells). These cancer cells 'overcome' replicative senescence/Leonard 'Hayflick Limit' and then transform/immortalized/dividing forever - Never accumulating progergin/lipofuscin/Never having a rise of ROS (like normal cells)/never having telomeres go below 2KB size (telomerase keeps on adding telomeres and there is Net Gain in telomeres size (over time) rather than net loss); plus, as said, the telomere shortening speed is eventually stabilized and so the cells can stay diving infinitely (effecitly, 'bypassing' replicative senescence/imm*rtalized). Normal cells can't avoid replicative senescence; it's why NAD/nicotinamide only makes normal fibroblast reach 120 PDs max...and then replicative senescnce Once again (the Barrier). Of course, it's pretty good because that is Double the replicative lifespan...but it is not Imm*rtalization neither. And yet we see that NAD/Nicotinamide cannot stop the ROS Burst elevation, just abates it/slows it gently and it does not stop p21 from 'appearing' just at that moment that ROS elevate drastically.
Thus, for humans to live 500 some years...will we have to Attack either mitochondrial ROS Elevation, abrogate p21 (we tried...and failed because..ROS ends up accumulating even so (thanks to mitos ROS); maintain ATP levels (albeit, I'm not too sure on that because senesceen can happen in low or medium/high ATP levels; cells can survive on low ATP); possibly repair DNA frags/stand breaks - not too optimistic because we tried that too (we have efficient DNA repair already..and can't live more than 120; albeit it would need to be sustained and error-free); stopping of demethylation (of specific genes like p21) in epigenome, stopping of loss of 5-methylcytosines which are important for methylation/methylome/epigenome gene silencing; Maintaining the redox (that could be the safest/strongest bet (NRF2/ARE2/Phase II Detox/ROS Consumption/ROS and End Product Detoxification...but it may not be enough as we tried mitochondrial antioxidants with mild results (most therapy end up 'too weak' in the long run or ahve to be Started Very Young (the more I read on aging, the more I realize aged person is doomed unless we rebuild everything in them; Only Young Person will benefit because have sustained low enough damage (we think we will repair damages in old...but it is only if the cells are Returned Epigenetically to Young Signature (like Yamanka epi Sox/Oct/Nanog cell Reprogramming which restrores Telomere Length, repairs DNA frags, remove lysojunk, and Abrogates cell p21/mtROS); it means we must knock them all at the same time; because alone (isolated therapy) it seems not enough to make lifespan above Maximum Lifespan; just avg elongation).
Just a 2 cents.
You said it pretty comprehensively CANanonymity, we can't win by slowing the clock, we have to rewind it. And the only way to do that is in the nucleus via telomeres and epigenetic reprogramming. That way hopefully we can play the clock multiple times.
ps you have my sympathy - the same thing happened to my mother - massive destruction of the body via chemo when the final outcome was never in doubt.
PPPS: Thank you, ..
you have my sympathies too.
I hope that we can play the clock too, the study of epireprogramming is showing lots of promise (but in biogerontology, never make a promise...or else be deceived later when can't keep promise); like the study where there epireprogrammed cells in
''They started by testing the approach on cells from mice with progeria, a disease that causes accelerated aging in both mice and humans. The results were promising, so they decided to see if they could induce the same process in live animals.
They genetically modified mice to respond to the antibiotic doxycycline by switching on four genes that produce the Yamanaka factors before cycling the mice on and off the drug, administering it for two days and then withholding it for five.
This partial reprogramming extended the mice' lifespan from 18 weeks to 24 on average. The mice looked visibly younger, their organ function improved, and importantly, they did not develop tumors.
To see if the approach was isolated to mice with progeria, the researchers then tested it on normal middle-aged mice. They found that partial reprogramming enhanced the regeneration of muscle tissue and beta cells in the pancreas after injury.''
'' preliminary method to partially reprogram adult cells in mature Hutchinson-Gilford Progeria Syndrome (HGPS) mice by transient induction of the Yamanaka factors OSKM (Oct4/Sox2/Klf4/c-Myc) appears to ameliorate aging-like phenotypes in HGPS mice, and promote youthful regenerative capability in middle-aged wild-type individuals exposed to beta cell and muscle cell-specific toxins. However, whatever epigenetic repair is induced by transient reprogramming does not endure and may be due to the induction of key homeostatic regulators instead. Some of the effect of transient reprogramming may result from increased proliferation and enhanced function of adult stem cells.''
These first stepping-stones, as long we make sure to not 'over'-reprogramm (if too long exposure to these reprogramming genes), because that will cause cancer/teratoma formation as the body goes into 'extreme cell cycling' to rebuild the tissues; this primordial 'stemcellness' (just like cancer cells) allows cancers to form spontaneously simply because there is so much proliferation/cell division going on to rebuild tissues.
The bit they said they reprogrammed cells in old mice and make them rejuvenated is great news (same for HGPS people...the HGPS mice were now 'normal life' after their cells reprogrammed...almost); But, these mice did not reach the age of of a naked-mole rat (35 years) neither and that is what worries me; how much 'impact' can this reprogramming really have? For now it's early but they are effectively 'younger' by the clock; but it needs to be Sustained and as you said - Played - so that we can play/rig the clock, continuously/repeatadly which would equal Eternal life/continuous post-poning of death/contiuous post-poning of 'the maximum lifespan' possible of this specie.
''However, whatever epigenetic repair is induced by transient reprogramming does not endure''
''...the researchers then tested it on normal middle-aged mice. They found that partial reprogramming enhanced the regeneration of muscle tissue and beta cells in the pancreas after injury.'' (Ok...but what about their Lifespan...how about making Young mice of these old mice so they live above their MLSP). That's where I'm cautious, if they could not make the old mouse have extreme lifespan extesnsion from these 'reprogramming factors', it means it's either 'preliminary' yet (we are not there yet) or they are not enough; at least, it's a great start, but these epigenetic reprogramming studies must focus on lifespan extension, avg And Maximal. Otherwise, the study is purely 'health' promoting rather than life extending. In HGPS mice they go back to normal - but it's normal lifespan; not eternal; thus the question begs...can we rig/play the clock on and on/do the loopdiloop rewinding, and it sufficiently 'reversing' all the damages/changes of aging - to create lifespan extension - However long we wish it (thus we could revert the clock infinitely which wiould equal to infinite lifespan extension (Theoritically)))?
Hopefully we can (kind of like Mrs.Parrish having a telomerase therapy..once per 10 years...that could be the case...the danger of cancer would be offset but the large amount of time Between each therapy..so the Lessen the danger of cancer formation (since telomerase will be Fullpin during the subsequent time after the therapy); and these epigenetic reprogramming there is often telomerase activation (they say the telomeres were lengthened anew).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679279/
https://singularityhub.com/2017/01/13/cellular-reprogramming-rejuvenates-old-mice-and-boosts-lifespans-30/
https://www.ncbi.nlm.nih.gov/pubmed/28314379
PPPS: Here is the full version Cell text of it
https://www.cell.com/fulltext/S0092-8674(16)31664-6
''Lastly, rescue of these age-associated phenotypes in LAKI 4F mice was independent of changes in lamin A/C or progerin, as cyclic OSKM induction did not alter the levels of lamin A/C or progerin in any of the analyzed tissues''
This is what worries me; the epigenetic reprogramming is capable of extending the lifespan of HGPS mice...without reducing their lamin/progerin content ?; they have telomere extension, reduction dna frags...etc...but not reduction of lamin A/progerin...that is woorysome because healthy people, accumulate progerin (at a low speed vs progerin in HGPS people), it means that epigenetic reprogramming may not enterily remove 'junk' of aging. We would ahve to completemy that by targeting progerin + lipofuscin + other residues because clearly, the HGPS mice when epireprogrammed still died at 24 weeks - and they had progerin in them. It means that the Junk may be more consequential than we thought (especially, progerin and lipofuscin).
If healthy people accumulate progerin, very slowly and die at 120; and HGPS mice die at 24 weeks - after epireprogramming and - have same progerin levels; then, it means, that humans Also would die - at 120 - Even So of Partial/'Timed'-Epigenetic Reprogramming; because the very slow progerin will have accumlated over all these years and, epireprogramming did not remove it in HGPS mice. And this is important, they say in the study 'we repeated the experiment, we 'reexposed the cells to OctSoxNanog...repeatedely...and it reduced damages Again' (so the repeatability of epireprogamming Works, it would reduce damage Each SubSequentTime - if infinitely repeated) - But - progerin Still did not reduce. It's why (I believe) that the HGPS mice only lived 24 weeks and it could Not Stop Completely the aging process (because progerin was stil there; if nuclear lamin/progerin is there = lipofuscin too; these are age hallmarks and were not changed). Either we have to hone the epireprogramming or target these resiude Junk at the same time. Because alone, epireprorgamming, Would Not, increase maximum lifespan if it cannot target/remove these accumulating Junk.