Reviewing the Role of Cellular Senescence in the Aging of the Heart

A slow accumulation of long-lived senescent cells takes place throughout the body over the years, and is involved in the age-related decline of all tissues. Cells become senescent constantly, in response to damage, a toxic environment, participation in the wound healing response, or simply reaching the Hayflick limit on replication. Near all newly senescent cells either quickly self-destruct or are soon hunted down by the immune system, but a tiny fraction survive to linger. Senescent cells do not replicate, but are very active, secreting a potent mix of inflammatory and other signals that disrupt cell behavior and tissue structure. A sizable fraction of the chronic inflammation of aging is produced by the activities of senescent cells, and this inflammation drives the progression of all of the common age-related diseases.

Fortunately, senescent cells can be reduced in number, a fraction selectively destroyed, via strategies ranging from small molecule senolytic drugs to suicide gene therapies. A fair number of startup biotech companies are moving towards human trials for their approaches to therapy, while at least some of the presently available prototype senolytic compounds appear likely to be effective enough and safe enough to consider using. Given the continued intermittent arrival of new evidence showing the sizable contribution of senescent cells to conditions from type 2 diabetes to Alzheimer's disease to lung disease to kidney disease and atherosclerosis, and that removing these cells reverses the progression of these age-related diseases, the future for this part of the field of rejuvenation biotechnology seems bright.

Cellular senescence in cardiac diseases

Aging and age-related disorders progress through an integration of complex biological processes, and do not allow a simple approach to understand the whole picture, however, evidence indicates the central roles of cellular senescence in the pathogenesis of these conditions. Prevalence of age-associated diseases, including atherosclerotic disorders or heart failure increases with chronological aging, and cells positive for senescent markers are now well recognized to have causal roles for the progression of pathologies in these age-related diseases. In vitro studies showed that exposure of young somatic cells to senescent cells promotes senescence of the young cells, and this is described as the "bystander effect". Pharmacological or genetic depletion of senescent cells contributed to reverse aging phenotype, and suppressed pathologies in chronological as well as age-related disease models.

Adult cardiomyocytes were long thought to be terminally differentiated post-mitotic cells, however, accumulating evidence indicates these cells retain proliferative capacity. It was previously reported that in humans, cardiomyocyte turnover was at a rate of less than 1% per year, and this was demonstrated to decline with aging both in humans and mice. The underlying machinery of diminished cardiomyocyte turnover with aging is yet to be defined, and whether this is attributable to cardiomyocyte senescence is not clear due to the lack of specific senescence markers. In mice, it was reported that chronological aging links with an increase in cardiomyocyte size, together with reactive oxygen species (ROS) production, telomere attrition, and high level of p53 or p16Ink4a expression. In this study, compared to young mice (4 months of age), aged mice (20-22 months of age) exhibited increased left ventricular weight and cardiomyocyte volume, and showed reduction in cardiomyocyte number, together with reduced ventricular function, indicating the pathological roles of cardiomyocyte senescence in the aged heart.

Heart failure can be characterized into two types depending on the level of systolic function. One is described as heart failure with reduced ejection fraction (HFrEF), another is classified as heart failure with preserved ejection fraction (HFpEF), and both types of heart failure are prevalent among elderly persons. In the failing heart, chronic sterile inflammation develops, and this is well recognized to promote cardiac remodeling. Inflammation in coronary microvasculature is now thought to have central roles in the pathogenesis of HFpEF, and it was recently indicated that cellular senescence in endothelial cells may also be involved. When senescence-accelerated mice were fed a high-fat high-salt diet, endothelial cell senescence developed in cardiac tissues, and this coincided with the typical hemodynamic and structural changes of HFpEF. Given that aged and/or obese population has higher prevalence for HFpEF, inhibition of endothelial cell senescence pathway may become a next generation therapy for this untreatable disorder.


Hi there! Just a 2 cents. Ok this one is big (TL DR: 1 line to explain this..come on).

I think I have finally aging 'figured out'...(just took me 10+ years but now it's figured).

Aging, in the 'time passing' sense, is the accumulation of mutations, gene alterations, damages and residues depots; put, simply, bluntly. And it is the stochativ limits from many ends which all limit you (analogy: like 4 pathways leading to the same end/point - all limit you because all 4 are interconnected, think of it like a maze in tic-tac-toe shape...there is not real start or end to it; just you are in it and there is no 'side of the' tic-tac-toe that is more 'the start or the end'; hence, you are limited - everywhere of the design itself).
Think of it like an X...the middle of X is the moment it ends/you die, you can start in X in top left corner, top right corner, bottom left corner, bottom right corner...all roads lead to the middle (joining/intersection) of the two strands composing X. Aging is just the same. ''All Roads lead to Rome''.
We had known that, but we could not put a finger (on it) on what is the main driver...well, technically there is no 1 main driver,
as said, they are all interconnected/intertwined/intertangled pathways...anywhere you start in end up same point - Rome/the end.
(So stay as far possible...)
Because aging is never stopping, you can't just stay in that die in it of 'being lost' to find the exit/every second you lose your insanity/energy/'life units' from 'going around in circles' and 'hitting dead ends' (and 'hitting/banging your head on the wall'/litterally/maze dead-end walls) trying to escape the exit-less maze 'of aging' (just like rat maze or Jack Nickelson's Jack Torrance Character (in The Shining 1970s film of Stanley Kubrick) being stuck in the English Garden Labyrinth by The Overlook Hotel in winter, and dying freezing in it while trying to catch the little boy running/fleeing from his now-psychotic homicidal insane schizo-father).

I see time-passing aging in major categories and all them - if altered - should extend lifespan, because they are intertwined - one cannot be without the other:

- nuclear DNA nucleotide C > T error substutition (Thymine incorporation, instead of Cytosine), this drives mutation errors in DNA, and causes cancer over long time by 'demethylating' the genome (compromising it/'unsilencing it' (un)gene silencing)) and 'hypermethylating' pockets of genes causal to inflammation/oxidative stress. BER (Base Excision Repair) is the main excisor/repair machansm (OGG/exonuclease) when DNA Mismatched Repair Response happens due to faulty nucleotide incorporation during cell division.
- intracellular/extraculluar residues (the entire bunch of them) : Progerin/Prelamin A, Lipofuscin/ALEs, AGEs, Protein Clumps/Aggregates/Beta-Amyloid/Tau, Ceroid, A2E..etc etc
- active demethylation/methylation : demethylation of nuclear DNA, methylation of nuclear DNA; global methylation levels drop (5metC) and become oxidized (5HmetC), this in turn causes demethylation of important safe-guarding genes and hypermethylation of oxidant/inflammation causing genes/proteins/kinase (TNF/C-Reactive/p53) to stop cancer invasion as the genome becomes demethylated in its cytosine residues/loses GC content; and loses TTAGGG nucleotide repeat content (end telomeric DNA, the telomeres on chromosomes)
- mitochondrial ROS : alter redox and cause the entire cascade of damages, ROS are less and less quenched/consumed as time goes; thus, more and more damaging and accumulating.
- nuclear end-chromosomal Telomeres shortening/accumulation of % of small telomeres in a bunch of tall telomeres (increasing subpopulation of short telomeres) : Hayflick/replication 'end-problem'. 'nough'said.
- antioxidation loss/oxidation increase, Redox homeostasis loss/unbalance between antioxidation and oxidation causes redox shift towards oxidized milieu (thus 'oxidative stess' chronic/continuously)...
- Due to genome demethylation, this causes telomere demethylation/sub-telomeres/centromeres become 'loose' and unmethylated - this will cause telomeres to Uncap (become unstable and will cause chromosome breakage/damage/decompaction of DNA coil (more gene activation/mutation acquiry)) and cause sudden senescence (at High or Low telomere length, or High Numbers of Total Short Telomeres or Not - no matter). This was demonstrated in 'spontaenous senescence', 'premature senescence' or 'sudden senescence' cause by oxidative stress causing DDR (DNA Damage Response) signal at Telomeres when Telomeres are Attacked Viciously - they can cause entry to senesnce - Immediately, Whatever/Despite their length or count.

Now, I have seen tons of studies but there was always contradictions and dubious results....
like why is it ONLY CR that is capable of extending is because of autophagy...of low mitoROS...because of NRF2 hormesis response...because of slowed telomere loss...because of slowed AGEs residue...because of demethylation stop...because because because...

OR...maybe...ALL OF THEM.

At the same time.

That's the sort of right answer I think. All roads lead to Rome. North, East, South, end up in Rome. The End.

One CANNOT experience aging without any of them - they are ALL happening at the same time and ALL contributing to aging.

We tried interventions...and only CR increased lifespan...that's because it SLOWS THEM - ALL - at the same time. Either by targeting ONE or MANY pathways.

It might JUST go/target reduction of AGEs residue for all we know...or JUST mitochondrial ROS...or just telomere rate loss....etc...
doesn't really matter, because all of them are interconnected, you push one (enough) - you push all the others at the same time. IT's a connected 'balance'/homeostasis.

Studies that saw no increase in lifespan potential is because the impact/weight of the results were too weak to matter on 1 or more targets; there must be a sizeable effect (to matter) - TO EFFECT/AFFECT the others too at the same time.
CR, sizeable effect, and thus, all are affected too. At that moment there is avg.mean lifespan extension (healthspan) AND Maximum Lifespan Extension (true maximal specie Longevity).

Many studies have failed to increase lifespan because many interventions have 'deleterious' effects.
Like for example, increasing methylation - though good, for it stop active global DNA demethylation and thus slows epigenetic clock aging,
REMethylation of genome is Highly Toxic to cells...

This means the genome was made to 'not be touched' a sense, if you touch it, you cause signals of 'inflammation''s a 'program' that is meant to 'continue its course'.

It's why studies that increase methylation of DNA saw signs of toxicity; like for example, NRF2 is an antioxidative/Phase II detox enzymes activating element that relocates to nucleus and increases methylation again (by activating DNMTs DNA methyltransferases which catalyze methyl addition),
yet, this very step is toxic - NRF2 is CAUSED due to oxidative stress or mild 'hormesis' (oxidative stress 'resistance'...when a stress is 'low' (enough) 'to mild'..but not enough to kill you)
the body compensates and activates NRF2 to 'curfew' ER (endoplamsic reticulum) stress and mitochodrial stress/telomere stress; NRF2 translocates to Nucleus where it activates a ton of genes (SIR2/DAF/GST/CATALASE/EC-SOD/etc...)
this in turn reduces ROS emission rate at the mitochondrial level (Complex I/III/IV ETC IMM).

But, If, NRF2 is caused due to oxidative stress - then, indeed, 'damaging you' is what causes your body 'to respond to it' (feedback loop/compensation).
Thus, a balance.

And, why, there is toxicity in certain antioxidants that turn turn toxic or remethylating ages that are hypertoxic...because they cause oxidative stress trying to 'affect the genome' - which is 'meant as untouched'.
The genome is supposed to stay as it is - intervention affecting it, will, likely, cause toxicity.

With that said, there seems to be 'dose-reponse' to everything, where hormesis/uncoupling of proton gradient at IMM (Inner Mitochondrial Membrane) can be very useful because they reduce ROS emission rate.

The main interventions and why they failed or were not super strong in effect:

- hTERT/hTR... hTERT is capapble of extending replicative lifespan and also imm*rtalize cells (Stem/cancer cells) beyond Hayflick limit....
yet studies increasing hTERT/hTR were not capable of making ultra-long lived naked mole rats out of mice that had hTERT...thus, hTERT
compensate for telomere loss/accumulation of short telomeres...but there is no NET gain - you still lose telomeres..hence hayflick one day.
In humans: 40bp/year avg. (40 base pairs DNA telomeric nucleotide loss, 20-60bp overall in all tissues) for regular healthy aging (up to 120 years old MLSP), HGPS (Hutchison Gilford Progeria Syndrome, 15 year lifespan) 500bp/year, Werner Syndrome 300 bp/year, Diabetes 75-200 bp/year, Dogs 500 bp/year (15 year lifespan), Mouse 2000-5000 bp/year (2-4 year lifespan)
telomerase (at maximal activity With Both hTERT transcript + hTR (RNA template catalytic subunit) = 0.4kb-1kb (800-1000 bp/year) increase in telomeres but only FOR BOTH transcript + template of telomerase
telomerase hTERT or hTR alone = 0.1kb or less....thus no real NET gain per year, until in old age, there is still loss of telomeres despite telomerase activation.
hTERT = 1.0 telomerase activity
hTR = 1.0 telomerase activity
hTR+hTERT = 5.0-220.0 telomerase activity (5x up to 200x folds higher activity and processivity rate/speed elongation at telomeres), not surprisingly, BOTH hTERT+hTR increases cancer/teratoma formation far more than one or the other alone.
Thus, telomerase is only effective in certain situation of activation of its components, otherwise 'it's not enough' to 'counter' telomere loss (no net gain of telomeres/year, only loss - despite 'adding/elongating' telomeres at the same time).

- SAMe (S-AdenosylMethionine) increase methylation but it is toxic at high dose...because of METHIONINE, methionine restriction increases lifespan in mouse...but SAMe elevation Still makes methionine elevation too..and ends up increasing SAH too (homocysteine, a very toxic element of the redox). Methionine amino acid is Highly susceptible to oxidation (vs other amino acids) and it's why methionine restriction increases lifespan in mice...evolution 'chose' methionine for 'extinction' of the genome. meaning it knows that methionine is a 'high risk' amino acid.
Same thing...for methyls...methylation itself is HIGHLY mutagenic/mutation causing - studies showed that the methyl itself 'solidifies' the GC loops in DNA...but the action of it is highly toxic...and it's why Hypermethylated pockets of genome show highest toxicity/mutation load; while demethylation is the inverse it is a far less toxic phenomenon to genome. Demethylation CAUSES the genome to become unstable by losing its content...but the demethylation process in itself is LESS toxic than METHYLATION itself - it's why methylation causes toxicity (Such as activating NRF2 when DNMTs increase and add methyl groups; oxidative stres does the SAME - it activates autophagy, NRF2, HSP, HIF, DNMTs...all 'to compensate' oxidative stress tocixity; thus methylation is a toxic event but 'compensates' genome loss/revesring aging (who would have thunk that reversing genome aging would be toxic (evolution - it is 'feedback' response mechanism 'in response' to oxidative insults - but the response, itself, is toxic; my take is that evolution did this, in order to make sure that you cannot overcome genome loss, overcoming it creates toxicity (it's the old 'Fight Fire with Fire' is great to fight fire..but it's STILL fire...and it need water instead).
- NAD+/Nicotinamide (Adenine Dinucleotide) activates NRF2 - thus NAD/NRF2 is a response to oxidative stress 'mild hormesis', plus it also increases redox GSH:GSSG ratio to maintain intracellular, and most precisly, intramitochondrial subcompartment of GSH thiol pool - unoxidized.
NRF2 -> DNMTs...thus NRF2 remethylates genome cytosines via DNA methyltransferase...and what increases DNMTs...oxidative damage. Thus, hormetic response.
But, as said, toxicity by remethylation. Nicotinamide or NAD supplements in very high dose are toxic...Nicotinamide/vitamin B3 (niacin(amide)) causes liver failure, because can't detoxify too high concentration of it - that's due to toxicity of remethylation (which will cause a shift in SAM:SAH (s-adenosyl-methionine/-homocysteine) concentration of the transulfuration pathway).
Nicotinamide supplement makes replicative cells have about 30% extension of replicative lifespan; when normal human skin fibroblasts are incubated in Nicotinamide (which increase NAMPT/NAD+ levels) at an early PD (population doubling) the cells are 'extended' in replicative lifespan - going from 80PDs (regular healthy aging) to 120PDs...thus obtaining 40 PDs extra...BUT STILL SENESCING..only later; this would be 80PD/year to 120PD/year; which means in human years life - 80 years old to 120 years old lifespan extension (1 PD per year speed).
There are have been several accounts of liver toxicity with high dose Nicotinic acid/Nicotinamide/Niacinamide/Niacin...thus, oxidative stress caused due to too high levels of NAD (remeber NAD restores Redox shift...but may cause 'ultra' 'reduced' state where there is not enough 'oxidation vs antioxidation' balance - causing mitochondrial mPTP....loss of cytochorome in mitos). It's a fine-tune 'careful' balance between oxidant - antioxidants.
ROS extinction = senescence
ROS elevation = senescence
ROS level/signal maintenance = reduced agind speed.

It's why it's so finnicky with ROS 'hormesis' studies...where just a 'little bit of elevation of ROS' is benefitial by 'priming' the body to 'respond to it'...and scavenge it. It's balance. Unbalance it and you obtain senescence - from both sides (no ROS or 100% ROS).

Anyway, I guess we are not out the 'the Shining' rat maze.....yet. But, closing in.

Just a 2 cent.


The study that saw increase in replicative lifspan in NAD/nicotinamide/NAMPT fed fibroblast...demonstrated a VERY important 'prover' of aging :
&mito/cellular ROS accumulation with age& - it is NOT steady....ROS ELEVATES with age (especially around 'mid-life' going from DCF 30 signal (low ROS) to 100 signal (high ROS) at senescence) and correlates with the MLSP (Maximal Lifespan)...
The telomeres of the NAD fibroblast were : Control, -40bp/y loss; +NAD, -13bp/y loss....this equalled 40 PDs increase (80 vs 120)..will it mean 1PD per year, I'm not sure (as the extra PDs may 'increase actual chronological lifespan (vs biological lifespan/PD total)' (i.e. Maybe it will be 0.5PD/year instead...doubtful, 99% of studies show 1PD/y), but in humans, fibroblast 1PD = 1 YEAR..thus, 120PD = 120 years human lifespan (roughly).
I calculated a dooole graphic (low brow) to see how we could make a 500 year lifespan from this. In order to reach 500 years we would have to have
telomere attrition rate of +30b/y...NO LOSS...only NET is, impossible, to reach 500 if there is no net gain....
this means TELOMERASE is CRUCIAL to reach 500...there must be maintenance of telomeres and Net Gain no Net Loss....NAD causes 13bp net loss..vs 40bp net are still losing it.
120 PD (-13bp/y), 500 PD (+30bp/y), there are animals that have 0 bp loss per year...and they STILL it means telomere must absolutely not shrink and MUST increase in size. They CANNOT lower, is impossible at the 'regular rate' of healthy aging (40 bp/year human avg.).

The good news - is we might able to reach this (only if ROS maintenance or if removal of damages is able to stop ROS-telomere damage/mitochondrial destruction) - NAD is not capable of stopping ROS accumulation and it is WHY the cells senescence at 120 PDs and despite NAD activating telomerase; you can see a clear 30 to 100 DCF signal in midlife of fibroblast...thus we must keep ROS in check (never increase above 30% ROS signal whole life, because around mid-age ROS accumulation signal rises to 50-60% and by the end reaches 100%) in order to GO ABOVE Maximum* Lifespan Potential.
ROS maintenance = Telomerase maintenance = Telomeres size maintenance; ROS maintenance will yield maximal telomerase activity; telomerase itself increase methylation thus it will increase global DNA methylation and it increases redox potential too. This goes to show how undervalued telomeres/telomerase/hTERT/hTR is in the maximal lifespan of an animal. Cancer is what will have to be careful...but as said, telomeres increases DNA methylation (Telomeres become remethylatted/solid/capped), thus it improves genomic stability/lessm mutations/more immune function = LESS cancer not more (high telomerase is highjacked by cancers...but when there is No inflammation/by high telomeres/high methylated 'silenced' genome = Less cancer)

Posted by: CANanonymity at June 23rd, 2019 4:06 PM

PPS: how did I come up with +30bp/y calculation for 500 year lifespan is (studies have shown that at 5-10bp/year loss it is 'saturating', there won't be much reduction, I might go down 1 or 2 or even 0.00001 bp/year.. though unlikely because, 'end-replication' problem, there will always be about 1 bp/y loss as most minimal, it's doubtful it would be 0...or minus -40 (net gain vs net loss)...etc... the telomere rate would 'essentilally' be '1 bp/y' or '0.00000000000001 bp/y' (basically 0 but not total 0)...but it would stil lose telomeres even so):

-40bp/y = 100 years lifespan rough; 8kb telomere size = 8000bp, senescence -4000bp, -40bp x 100years = -4000bp.

+30bp/y = 500 years lifespan rough; 8kb telomere size = 8000bp, senescence -4000bp, -40 + 70bp = +30 bp,
70bp added/year to obtain a final net gain speed of +30bp/y telomere rate speed. Thus, telomerase must add 70 bp/y to overcome -40 bp loss/year; and thus, obtain a final speed of +30 bp/year (30 bp net gain). 70bp/y extension = -40bp. -1bp/year loss (minimum value) x 500 years = 500bp lost (20 years rough lifespan lost if at htE Lowest Value..which most likely it won't...).
BJ fibroblast had a telomere attrition rate of 9 -/+ 29...thus 9 bp/y...more or less 29 bps up (38 bp)
or (-20 bp). For avg. of 9 they were already BELOW 0 bp/y loss -9bp + 29bp = 0 (+20).
So it's possble that some BJ were already at +20bp/y, already, so there had a Net Gain of telomeres..and these fibroblast senesce after 90 goes to show that at very low bp/year loss...the correlation to telomere shortening rate muddies vs total lifsepan, and becomes are to predict; it's not 1:1..anymore. If some BJs fibroblast have net gain +20bp/year and Still senesce after 90 PDs...then it looks even worse/need even More Telomerase elongation... because it would mean we would need +100bp/year net gain (over 140bp/year net addition to counter net -40 bp/y loss avg. in order to reach 500 years) to make a lifespan of roughly 500 y (90 PDs x 5 (20bp x 5 = 100bp) = 450 years rough).

You could also calculate simply as : [-40bp/year = 100 years] x 5 = +200bp/year (+160 bp net)=500 years.
The calculations that -40bp divided by 10 = -4bp would mean a 1000 years [-40bp/year = 100 years] x 10 = 1000 years; -40bp / 10 = -4bp/y. That calucation does not work in Very Low bp/ BJ fibroblast need More bp/y/telomere elongation when the bp/y telomere rate loss approaches 0 bp/y. (It is a linear calculation up to 5 bp and then it it's not linear anymore; and why 'simply dividing' the -40 bp/y avg speed say 10 (to -4bp/y)...does not correlate to an extension of 10x times (1000 years)). It seems the 'multiplier' 'weakens' as the bp/y lowers..and why you need to add More bps to overcome net loss of telomeres.

Posted by: CANanonymity at June 23rd, 2019 6:26 PM


I don't think NAD activates telomerase; the effects on extending the lifespan of fibroblasts were purely due to holding down ROS to youthful levels until just before eventual replicative senescence. It's interesting nicotinamide can do this; methylene blue does something similar in vitro - 30% reduction in ROS, 30% extension in population doublings, which shows that ROS is the main mechanism for telomere loss in vitro. But sadly in mice, no lifespan extension from methylene blue - perhaps the dose was wrong (too high dose loses the benefits - want it in nano molar range), but most likely explanation is that ROS is far higher in vitro than in vivo (especially for humans rather than mice). Probably due to exposure to much higher O2 concentration in culture than humans have in their tissues. Yes, sometimes in an ischemia-reperfusion injury, like a heart attack or stroke, you lose O2 and then get a delayed dose of really high O2 (that does the damage), so in this case MB or nicotinamide or MitoQ, etc. would be useful - but in normal circumstances none of these substances are going to help, so no lifespan extension.

Telomerase is a different story. Even in mice, who have much higher ROS than humans, the gene therapy increased mean and max lifespan (and that gene therapy was only applied once, not repeated, and only expressed extra telomerase for a short period of their life). Likelihood in humans is that this would be far more beneficial due to the fact we don't have active telomerase in our tissues (it's pitifully low- only just detectable, in large mammals the longevity approach is to 'look after the cells we've got', not make more, by lower contribution of ROS to telomere loss). Understandable as this counteracts cancer and lets us live 'long enough', but we will not live>120 years without telomerase being turned on for short bursts or having infusions of lots of new pluripotent stem cells (effectively, same thing).

Posted by: Mark at June 24th, 2019 3:45 AM

Hi Mark! Thanks for that. Just a 2 cents.

Studies showed that NAD affects the redox (and is the reason/mechanism why NAD works if it didn't NAD would do nothing), and the redox itself controls telomerase activity (as shown in gsh depletion causing drastic telomerase loss. NAD activates NRF2...which itself activates the redox enzymes to detoxify and scanvenge ROS - and the redox itself - activates telomerase.). One study showed that gsh is crucial in the cell proliferation control (study 4).

''For instance, we found that telomerase is regulated by shifts in glutathione redox ...'' This means the GSH:GSSG ratio is causal to telomerase activity. NAD needs the redox, and telomerase to improve things. It is not simply ROS reduction, telomerase has a dual role of ROS reduction (and mostly uses GSH to fill that role, letting it do it), but its main role is telomere addition - and telomerase elongation is tighly coupled to redox. It's not simply ROS reduction. Telomerase adds telomere repeats to counter less...with that said, studies said that telomerase is 'too low' in somatic cells (like fibroblast...) and thus say that these cells are 'telomerase negative'. But, other studies showed taht there is Still a minuscule processing going by telomerase even in the most 'negative telomerase' cells. It may just not be 'picked up' and they can't 'see' the telomerase acitvity because its so low/slow. Does not mean there is none or happening. That's the problem with assays and enzymatic measurments in labs they may not always be true/accurate, errors happen and it's why 'new studies' happen in 'correct past ones' (just like 'errata/erratum' in followup study papers').

Many stduies were saying, if telomeras was Truly would be a Faster loss of telomeres then it is right now...telomerase is just 'kept in check/at low processivity' to reduce tumorigenesis/muatation.

But I could be totally wrong, and indeed, the fibroblast are only 'surviving' due to the redox activated by NRF2 (from NAD). And no help from telomerase. We may be underestimating its role in replicative lifespan. Even 'obscuring it', as studies show..they think the cells are 'telomerase negative'...that could be true but this obscuring effect may not be right; telomerase may be (too) obscure 'to detect'/very low dose, but it's still happening.

I agree too that it's incredible that niacinamide can do really extends lifespan, solidly - equalling CR. Instead of 80 years old, you can reach 120 years old - 40 extra years of lifespan, that is CR-like effect in terms of weight. Will it be really 40 I'm not sure..but thigns point to that.
It's just we have to be careful because of toxicity by it over long term (your liver is fried).
Thus, low dose is best to be safe. All this is due to NAD/NRF2...and at the end of it, the redox.

yes, methylene blue is's not surprising methylene contains ends up methylating too. Exactly, ROS is highly contributory to telomere rate loss. If they saw no increase in lifespan it would mean that 30% is not enough to affect/effect 'the needle' would be pretty substantial of course and I'm sure methylene did have 'some' effects in them - take is that it was not enough; levels should be at 30%...I'm sure the levels work is possible also that the redox was not really changed...redox is the one that alters ROS emission, at the mitochondrial level; if none of that happens there won't be lifespan extension, even if ROS might reduce a bit.
We have to remember that there is true correlation between ROS emission rate in longevity of mammals in several organs - from the short mice to the cow to the human...there is a clear correlation.
Now why would mice not live longer then...because it may not tell the whole story...with time the levels of ROS of these methylene mice..still ended up accumulating (ROS elevation with age) - and hence, saw no incrase in lifespan. You only see lifespan extension If ROS elevation (of aging) is abrogated or 'softened'.

That's a good explanation...maybe, as you said, the in vivo ROS levels we smaller (in vitro much higher) so in normal circumstances...there is thus no lifespan extension. Maybe as you said, the ROS levels did not change at all (in vivo) while they did in vitro simply because of 'exaggerated ROS' in vitro...not what happens in vivo/much less ROS to begin with.

But the correlation of mtROS to MSLP still stands in mammals of orders of magnitude lifespan difference.

I hope that pluripotent stem cells are the real deal...but lately I read something that drastically reduced my hopes....japenese researchers said that iPSCs are not 'stem cells' like in your the sense, they are 'different'...and after passaging them in culture they senescece..and can form teratomas/spontaneous cancerous transformation or immortalization. Basically.. they are saying that this is like the 'dolly' the clone sheep problem...she is a sheep...but a clone and she had loss of telomeres faster...because she is a clone instead of real thing. Clones can carry defects which they give down to generations. It is the old 'Original vs Copy (of Original)'...the original is alwaus 'truer' and 'the one'...vs a copy of it (like say a painting..the the original..the copy/clone of it a clone/fake...and it fools most people but not the experts).I hope they can somehow fix the problems of cloning so that the cells are viable enough to differentiate in all other cells - it's clear that these are 'mutant (clone)' cells that we would use to rebuild tissues, but there could be consequences because they are not original - they are 'changed/identity/cell identity-wise'...maybe this is for only epigenetically reprogramming/iPSCs and the others that are back to age 0...lose completely their identity and come back to complete start - this would make them 100% copy and not a 'slightly different' 'clone' makes me think of robot/human cloning...they could be copies..but some of these copies could be 'slightly 'off'' (not pure exact duplicate copies but 99.99998% copies, that 0.00002% could change the whole thing)...and then all bets are off (they could revolt).

Just a 2 cents.


Posted by: CANanonymity at June 24th, 2019 5:07 AM

I don't think you need to worry about iPSCs; a recent study showed you can inject them in large numbers into circulation and no terratomas - that only happens if there are too many of them in one place and they 'dominate' the signalling environment. In an aged body they'd zero in on areas of damage an effect repairs.

I still don't think the nicotinamide studies showed any telomerase boosting, it was simply reduced telomere attrition because of ROS control. I know antioxidants can preserve the tiny about of telomerase in the nucleus and stop it being 'exported'; and this will mean more and faster cell division - which is a state in which DNA is split apart and copied and this probably explains the increase telomerase (for it can't be repressed in this state).

There is a small caveat to this, in that bizarrely SIRT4 seems to be able to extend telomeres (one in vitro study from 2015, never confirmed) - so maybe there is a connection somewhere between NAD and telomerase, but I've yet to see this explained anywhere.

Posted by: Mark at June 24th, 2019 7:15 AM


THat's good news, thank you.

Talking about SIRT4, I found this and this may explain that some telomerase might be going on; this studies says so though it may not be the specific case with nicotinamide, but clearly, here, like resveratrol, nicotinamide would, also, increase *nicotinamide phosphoribosyltransferase*, which would lead to telomerase.

nicotinamide phosphoribosyltransferase (NAMPT)

''Here, we report that resveratrol activates human nicotinamide phosphoribosyltransferase (NAMPT), SIRT4 and telomerase reverse transcriptase (hTERT) in human aortic smooth muscle cells.''

''NAM [niacinamide], a precursor of nicotinamide adenine dinucleotide (NAD+), is converted into NAD+ by nicotinamide phosphoribosyltransferase (NAMPT)''

Nicotinamide/Niacinamide/Nicotinic acid/Niacin -> NAMPT -> NAD+ -> SIRT4 / hTERT


Posted by: CANanonymity at June 24th, 2019 12:06 PM

Not all sirtuins may increase telomerase but some do, sirt4/sirt6 do, and thus there is clear interplay between them. NAD would increase NAMPT, which it would increase, SIRTs...they would increase telomerase.

''Telomerase reverse transcriptase (TERT) mRNA (Pā€Š=ā€Š0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise''

Posted by: CANanonymity at June 24th, 2019 12:16 PM

Fantastic comments! Thank you all. Any comments on using epitalon to extend telomeres?

Posted by: August at June 24th, 2019 7:39 PM

Hi Chris! I thank you for your proposition, I sadly don't have time (yes I do have time to write long messages on fightaging..I agree but it is mostly the 'whole time' I have outside the other things); I will be looking forward to your messages here! for sure. Thank you again and wishing good luck in your endeavor!

Hi August! Thanks for asking. Just a 2 cents.

I would say that epitalon a tetrapeptide of 4 amino acid, Alanine (Amino) Aspartic acid (Vit C) Glutamic acid (causing Glutamate, one of the three amino building blocks for GSH) and Glycine (second of the three amino building blocks for GSH)...the third one is Cysteine (not in epitalon). If you take NAC (N-acetyl cysteine)..that completes the bill to produce more GSH. Or just consuming more protein (protein has cysteine in the 'whey' powder protein or soy isolate protein...they contain it).

Epitalon itself is pretty good and has some poweful effects: Aspartic acid - it scavenges oxidants/Vit C is a strong antioxidant (but Also oxidant...both), and it also increases demethylation (sadly), the reason is that Vit C/Aspartic acid/aspartate is a regulator or 'diffenrentiation' of cells just like Retinoic acid (an acid that controls growth and transformation..especially bone morphogenesis and affects the epigenome methylation (it demethylates it) to 'activate 'differentiation'...which is understandble...since we you age, you acquire 'differentiation' for cels, mostly the stem cells; but studies showed the 'staying' undifferentiated = immature state = dauer state. Basically, 'youth' state/dormant state/quiescent. Until that is you activate 'the maturing' program to make cell differetitation = maturation of cells = aging. Vit C is capable of STrongly affect epigenetic signal - negatively to 'make fast demethylation' and create 'maturing'...Vit C is thus a 'reproduction' vitamin, it'S meant to 'bring you to mature sexual state' - which means exit from prepubertal youth state (immature). Vit C/Asp are capable of oxidizing 5-metC (cytosines) in the genome...which you guessed it...causes formation of 5-HmetC (5-*Hydroxy*methylcytosine)..the oxidized version and that's what 'activates the epimaturing signal'..of aging cells/causing them to age 'advance in maturity'. The Hydroxy element is a combo of oxy + hydro ; thus ccreation of hydrolysis/racemization of amino acids (the aminos become from L-aminos to D-aminos...this ages you). So..vit c is thus a 'pleiotropic' 'antagonistic' 'response' to help you 'stay healthy'...but age age because of it. has good positives too, like as said, it reduces oxidant..but also..causes them. It's a very 2-faced vitamin. Vit C also increases collagen scaffolds and cross-links them to make solid collagen again..once more it's a vitamin that is just meant to 'make function'..and while doing it so..its 2nd to age you. Talk about 'double-edged sword'.

Glutamic acid causes rise of Glutamate - this one increases it counters the effect of Vit C...and the reason, is because glutamate (in brain neuron especially) is highly said, methylation is toxic event but it slows aging process when it keeps genome methylated and avoids activation of inflammtory genes with time (as it demethylates - 'the program'). Glutamic acid also has one great advantage it causes formation of GSH, which itself is an extremely powerful mitoROS regulator, along with its 'oxidized form (GSSG). THe most abundant one. IT's one of the amino blocks to fabricate endogenous GSH; cysteine is the rate-limiting one. Too much glutamic acid = toxicity..brain neuron cyotoxic 'shock' death. In epitalon, it's no problem. You can extra's always in complex proteins (like animal/vegetal proteins (whey/soy..etc)); thus, it's no different than eating a meal full of proteins (which contains glutamic acid by the many grams of its amino acid protein content 'profile').

Glycine with age they showed we are glycine deficient which causes GSH reduction is one of 3 substrate blocks for GSH. One study showed that glycine was the main amino reduced in people that over 70 years old...not Glutamic acid neither Cysteine...well cysteine yes too...but not as much as they fed it and there was dramatic increase in content..this helped boost back the needs all 3 blocks..not just 1 or 2. Glycine has many studies on it, and very many beneficial effects..from cacner..etc etc...great one.

Alanine is the other...and it's also another one that does ends up causing oxidative stress (which activate DNMTs to methylate 'in response' to said stress), high alanie has been shown to create mitochondrial dysfunction/Toxicity and senescence; it's often elevated in liver problems (alanine aminotrasnferase (ALT) hyperactivation) and other diseases...oftenly causing toxicity and the liver showing first signs. But in epitalon no worry, it's not enough to matter or create such toxic level; it's more if you consume Huge amounts of protein...then yes you will be getting way too much of it and this cause liver/kidney failure in long run.

Epitalon increased mice about 10-13%, mostly mice with cancer...but it does improve survivability and thus in humans years it might be 5 years or of increase in healthspan...i don't see this as doing 20 year lifespan extension (Above maximum)..but improving healthspan..defintely.. you could reach 100, more chances with it.

Just a 2 cents.


Posted by: CANanonymity at June 25th, 2019 1:39 AM

@ August - never tried epitalon; would be interested in anyone that has AND taken Lifelength tests to prove it has an effect. Sadly most users are happy to pay $100s per cycle but not any money to prove it does anything!

Posted by: Mark at June 25th, 2019 4:18 AM

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