Fight Aging!

Hi all !

Telomerase is the reason they are immortal.
They have no cancer because oxidative stress, mitochondrial DNA deletions, point mutations and cell replication stress/nucleotide bp combinational errors are negligible in their case, maintaining super tall telomeres non-stop is bound to make inflammation negligible + rock stable genome (think 200 year old rougheye Rockfish with negligible senescence and extreme telomerase in its tissues, just like the 150 year old evergrowing lobster full of active telomerase too, this fish should be recalled Rougheye RockStableGenomeTelomerazed fish, yet this fish dies whereas the sea anemones, jellyfish, medusa, polyp hydras cnidarians don't; telomerase becomes limiting in highorder animals, anemones are 600-million years ancient, simplistic and primitive in organ morphology, telomerase can be enough to rebuild their simplistic tissues and epigenome, it seems not for us. Human complexity meant an evolutionary trade-off : limited lifespan with lower cancer by increased inflammatory tumor suppressor genes activity, p53, p16, p27, p38, Tumor Necrosis Factor-a (TNF-a), all of those genes that fightoff our tumors inside of us but that damage all our telomeres through excessive oxidative stress production, thus contribute to aging) and inflammation is a helping evil for cancer; hypomethylation occurs in short inflammed telomeres, this brings about a drastic reduction in gene network integrity (the genome stability is compromised, cancer mutations rise with this genomic instability in short telomeres, where tumors try to steal unstable mutant hTERT telomerase for their own invasion survival and immortality) the sea anemones' continued strong primordial germ cell line stem cell ('interstitial cells') renewal, replenishment and stem cell differentiation potential keep them in a continuously rejuvenated state, aging doesn't proceed for very long and they soon backtrack all damages to their biological young self phenotype (their heightened stem cell telomeres biorejuvenate them once they replace old cells), ad vitam aeternam, hence immortality. Cut them their telomerase in their germ lines and they are now *mortal* like everything other animal.

Quote of Dr. Uri Frank on jellyfish immortallity :

" So why don't humans keep their pluripotent cells as adults [humans, just like in the immortal Irish jellyfish/sea anemone Hydractinia] ? It's a good question. Keeping them in a complex body like ours is probably too dangerous, as they can easily form cancer. It's not [so much] a problem in simple animals - [these jellyfish's pluripotent cells] they would probably cut a cancer off.
The price to become complex is to lose the ability to be immortal. "

Quote by Jennifer Viegas :

" Eternal life, from an evolutionary standpoint, however has a big drawback. Due to asexual reproduction, the species as a whole retains very low genetic variation. This means they could be particularly vulnerable to climate change [not have the adapted genes] and not enjoy immortality after all. "

Evolutionarily, it would make sense ressource-wise, low creational-ressource demanding simplistic pseudo-animals get the immortality. Simplistic systems are easier to maintain error free/damage free/mutations free. Complex ressource demanding animals, such as human who get to do lots of stuff with their complex bodies - get the mortality. Complex systems are harder to maintain error free/damage free/mutations free. Things even out.

1. http://www.ncbi.nlm.nih.gov/pubmed/19000774
2. http://www.ncbi.nlm.nih.gov/pubmed/9849895?dopt=AbstractPlus
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306686
4. http://www.biolbull.org/content/218/2/113.short
5. https://www.jstage.jst.go.jp/article/galaxea/14/1/14_53/_article
6. http://www.irishtimes.com/news/science/immortal-irish-marine-animal-provides-hope-for-research-into-ageing-1.1500113

@CANanonymity: Cancer as a driver for losing proficient regeneration of the hydra variety seems like a fair argument, though can we use naked mole rats and whales as something of a counterpoint?

How about the argument that damping down the regenerate everything all the time setup seen in these lower animals is necessary for the evolution of more complex nervous systems with long-lived neurons and stable neural structures capable of holding data for the long term? It seems that something as complex as a mouse or a human nervous system rather depends on not having cells and tissues consistently rebuilt and remodeled.

@Reason

Hi Reason !,

That is an excellent question, 35 year old NMRs and 211 year old bowhead whales are bit of grey zones and, much like humans, are outliers and paradoxal. Unlike us, the fact that we find little to no cancer in them is a sign that the 'cancer suppression equals short lifespan' evolution theory is not cast in stone and there can be exceptions. But still, the NMR lives only 35 years max, we can reach 122 max, if we are gifted genetically. NMR, a below ground sub-terranean rat, has clearly developed adaptive mechanisms to a hypoxic environment and thus can tolerate very low ambient oxygen, HIF-1 (Hypoxia Inducible Factor-1) is responsible for cell adaption as O2 levels plummet; yet in humans it is rapidly degraded in our higher ambient oxygen level. It contributes to hypoxic tumor formation in humans (cancers are by nature hypoxic and oxygen can also oxidize tumors (hyperbaric therapy), but in NMRs it doesn't happen because they are already adapted to low O2, their HIF-1, same thing for bowhead whales plunging into the depths below water and low O2, is highly adapted for these environments. Hypoxia in these animals, unlike us who need more O2 fuel for ATP energy creation, is greatly contributing to their capacity to withstand oxidative injury, hyperoxia is toxic ROS production (extreme oxidation) and thus severely damaging; if the cell has enough ATP energy at low oxygen, then oxidative process drops and the mitochondrial ROS production drops too (as long the mitochondrial membrane mV potential is maintained and does not collapse). In that case mitochondrial DNA lesions, deletions, point mutations drop too, yielding a solid hypoxic system. These oxidative inflammative lesions occur less in the first place despite low O2, gene network and genome stability is preserved with long-enough methylated telomeres ; thus tumors form less; tumors are by definition genetic instability and inflammation is a strong driver. NMRs also have special variants of p53 tumor suppressors, plus their ECM is full of high-molecular weight HA hyaluronan, the one that has capability to block tumor metastasis dead in its track; high HA builds strong scaffolds in extra cellular matrix collagen, these help stromal fibroblast cell to create stronger barriers to rupture for tumors to spread and evade immune eradication. NMRs collagen still accumulates AGEs glycation and Maillard crosslinks faster than us. And they are glucose unresponsive, whacked out or no insulin. As for Bowhead whales, they have hypoglycemia, low glucose, low glycation, better eNOS endothelial activity (vascular system is critical in extreme longevity), much like 175 year old Giant turtles, it's litterally the best of both (humans (longevity) and NMR (cancer free genes)). Arctica islandica (508 year old max clam) keeps perfect Redox 192 years, has no lipofuscin, no oxidatively modified proteins at least 120 years, is cancer free... all due to no oxidative stress and gene network stability for centuries.

I 100% agree with your 2nd argument, eventually it must go quiescent to let things evolve. This regenerative loop di loop di loop does not allow for much evolution to take place. I think the regenerative demand in face of oxidative process and aging is a necessity we cannot afford to lower too much or else damages win these evolutiions

@CANanonymity

I tend to agree with Dephinos suggested universal theory of aging of which dysfuntional telomeres play a part via the P-53-PCG-1a-Mitochondrial axis. The question is can we apply the rock solid stable genome that such creatures use in humans by maintaining telomeres and offsetting oxidative stress?

@Steve H

Hello Steve,

I believe that Telomeres are more than just telomeres. The fact that they are actual *DNA (telomeric nucleotides purines pyrimidines of mammal type 'TTAGGG' (Thymine/Thymidine, Adenine/ Adenosine, Guanine/Guanosine repeats) demonstrates they are crucial to organismal biological life.
Crucial to the (epi)genome and (epi)genetic phenotype program that runs its course and is interlocked/interweaved through gene silencing/expression/activity. They are after all right on the chromosomes' ends (capping them) and chromosome is pure genetic territory. Many studies show that certain cancer or bacterial cells evade telomerase mechanism by creating nasty chromosome telomeres breakage and lenghtening SCE (Sister Chromatid Exchange yielding telomeres fusion/fission between telomeres and chromosome arms (Alternate (Non)-Homologuous Recombination Telomeres Lenghtening). It's a bit like chopping/sectioning a fragment piece from the tallest telomere and rejoining it to a small telomere (to avoid death gene activation in that short telomere), this is catastrophic to genome stability and (sub-)telomere rupturing can immediately make senescence. The point I wish to share is that genetics, genes, genome and wide gene network is 100% linked to chromosomal telomeres, and the program (gene signature phenotype) is governed by the purines pyrimidines DNA repetition content in telomere (taller telomeres have more TTAGGG content, meaning gene silence and telomere signal are strong; those nasty death genes exist in low telomeric 'gene space' (as telomeres are shortened, at 1-5 kb the telomere signal is weakened continuously, that spatial height is where those apoptotic genes are expressed, so the only way to twarth the predetermined genetic death (pre)program phenotype signature is sticking tall).

To answer your question briefly,
Yes. It goes hand in hand, it is all linked. The proof is in the pudding as they say, you just have to check accelerated aging diseases such as SAMP mice (Senescence Accelerated Prone Mice), Progeroid people (Progeria), Trisomia (Chromosome breakage and body morphological deformation), Diabetes. All show an accelerated telomeres loss and higher genomic instability. As these inflammatory genes are activated it's like a big Auto Destruct gene signal. These animal species with extreme longevity all maintain stability. These are the most important words : Maintenance (damage is avoided altogether, very little repair needed - no inflammation, no damage, no repair (need), evolution has shown it is far more efficient to avoid damage 100% altogether, than continuously repairing it as it accumulates (i.e. evolution made pressure on lipid genes so for example, in order to block lipid peroxidation damage, membranes incorporated saturated and monounsaturated fatty acis in their phospholipids, this yielding peroxidation resistant membranes - instead of incorporating only peroxidation-prone polyunsaturates (whos peroxidation damage would have to be repaired/quenched with antioxidant systems) , this strategy avoids damage (and repair need) altogether and) repairing is resource expensive and repair systems fail too/overloaded by rising damage load; basically 'catch-up' mop-up work, it's bound to fail one day or another because it's continuous catch-up (repairing damages is very important as Reason and SENS say, it's the way to biorejuvenation. For now we are not there, telomeres dictate inflammatory damage, avoiding it the best we can (cutting the source of that damage : inflammatory genes activation blocking by telomeres protection, be it antixidant or telomerase, telomeres must be protected to protect genome and stop death program),

@CANanonymity

Thank you for this excellent answer. I have read many books and research papers on telomerase and am involved indirectly in research using telomerase. The Major Mouse Testing Program aka MMTP by the international longevity alliance is something I am helping out with. They are hoping to test a variety of interventions in mice to bulk test longevity effects and hopefully combinations of. Telomerase is one suggested intervention in a fairly large list of possible targets but interest in exploring it seems good, should tell us more if it is tested.

You certainly know your stuff are you a researcher? You can drop me a line at grand_justicar at yahoo dot co dot uk if you prefer not to say here or if you are interested in the MMTP, they are currently making a list of the top interventions to test before starting the project.

I would like to see some SENS approaches tested in the MMTP if we can too if anyone can suggest any drop me a line.

@CANanonymity

What you suggest is also backed up by a study this year into Longevity by Newcastle university. They basically say that good telomeres that shorten slowly tend to encourage longevity and get you to the 100 year mark, beyond that its mostly luck and genes. So it makes sense that the longer you can maintain telomeres, the longer you can resist oxidative stress, the loner you maintain a stable genome and the various other factors you mention. Something many people overlook (willfully in some cases) when talking about telomerase is its interaction with the wnt pathway and the link between telomere dysfunction and mitochonria via the P53- PGC-1a pathway which is directly linked to stem cell decline.

It makes me think that telomerase carefully used could help maintain genome stability and combined with importing fresh stem cells in artifical gel niche could effectively top up the body to allow continued operation.

The caveat of course is we would need SENS to repair any damage the body cannot deal with. Josh Mitteldorf has written about telomerase and suggests there might be such a thing as a free lunch if the cancer risk is proven to be incorrect in the human model. I guess Bioviva will find out even if the validity of an n of 1 test is being heavily criticized and declared valueless.

Back to the OP: Regarding Anemones I think you are correct and I have read similar things about some corals too which also maintain steady genome via telomerase. It does seem that trade off for complexity is mortality.

@Steve H

Hi Steve ! Thank you also for your excellent response too !
I'm no researcher, I studied biogerontology. Thank you for email invite, let us share here on fightaging. I definitely suggest putting telomerase intervention on top of the rest for your MMTP mouse. Not to be a downer but telomerase (like the Helen Blau study which you added that next consecutive telomerase effects were subsequetly weaker after each telomerase boost, reaching a limit as telomeres' sizes rise, negative autofeedback mechanism to not overlengthen telomeres) in telomere extension gene therapy through hTERT transfer is giving mild weak limiting results so far (albeit it's a good new start and because it only started recently, must cut it some slack, but immortality, not there yet). It means telomerase is under strict inhibitory control regulation. Until we see true repeated biorejuvenation in a mouse that we will make live even just *15 years; telomerase will remain modest in effect, until we find genetic mechanisms inhibiting it (outside oxidative stress and inflammation) and how to accelerate it's elongation exponentially (so far telomerase seems to be working maximal speed and the results of 1kb extension are nice but weak). Much like commenters, I did not join to read study fail results seen as
'Great Results (i.e. 25% median lifespan extension in mice by telomerase gene therapy) and that is also why I congratulate your MMTP program for trying and combining various interventions for maximum effect. Telomerase is still something extremely important and should not be cast aside. It is after all, via telomere gene control, one of the easiest, fastest way to immortality in cerain anemone species.

Exactly, telomere size maintenance = genome stability maintenance = redox/telomerase maintenance = oxidative stress avoidance maintenance = damage avoidance maintenance =
life maintenance = death evasion maintenance.

The cancer risk is there but strongly reduced, these systems are not perfect, spontaneous errors do happen, but if the genome is tip top shape rock solid, tumor formation is also reduced strongly because inflammation, the driver (oxidative stress short telomere inflammatory gene activation) becomes nearly totally absent. At short unstable telomeres, spontaneous formation Cancer tumors will want to survive in the host, invade and spread through entire body until mutational assimilation is complete, they will use hTERT or alternate recombination telomere lengthening (Think the sci-fi thriller original 1982 movie The Thing with actor Kurt Russell, the Thing is an ancient 30,000 years alien virus awaken from eternal freeze slumber that mutates and duplicates upon infecting/entering people's body by self-replicating, invading and totally assimilating body's cells; just like a cancer/ malignant metastatic invading tumor does).

@CANanonymity

Thanks I am interested in particular in the combined interventions. I would like to see something that effects mTOR pathway combined with something like TERT to see if there is synergy. The MMTP is being organized by International Longevity Alliance and involves a number of researchers and labs. I am no one of particular note in this project btw simply helping out with their volunteer program. They are planning a large scale intervention test plus are working on pressing for aging to be accepted as a disease by WHO.

http://longevityalliance.org/Projects/News/TabId/109/ArtMID/500/ArticleID/62/Major-Mouse-Testing-Program-Team-and-Subteams.aspx

With the bioviva work they inserted hTERT at chromosome 19 in order to lengthen telomeres using AAV2 therapy. Whilst I do not work for them I do have contact with them fairly often. From reading Dr Fossels book cells, aging and human disease I always thought they were very important and wondered how we might apply telomerase to longevity as Anemones do whilst avoiding Cancer. Josh Mitteldorf got me thinking with his suggestion that telomerase might be a "free lunch" and talking to Michael Fossel made me think it might just be possible to strike a balance.

I am very keen to see the data from the Bioviva test even if some people say an n of 1 has no value scientifically. I am unsure if we will see health benefits but no improvement of aging biomarkers so the data may prove interesting.

Regards the Blau work and other papers it does seem there is a natural buffer or limit to how long telomeres can be restored to using telomerase. I know some cancers can break this length limit but in healthy non cancerous cells it appears they hit that length limit and go no further with repeated treatment. How long the restoration is in relation to the original starting length would be interesting to learn as that would give a clue to how close to its original starting gene expression patter (Via TPE) it can be reset to.

Your point about complexity and mortality vs simplicity and immortality is a very interesting concept indeed. Of course this is not SENS strategy (A valid approach I support too and know we will need) but I hope we might be able to strike that balance or in other words have our cake and eat it.

@Steve

Hi Steve,

I wish you lots of success on mTOR + hTERT combination, who knows, so far it does not look miraculous stuff but getting there. mTOR is SIRT sirtuin/rapamycin/NF-kB/Histone H3 territory of endless data on caloric restriction through mammalian Target Of Rapamycin (mTOR). It has been covered to death and the best extension was 50-60% by rapamycin or caloric restriction or sirtuin gene activation. Combine that with 25% for hTERT and you could get a 60-75% increase; there could be a synergy that makes the effect dramatic (like say 300%) but that is highly unlikely because as specified telomerase is increased upon reduction of oxidative stress and inflammation (as the redox oxidative stress state changes, telomerase activity dramatically changes with it too); thus mTOR block is already helped from telomerase support. Adding extra hTERT will becoming adding of the same thing; it may be a weak addition effect since it is already a positive consequence of mTOR block. Still, in theory and pure conjecture, it coulp possibly synergize and hit the right buttons (genes) and multiply the effect dramatically. Very doubtful, I see an averaging effect or addition effect, not a multiplying effect. At worst little or no effect, let's hope it's not the case, it's just hope is getting on the thin and with every therapy under the sun that has been tried; this is like trying to find the ever elusive needle in the hay stack. It seems to not exist (ever searching blindly) and we are drowning in this hay, only to give up. Still, what else can we do, but carry on and not give up (I know the prodeath-loving fatalists will say 'just accept it already, be humble accept your defeat, resolve your soul and go die already'). But I'm proLife and
prodeath - to death itself -. Once Death itself is Dead too, we will live like anemones do.

He's right, hTERT is a free lunch, the saying goes...in life " There's no such thing as a free lunch ".
Let's not waste it and make sure to profit from this free opportunity. And the fact that the study with hTERT transfer in mice led to no cancer increase means it's safe in a non-inflammed stable genome context (meaning - already high enough telomeres (stability), but not enough that they can't be elongated further), already part of our genetic makeup.

Again, I feel telomerase therapy is really at its rate-limit, and that is why Rougheye Rockfish, Lobster and other far less complex systems than a human, have high telomerase and really benefit - but even then Rockfish and Lobsters live 150-200 years (just 50-75 years more than 122 max human lifespan), we are not talking a 5000 year lifespan like the Great Basin Bristlecone Pine
semi-immortal huge tree, which you guessed it, has telomerase in its meristem cells of roots/trunk (small wonder...eternal trees self-rejuvenating cells highjacked telomerase like anemone and cancer tumors, only they are simplistic organisms easily telomerazed, we are not simplistic). So with increasing complexity (Rockfish, Lobster, Human) vs simplistic (Anemone, semi-Eternal trees) telomerase yield becomes low overall. This means it is a limited avenue. Should refocus on the cause of aging (oxidative stress - Abrogation) that leads to genome dysfunction and telomere gene death program.

@ CANanonymity

I have been looking at PGC-1a and this seems to play a key role in regulating TERT (and thus telomere maintainence and steady genome), it regulates mitochondrial function both directly and indirectly (via telomeres and P53 axis), and it protects from ROS and thus oxidative stress. It also contributes to Gluconegensis, fatty acid oxidation and glucose utilization via the P53-telomere-mitochondrial axis.

If we want to protect from Oxidative stress and help maintain a stable Genome as seen in our friend the anemone does would it not make PGC-1a a prime therapeutic target as maintaining it has such a broad range of benefits?

I have a diagram that better explains my rationale compiled from a number of papers which I would like to take a look at, whats the best way to do this? Are you on longecity?

@Steve

Hello Steve,

I don't know about PGC-1alpha, it is definitely an avenue to explore, such as the study showing cooperation with hTERT but there seems to be a rate-limit to the potency and benefits of this energy/metabolism master regulator. PGC-1alpha overexpression yields -at max a great 50% lifespan extension like calorie restriction does in some species (their paths converge/interlap, calorie restriction activates PGC-1alpha, downregulates p53, helps telomerase boost) but up till now, that's where the buck stops, or should reiterate - where the fly Drosophila m. stops..

The gene power effect remains mild and standard stuff result to other studies' results, studies going above the 50% cap is rare. PGC-1alpha like caloric restriction seems a backdoor entry, it has its rate-limit from these studies results; not the golden nugget gene. But never give up, you're onto something, you could be the one who rethinks the approach and instill fresh optimism into
PGC-1alpha p53 hTERT axis if you rigg it to make Really big gains on lifespan extension. Metabolic Energy control is powerful but oxidative stress ultimate *cause/source* of aging exponentially more powerful approach ; think Orders of magnitude. Am only visiting fightaging.

1. http://www.ncbi.nlm.nih.gov/pubmed/22055505
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627054/
3. http://www.ncbi.nlm.nih.gov/pubmed/15716268
4. http://www.ncbi.nlm.nih.gov/pubmed/26414604
5. http://www.anti-agingfirewalls.com/2011/04/06/pqq-%E2%80%93-activator-of-pgc-1alpha-sirt3-and-mitochondrial-biogenesis

Interesting I have recently read this paper that shows how ALA induced up-regulation of PCG-1a modulates telomerase:

http://www.cell.com/cell-reports/pdf/S2211-1247(15)00825-6.pdf

This carried a host of benefits and was tested on a range of phenotypes which is good and builds on previous papers by the same group. In short:

1: PGC-1a disruption promotes vascular aging and
atherosclerosis
2: PGC-1a modulates telomere function and length as well as
DNA damage
3: High-fat diet reduces PGC-1a-TERT signaling to drive
vascular aging and arteriopathy
4: Enabling PGC-1a-modulated TERT and ARE/ERE signaling
obviates age-related pathology

What is interesting is that increased PCG-1a protects against Oxidative stress and ROS, Mitochondrial dysfunction, telomere dysfunctionm vascular ageing and stem cell decline. It also appears to keep P53 in check and encourages its pro-longevity side rather than its pro-ageing effects which occur when P53 increases in the face of falling PCG-1a and TERT. I am aware this pathway also interacts with the SIRT side of things too so thats a lot of bang for your buck especially if incrased PCG-1a helps resist ROS/oxidative stress slowing down damage to the telomeres via ERE/ARE increase.

The diagram here shows the benefits well:

http://www.nature.com/nrm/journal/v13/n6/full/nrm3352.html

It seems to link in with the work of Dephino and his Ageing Axis (telomeres - PCG1a - P53) that links directly to mitochondria. The diagram below shows the relationship well:

http://www.nature.com/nrm/journal/v13/n6/fig_tab/nrm3352_F2.html
http://www.nature.com/nrm/journal/v13/n6/full/nrm3352.html

But something I found very interesting was how the two pictures might relate to each other. I put them together and noticed that PCG-1a appears in two places in the pathway, it appears above TERT at the top modulating TERT and appears again after dysfunctional telomeres and increased P53 which increases to inhibit it leading to cell decline etc... I might be off base here but am I looking at a feedback loop that increasingly reduces available PCG-1a with each "cycle" leading to increasingly a dysfunctional system with each pass and ever increasing reserves of available PCG-1a further reducing TERT and increasing telomere loss?

The first paper seems to suggest this is the case as reducing PCG-1a lead to faster telomere attrition and a resulting loss of stability.I could of course me reading too much into it but it seems odd that PCG-1a appears in two places.

Opps I made some errors the last bit should read:

But something I noticed was how the two pictures might relate to each other. I put them together and noticed that PCG-1a appears in two places in the pathway, it appears above TERT at the top modulating TERT and appears again after dysfunctional telomeres and increased P53 which increases to inhibit it leading to cell decline etc... I might be off base here but am I looking at a feedback loop that increasingly reduces available PCG-1a with each "cycle" leading increasingly to a dysfunctional system with each pass and ever decreasing reserves of available PCG-1a further reducing TERT and increasing telomere loss?

@CANonymity: Niether rapamycin nor sirtuin gene activation extends lifespan in mammals by 50-60%. The only report of which I'm aware of lifespan extension of that magnitude in mammals is one report of CR in mice at the very extreme of what mice can handle. Rapamycin has not been reported to increase maximum lifespan more than 25% at any dose or age of onset in males, and in most reports it is more like 10-15%; females tend to fare better, but do not gain even a 30% increase in lifespan. Sirtuin activation does not extend lifespan in mice, although it does confer some health benefits, and its effects in invertebrates are controversial.

I should also introduce some caution on telomerase. When induced starting early in youth in mice, it consistently causes a predictable increase in cancer unless counteracted by combination with "super" senescence-induction with transgenic p53 and p16. There is a much more promising report of delayed aging and an increase in lifespan with no increase in cancer in adult and old mice with transgenic telomerase, but the translatability of that report must be considered against the background of the different physiology of the mouse: telomerase is a much less important bulwark against cancer in mice than in humans, which allows them have much longer telomeres to begin with than we do, so that any cancer cells that they develop are in much less danger of running down their telomeric "fuse" before becoming deadly to begin with. Mice also have active telomerase enzyme in nearly all of their tissues by default, whereas in humans, our larger size dictates that telomerase be shut down pretty firmly in most cells, and tightly regulated in the few where it is occasionally active (like the white blood cells), to protect us against cancer in the face of our greater cellularity and longer lifespans (a phenonmenon seen across mammalian species).

@Steve, Michael

Hi Steve and Michael!

Thank you both, for the graphical details on PGC-1alpha, PGC-1alpha dysfunction is definitely a co-driver of aging and pathologies. Michael, from your comment, it seems a shot in the dark, seeing mammals calorie restriction barely or not increases their lifespan yet ironically calorie restriction activates PGC-1alpha/sirtuin axis. How can we than pretend PGC-1alpha would really increase mice Lifespan above it's median average or even its MLSP (Maximum Lifespan Potential) ? As Reason said often and you too Michael, these calorie restriction studies' interventions fail at lifespan extension but have success at improving health-span (quality of life in an average lifespan/reducing pathologies mortality, not Actual Longevity extension beyond mammal specie's regular MLSP). As Reason suggested it is not true genetic biorejuvenation (age backwards reversal), but soft slowing of damage accrual via calorie restriction pathways.

Michael it is interesting your take on telomerase, thank you. As a counter point, though not mammal, lobsters which can reach the size of a large child 100pounder through exoskeleton shell shedding body continuous growth from inside exoskeleton shell, have plenty telomerase in somatic tissues and organs, no cancer, plus they live nearly 50 up to 150 years. Thus, can even live longer than humans and live extremely longer than mice. It seems, in mammals, as you say , our greater cellularity and organ complexity allows cancer to spread, thus telomerase must be kept shut in our somatic tissues. Outside mammals, the trend seems to not apply anymore.

Another one that defies this, the bowhead whale which may live 200 years, has more cellularity, larger size/mass, barely gets cancer (reaching two centuries, your bound to keep tumors away) and the most important point is a mammal. Although telomerase could also not be activated like in humans seeing beluga whales (close relative) have no telomerase in their somatic tissues.

1. http://www.ncbi.nlm.nih.gov/pubmed/9849895
2. http://www.ncbi.nlm.nih.gov/pubmed/25565328
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693359
4. http://www.ncbi.nlm.nih.gov/pubmed/23022483

Part 2,

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693359

From the 3rd study it thus seems that telomerase is directly linked to body mass, heavy humans must repress telomerase activity to avoid cancer. Same thing for extremely heavy Bowhead whales (weigh 75 Tons, 200 000 pounds), their telomerase repression must be Extreme that they have absolutely no telomerase whatsoever (except sexual germ and immune cells needing telomerase). This means TERT transfer in a Bowhead whale would be a Bar Open Buffet Haven-filled with tumors. Scary.

@CANanonymity

I think CR achieves little but PCG-1a has a far more important role in ROS protection, TERT and telomeres and of course the whole P53-mitochondiral axis which governs stem cell activity.

I think this is why in studies with PCG-1a we do see life extension in rodents, not due to its role in SIRT so much as its effect on genome stablity via its influence over telomeres (via TERT), its influence on stem cell mobilization, and its direct influence on Mitochondira not to mention the other things it regulates.

I personally think very little of value will come from CR in humans but PCG-1a and telomeres are far more interesting.

@Steve H

Hi there,

Steve I have tried to find a study that says PGC-1alpha increased the maximum longevity of any rodent (average lifespan is increased by PGC-1alpha seeing calorie restriction does so in mice and calorie restriction strongly activates PGC-1alpha already, PGC-1alpha seems rate limiting so far, it seems a health controler more than an oxidative stress regular. It does reduce ROS production and energize the body (doing exercise strongly activates skeletal muscle PGC-1alpha and brown adipose tissue burning too, same effect as calorie restriction, but overactive in exercise and calorie restricted mice live never Beyond their Maximum Longevity MLSP, they just have an improved health span and Regular Average median lifespan that all other mice have). Please help me, I'm only curious like you do you know a study that shows PGC-1alpha extension of Maximum lifespan in any mammal or rodent, not average ? Pls tell me the % of extension and link. Thank you greatly !

The researchers demonstrated in this paper that PGC-1a directly modulates TERT which from the Blasco tests is known to extend lifespan in mice. It is true there are few data sets for rodents so its probably a good reason to test this in the MMTP. This linked study and their previous paper demonstrate reduction of vascular aging and a raft of other health benefits, it may only improve health but I strongly believe healthspan improves lifespan so more testing required. It does interact with the mTOR pathway too but I am more interested in it's effects on TERT, P53, telomeres and mitrochondrial function.

http://www.cell.com/cell-reports/fulltext/S2211-1247(15)00825-6

" The enabled telomerase activity is likely due to the elevation of TERT expression. Further, enforced expression of PGC-1α-CA upregulated multiple salutary pathways, including Nrf-1, Nrf-2, mitochondrial transcription factor A (TFAM), SIRT1, heme oxygenase-1 (HO-1), and MnSOD (Figure S2B). Many of these molecules mitigate oxidative/electrophilic stress, inflammation, and metabolic and mitochondrial dysfunction. In particular, Nrf-2 and HO-1 are pivotal for ARE/ERE adaptive electrophilic responses (Vriend and Reiter, 2015). "

I will have to search through the MMTP archives to see if we have more data but this is certainly something we should test for longevity. Look at the varied phentotypes they have tested and the previous papers findings too.

@Steve

Thank you for that Steve, health span does increase average lifespan and PGC-1a by increasing telomerase does so too. But, much like TERT transfer in mice the extension is about 25 %. We are not talking about a doubling or tripling of maximum lifespan, but under 50% average lifespan extension and for maximum lifespan extension too. In that study you provided, they use ALA alpha lipoic acid, a strong activator of PGC-1a and - also TERT.
It is hard to find a single study where it says ALA increased maximum lifespan and me, like you, cannot find a single study that says so. Thus PGC-1alpha +TERT activation , together, by ALA seems is rate limiting and can't do more than therapeutic slowing of aging, yielding a bit longer average lifespan, but maximum life span seems unchanged. I.e. a human living 80 years with PGC-1a+TERT addition would get an extra 20 years to reach 100. This human, even if he got PGC-1+TERT gene therapy, it would only amount to about 1 kb telomere size increase at max TERT telomerase elongation activaty (1 kb being rough 20 biological years), he would - not live over the Maximum lifespan of 122 years of humans even so. He would die before or equal to 122, and later than 80. He would die roughly at a 100 by getting an extra kb of telomere chunk, if his
telomeres were 70-80 biologically in kb height already (about 5kb at 80).
PGC-1alpha -TERT axis seems to remain therapeutic only, extreme lifespan elongation/true biorejuvenation seems not possible with that intervention. But as said, maybe your MMTP mouse mixed intervention could change that. All we can do is hope for the best/try our best even if the signs in the sky seem to tell otherwise.

" Lipoic Acid ... has failed to extend lifespan in normal mice and rats in numerous studies, either alone or as part ..."

@CANonymity: When you say "these calorie restriction studies' interventions fail at lifespan extension but have success at improving health-span[...] As Reason suggested it is not true genetic biorejuvenation (age backwards reversal), but soft slowing of damage accrual via calorie restriction pathways." You do understand that CR itself does quite clearly extend lifespan in multiple mammalian species, with the contentious possible exception of rhesus monkeys — yes? CR does this exactly by slowing of damage accrual (which, however, as you rightly say, is not rejuvenation).

As far as "calorie restriction pathways" goes: the problem is the leap from "CR causes this pathway to be modulated" to "CR retards aging through this pathway." CR causes a panoply of metabolic shifts in the body, most of which presumably have little or nothing to do with its effects on aging and simply help the organism to survive in the short term. There has been far too much enthusiasm for assuming that any given effect of CR is intimately tied into its anti-aging effect, or that even if it is, that modulating that pathway in isolation will mimic even partially the effects of the sweeping changes induced by actually restricting energy intake — or that we can do so with the fine, regulated precision required to actually reap the benefits.

Lobsters, in addition to not being mammals, grow throughout their entire lives, and so of necessity require a more accommodative telomerase regulatory regimen. I wouldn't jump to any conclusions about its connection (or lack of it) to their apparent lack of senescence. Importantly, their lifelong growth (for which their telomerase regime is a necessary but not sufficient precondition) allows continuously dilute damage out of their cells: simply giving a mammal with a fixed body form and postmitotic cells will not enable lifelong growth (thank goodness), gives no mechanism for damage dilution, and takes the brakes off of precancerous cells.

@Steve H and CANonymity: several messages in your exchange seem predicated on the idea that PGC1-α transgenesis has been shown to extend lifespan. Where are you getting this from? Is it a mammalian system, and are the mammals in question otherwise normal (no break-a-mouse-and-unbreak it nonsense, etc)?

Hi Michael,

Thank you for those precision ! Yes I'm aware that CR does increase lifespan of mammals. I meant that CR does increase lifespan, average median lifespan and maximum lifespan in mammals, but that the potency effect is marginal. And also that theses studies seem to imply that the transferability of the effect obtained in the short lived specie will translate to same effect in long-lived mammals (i.e. 25 % lifespan extension in mice will translate to 25 human years extra). And also long-lived mammals do not share same evolution survival strategy (i e Short-lived species high birthing colonizing to offset short lives/rapid population death loss, gene selection pressure on sexual reproduction genes rather than investment in protective longevity genes,

Part 2

Long-lived species low birthing (can afford to because long lifespan maintain population count/low mortality deathloss), gene selection pressure on longevity genes (those genes already studied to death - Foxo, SIRT, IGF-1, NRF2, SOD, mTOR, TNF-a, IL-6, IL-10, TERT, p53, p16, PGC-1a, ...) rather than investment in sexual reproduction genes). This difference is why you could see rhesus monkeys have a minimal extension. They are evolutionnarily, like us, both primates, are already gene optimized for longevity thus the potency of the effect in short lived species who benefit greatly is lowered in long lived species: being already optimized through gene selection pressure on longevity genes enumerated above.

You are right, CR is not really influencing fundamental intresic aging process and should be seen as a state.

Concerning PGC-1a, it was suggested that it can lengthen lifespan in mammals but we could not find anything in terms of research. I told Steve that PGC-1a + TERT by alpha lipoic acid improves the health and average lifespan, in mammals could not fing anything, alpha lipoic acid activation PGC1-a and TERT fails to increase mouse lifespan. Although TERT therapy increases mouse lifespan ironically.

1. http://www.ncbi.nlm.nih.gov/pubmed/22585399
2. http://www.nature.com/onc/journal/v24/n13/extref/1208413x1.doc
3. http://news.wisc.edu/22672

Hi again CAN:

CANanonymity at October 23, 2015: Yes I'm aware that CR does increase lifespan of mammals ... but that the potency effect is marginal.

I suppose that depends on what you consider "marginal:" lifelong strong (40%) CR can yield a ≈40% increase in mean and maximal LS in rodents. That's far short of what could in principle be achieved with robust rejuvenation, but it's a dramatic effect and as potent or more than anything else in our current armamentarium.

CANanonymity at October 23, 2015: And also that theses studies seem to imply that the transferability of the effect obtained in the short lived specie will translate to same effect in long-lived mammals (i.e. 25 % lifespan extension in mice will translate to 25 human years extra).

Here, you seem to be saying that the data do imply a strong, proportionate translatability; below, you seem to be saying that they imply a lack of such translatability. I would say, IAC, that even full translatability would only yield a 25-year increase in LS in response to 25% CR if that 25% CR began in newly-weaned humans: the later you start, the less the absolute effect will be.

CANanonymity at October 23, 2015: And also long-lived mammals do not share same evolution survival strategy (i e Short-lived species high birthing colonizing to offset short lives/rapid population death loss, gene selection pressure on sexual reproduction genes rather than investment in protective longevity genes

True, but I've never seen an argument from that to a lack of translatability that I've found remotely compelling.

CANanonymity at October 23, 2015: You are right, CR is not really influencing fundamental intresic aging process and should be seen as a state.

Er, well, I would say that it's pretty clear that CR does really influence (retard) fundamental intrinsic aging processes. I'm not clear what you mean in saying that it "should be seen as a state."

@Michael

Cool, then. Thank you.

Yes, I agree 40% is not nothing, it's sad that us more aged people, if we try CR it would give us half those results because of our age/accumulated aging damage. Does this mean babies and infants will have to be fed CR style by mother for life to get those extra 25 years (society transformation or just copy ancient tribe mothers doing CR to their children unknowingly), while us old folks in 30s 40s get barely 15 years extra for trying CR. Not to put down CR...Therein lies the dillema, people of age are not willing to sacrifice quality of life (continue eat crap junk (sugary, fatty), avoid bland granola diet of veggie+fruit+exercice) in eating, nutrition to hell with it, starvation same, fasting one day per month, nope, depriving themselves quality-wise for the goodness of their health, neither, especially reading something like CR started too late in life gives you a 10 year extra if you start at 65 years old..To them there is little incentive even if health span, thus quality of life is improved. What this means is simply moving the hurt elsewhere. Do you prefer a +10 years with starvation CR life style or all you can eat buffet for life but you could be dead tomorrow !? - at this point in their life, people will gamble (their life) on the latter. That is the problem, though future children getting CR would get 25 years, very great but I'm 100% sure not half of all future children will even continue this trend for entire life, we are just not a CR society in north america and it could change in future but little people are dazzled by 15-20 years extra lease on lifespan. As Reason said, CR research must slow down for money to go to reversing aging genetically (retroprogramming) .

CR does retard aging damage but from your message it seemed otherwise, my apology for misunderstanding.
I meant metabolic state (fasting/partial nutrient deprivation/starvation)

In your previous message :
" CR causes a panoply of metabolic shifts, in the body, most of which have little or nothing to do with its effects of aging... "

"CR does retard aging damage but from your message it seemed otherwise, my apology for misunderstanding.

I meant metabolic state (fasting/partial nutrient deprivation/starvation)"

This metabolic state would be a form of hormesis. Josh Mitteldorf wrote an article about this last year suggesting that the body can be "shocked" into this metabolic state and that it spurs rejuvenation. Makes sense and I have seen papers to support this.

Regards PGC-1a it has a host of benefits to health and does indeed seem to improve average if not maximal lifespan. However the researchers in the recent paper who used ALA to activate this cascade do seem to imply that the action of TERT would improve lifespan as a matter of course. There also seems to be a bidirectional interaction between TERT and Wnt–β-catenin signaling. For example, in mouse embryonic stem cells and Wnt reporter mice, TERT can act as a transcriptional activator of Wnt signaling by complexing with β-catenin (Park et al., 2009). In embryonic stem cells, TERT expression is significantly decreased in the absence of β-catenin, and overexpression of β-catenin increases TERT expression and lengthens telomeres.

I think PGC-1a warrants further animal testing and is on the MMTP list of possible targets to test. We are also looking at ALK5 inhibiting, TERT and Oxytocin as possibles for the first batch of test interventions. We hope to test in mice and rats if we can.

@Michael That said is there anything that SENS might like us to test and share the data? Is there an intervention you would suggest for our first phase short list? Senlyotics perhaps or some other approach you want us to try?