Persistent False Beliefs Hinder Progress Towards the Medical Control of Aging

Progress in gathering support for rejuvenation research has long been hampered by a number of widespread false beliefs. Every time we pitch someone unfamiliar with the topic, seeking material assistance in the long process of developing clinical treatments to control aging and thus extend life, the same initial hurdles must be overcome: the false belief that longevity assurance therapies would make people older for longer, not younger for longer; the false belief that overpopulation is inevitable if life spans increase; the false belief that only extremely rich people would benefit or have access to therapies. These are resilient myths, surviving in spite of the fact that they are easily disproved, and despite the fact that scientists explain over and again in detail as to why they won't come to pass.

No-one aiming at the treatment of aging is trying to build treatments that will make old people linger in increasing decrepitude. It isn't even possible to do that with a rejuvenation treatment that repairs damage: aging is an accumulation of damage, and reductions in that damage translate directly into a longer maintenance of youthful physiology. Researches have published countless papers on overpopulation in the general sense to show that what people see as overpopulation is simply poverty resulting from bad choices and bad governance, people choosing to make a wasteland in the midst of plentiful resources. Malthusians predicting vanishing resources have always been wrong; resources are created and replaced the moment that price increases look likely. Where researchers have created models of future population growth under the influence of radical life extension, populations do not grow rapidly. Wealth, security, and longevity produce incentives that reduce population growth.

As to only the wealthy having access: every mass-produced medical technology is initially briefly expensive, and then later affordable, and then later again dirt cheap. You don't have to take my word for it. Go out and look at the price histories of thousands of drugs and other treatments. Treatments to repair the damage that causes aging will be the same for everyone, infusions and injections that are turned out in bulk from pharmacological assembly lines, or available in tens of thousands of clinics where cell samples are needed to produce personalized therapies from a standard template. These treatments will be similar in manufacture and distribution to drugs that today range in cost from a few dollars to a few thousand dollars. The challenge will be delivery to the third world, because that is a challenge for every technology, not delivery to the average person in the first world. It is nonsensical to think that treating aging will be any different from the past treatment of disease in its logistics.

There are many other resilient persistent false beliefs that impact the ability to talk sensibly about the development of medicine for aging. The idea that multivitamins and antioxidants are a good thing, for example. The supplement industry continues to drown out the voice of the scientific community in this matter. It is done and settled in medical science that high dose vitamins and antioxidants do nothing or cause a modest level of harm, but you wouldn't know that from a tour of any shopping center. When people fixate on supplements, they tend to shy away from consideration of supporting research: doing something, anything, now satisfies the need. Of course it does nothing to actually help matters when it comes to living a longer life, but no-one should claim that we humans are particularly rational or consistent in our approach to life.

The science myths that will not die

Scientists once rallied around the free-radical theory of ageing, including the corollary that antioxidants, molecules that neutralize free radicals, are good for human health. By the 1990s, many people were taking antioxidant supplements, such as vitamin C and β-carotene. It is "one of the few scientific theories to have reached the public: gravity, relativity and that free radicals cause ageing, so one needs to have antioxidants."

Yet in the early 2000s, scientists trying to build on the theory encountered bewildering results: mice genetically engineered to overproduce free radicals lived just as long as normal mice, and those engineered to overproduce antioxidants didn't live any longer than normal. It was the first of an onslaught of negative data, which initially proved difficult to publish. The free-radical theory "was like some sort of creature we were trying to kill. We kept firing bullets into it, and it just wouldn't die." Then, one study in humans showed that antioxidant supplements prevent the health-promoting effects of exercise, and another associated them with higher mortality. None of those results has slowed the global antioxidant market, which ranges from food and beverages to livestock feed additives. It is projected to grow from US$2.1 billion in 2013 to $3.1 billion in 2020. "It's a massive racket. The reason the notion of oxidation and ageing hangs around is because it is perpetuated by people making money out of it."

Fears about overpopulation began with Reverend Thomas Malthus in 1798, who predicted that unchecked exponential population growth would lead to famine and poverty. But the human population has not and is not growing exponentially and is unlikely to do so. The world's population is now growing at just half the rate it was before 1965. Today there are an estimated 7.3 billion people, and that is projected to reach 9.7 billion by 2050. Yet beliefs that the rate of population growth will lead to some doomsday scenario have been continually perpetuated.

The world's population also has enough to eat. According to the Food and Agriculture Organization of the United Nations, the rate of global food production outstrips the growth of the population. People grow enough calories in cereals alone to feed between 10 billion and 12 billion people. Yet hunger and malnutrition persist worldwide. This is because about 55% of the food grown is divided between feeding cattle, making fuel and other materials or going to waste. And what remains is not evenly distributed. "Overpopulation is really not overpopulation. It's a question about poverty. Even people who know the facts use it as an excuse not to pay attention to the problems we have right now."

Comments

We need to write a book that debunk these myths (with pointers to the relevant literature) and briefly explains the SENS approach. Ending Aging is good, but it isn't much comprehensive when addressing the myths, and anyway naysayers will not buy it. This blog is also good, but the information is sparse, divided among many separate pages. It's necessary something like the Longecity book, that can be freely downloaded.

Posted by: Antonio at January 13th, 2016 6:59 PM

There is also the 'big myth' that aging is this constant immutable process that just happens to everyone. I hope a rejuvenated mouse turns up at some point to chip away at it.

Posted by: Jim at January 13th, 2016 7:10 PM

@Jim

If bioviva's telomerase therapy rejuvenates skin like it does in the lab and people are physically able to see the difference than that will likely change the opinion of many people.

Posted by: Santi at January 13th, 2016 9:57 PM

@Santi - There is not much chance of Bioavia's telomerase therapy doing anything. Even if it does turn out to revive stem cells (highly unlikely) you still have all the other classes of SENS damage making the skin look old.

Posted by: Jim at January 14th, 2016 3:51 AM

@Jim: I agree. In particular, the telomerase therapy won't break AGEs in the skin.

@Antonio: If you write such a book, I will certainly buy it. Go for it :)

Posted by: Nicolai at January 14th, 2016 5:11 AM

Wrt to the Tithonus error, it is interesting that aging is the only disease it's applied to. When talking of curing AIDS, we don't hear people debating how desirable it would be to linger for decades with barely an immune system to speak of. When talking of an ebola cure, people don't imagine a person being somehow kept alive indefinitely whilst constantly hemorrhaging. But when talk is of an aging cure, what is imagined is a person effectively in an "undead" state, a person who keeps deteriorating, but somehow keeps walking about well after their body has suffered what should be a fatal amount of damage.

Posted by: Arcanyn at January 14th, 2016 7:50 AM

Hi all,

I too was dubious about telomerase doing anything (or the irreversibility of certain irreversible chemical-reaction damages) but upon reexamination I made a change of mind. Telomerase therapy won't stop everything (for a first, it is shunted away from the nucleus' chromosome telomeres during oxidative stress; when oxidative stress is low enough, hTERT gets back in the nucleus and tries to reduce ROS and increase telomeres (it has dual function, studies showed it reduces some ROS and oxidative stress, but clearly excess makes the telomerase leaves its nest; I think this a evolutionary mechanism to let things happen (die), avoid oncogenic transformation and unallow hTERT highjacking by cancerous cells and mutations promoting inflammation and oxidative stress; by leaving the nucleus, it blocks the cancerous mutational highjacking ability since it is now unavailable in the milieu where it is needed for the cancer transformation (the heart/nucleus chromosome telomeres).

Jim, I will try bullet point this :

- Lipofuscin is a terminal pigment and it is composed of these damages we talk about. Be them, lipid peroxidation products, dead mitochondrias, unfolded proteins, damages nucleotides or glycosylation/glycation residues. We may not be able to remove some of these damages (lysosome hydrolase can't for some) but the cell has evolved a neat way of dissolution during cell cycle. Some of these damages are irreversible/irreversibly undegraded but they are removed during the cell cycle ejection and dissolution/dilution, with the help of the proteasomes, autophagosomes and lysosomes. Thus not irreversible, but reversible.

- ''The amount of the ageing pigment, lipofuscin, found in replicating cells depends both on its rate of formation as well as its rate of dissolution by cell division.''

- '' Lipofuscin is membrane-bound cellular waste that can be neither degraded nor ejected from the cell but can only be diluted through cell division and subsequent growth. ''

- ''According to Arking (2008) a summary of the theory of residue accumulation proposes that cellular ageing is caused by an agglomeration of intracellular resi- dual products that cannot be destroyed or eliminated, except by cellular division.
Lipofuscin is a product of lipid peroxidation and evidence of oxidative lesion, since it is an end product that results from non-enzymatic cellular glycosylation and incomplete degradation of damaged
mitochondria that culd not be degraded by lysosomal hydrolases nor be exocited (Silva & Silva, 2005; Schutt et al., 2003; Kishi et al., 2008). Accumulating over time in post-mitotic cells, these residues are not degraded during cell division and can develop into diseases.''

- ''Western blot analysis for lipid peroxidation- or glucoxidation-induced damage-in particular, by malondialdehyde (MDA), 4-hydroxynonenal (HNE), and advanced glycation end products (AGEs)...
a variety of LF-associated proteins [LF, lipofuscin] were damaged by aberrant covalent modifications of MDA, 4-HNE, and AGEs ... The identification of ***lipid peroxidation and glucoxidation products - in - proteinaceous LF components in human RPE*** supports the hypothesis that these compounds are involved in lipofuscinogenesis and may contribute to the cytotoxic effects of LF in retinal diseases.''

- The 'in' is the important part, lipofuscin is hard to charaterize, it is a jumble of residue stuff.; but it's 'certain' things and 'all of them' damages at the same time; the line is not very clear. What seems clear, it that they contribute to lipofuscinogenesis and are a quantited part of it (inside) of it. Meaning, that - total - irreversibility is false; reversibility is possible..through a dilution-cell cycle mechanism...so long as the cell keeps on dividing and replicating.

- That gives creedence to telomerase being capable of True Biorejuvenation, including damage disposal.
Replicative Senescence is a telomere-based problem. Cells that accumulate near immortal numbers of PDs (population doublings) never accumulate this trash/damage. Ironically, they never accumulate lipofuscin either.
That tells us, as long as these immortal cancerous cells keep on proliferating - and keeping their telomeres high (a necessite requirement); they evade replicative senescence, they evade lipofuscin-caused replicative senescence, they evade damage-accumulation causing lipofuscinogenesis; all due to keeping high telomeres.
High telomeres instruct high crap dilution during cell cycle - but intact one - as long as it keeps functioning (and for that telomeres - must - remain high and not lose base pairs), then the cycle keeps on dividing.

- Keeping on lengthening telomeres/by telomerase = keeping on dividing/cell cycling = keeping on diluting lipofuscin/damages residues during cell cycle = keeping on avoiding replicative senescence = immortality.

That is what I believe so far (I could be wrong, I have been quite oftenly : ). It makes a lot of sense. High telomeres are a True Biorejuvated (Reveral of Aging to Prior Young) Phenotype State; with damage removal and all. It may not be entirely immediate, but it won't take long and this damage - will be diluted. How long I don't know, but a couple of PDs is a probability (a matter of days or maybe a few years of - De-aging (Aging in reversal).

1. http://www.ncbi.nlm.nih.gov/pubmed/12882821
2. http://www.scielo.cl/pdf/ijmorphol/v32n3/art05.pdf

Posted by: CANanonymity at January 14th, 2016 8:02 AM

@Jim

Why do you say there is no much chance of bioviva's gene therapy having any effect? In every study I have ever read on extending telomere length it has had some beneficial effect especially in the skin. I always like to understand the opinion of someone who has an opposing view point, what studies have you read that show that there is no beneficial effect of extending telomere length in animals or humans?

Telomerase expression restores dermal integrity to in vitro-aged fibroblasts in a reconstituted skin model.
http://www.ncbi.nlm.nih.gov/pubmed/10896778

Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice
http://www.nature.com/nature/journal/v469/n7328/full/nature09603.html

"Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines."

Posted by: Santi at January 14th, 2016 1:45 PM

@Santi

I'll point you to Michael Rae's excellent summary of telomerase research:

http://www.sens.org/research/research-blog/tale-telomerase-lessons-and-limits-late-life-launch

"But supposing that Blasco's latest observations in late-life telomerase (9) could be directly and safely translated into a therapy for aging humans -- what then? Despite the apparent "rejuvenation" of the structure and function of some tissues reported by DePinho in late-generation telomerase-knockout mice upon telomerase induction,(8) extending flagging telomeres across a wide range of tissues in this study of wild-type mice undergoing "normal" degenerative aging did not reverese aging phenotypes, but was only able to decelerate the age-related slide into frailty and dysfunction, even in the subset of tissues with strong AAV9-mTERT expression. By contrast, the rejuvenation biotechnologies whose development SENS Foundation advocates and works to catalyze with key research investments will remove or repair the cellular and molecular damage that underlies age-related pathology, leading to the arrest and regression of degenerative aging changes."

Posted by: Jim at January 14th, 2016 5:30 PM

@Jim

Thanks for the link. That was a good read. Most thought provoking and relevant to the discussion is the part of on AAV9-mTERT gene therapy in middle aged and old mice. It seems very similar to Bioviva's AAV gene therapy for humans. Interestingly the author never disputes the apparent decrease in rate of aging or age related damage in various parts of the body. Nor did he offer a counter point to the increase in coordination and memory found. Surprisingly he said "These results of this new study are exciting."

His caveats to saying the results were exciting were

1. Regarding the lifespan extention reported, it is impossible to confirm without a doubt that the lifespan extention was a result of the telomere extention.

This is true we need additional studies to confirm lifespan extention effects of telomerase therapy in mice.

2. Humans are different than mice so even though it didn't cause an increase in cancer in mice doesn't mean that it won't cause an increase in cancer in humans.

True also. However, since in humans telomere shortening is strongly correlated with an increased risk of cancer it is also possible that it could increase chromosomal stability and slow the increase in cancer risk that comes with aging.

3. Decreasing the rate of aging isn't as good as complete SENS damage removal.

Comparing one anti-aging therapy tested in mice against multiple untested ones seems silly.

In his conclusion he states "this new report from Blasco's group at CNIO reveals telomerase therapy as a surprisingly wide-ranging intervention against the age-related slide into frailty and, perhaps, mortality."

Posted by: Santi at January 15th, 2016 3:13 AM

Speaking as someone who spent a lot of time researching telomerase/telomeres I suggest repairing the underlying damage would be a far more effective approach than trying to patch up downstream consequences.

Posted by: Steve H at January 15th, 2016 7:12 AM

@Santi

"2. Humans are different than mice so even though it didn't cause an increase in cancer in mice doesn't mean that it won't cause an increase in cancer in humans.

True also. However, since in humans telomere shortening is strongly correlated with an increased risk of cancer it is also possible that it could increase chromosomal stability and slow the increase in cancer risk that comes with aging. "

A decrease in telomere length in humans is also correlated with age, which is correlated with cancer. Correlation does not imply causation when the correlated variables are co-factors of a third variable.

With regard to telomerase being perhaps a single silver bullet against aging, versus the SENS approach of a panel of therapies... I get the feeling that people are exhibiting some wishful thinking unfortunately.

Posted by: Jim at January 15th, 2016 7:52 AM

There's a bunch of people calling for the overpopulation myth comment to be retracted, because of issues with who made the comment. Interesting...

Posted by: Ham at January 15th, 2016 1:39 PM

Well, there are also comments that say that the speed of light is not constant, so it seems that cranks too read Nature these days...

Posted by: Antonio at January 15th, 2016 2:22 PM

Definitely, ecocranks are a big problem here in Europe. GMO for human food are almost prohibited in Europe "thanks" to them. OTH, GMO for medicines are massively produced (for example insulin-producing bacteria). I wonder what kind of mental state can make someone think that it's dangerous to eat something but it's OK to perfuse it in their blood...

Posted by: Antonio at January 15th, 2016 2:31 PM

The problem I have with telomerase induction is its potential to increase cancer risk.

Here's the key excerpt from the same article Jim linked to:

"While telomerase overexpression initiated late in life may not have significantly increased the burden of cancer in Blasco's AAV-mTERT mice, there were worrisome suggestions in several organs. Similarly, even transient induction of telomerase in DePinho's late-generation, progeroid mice caused an increase in chromosomal instability, albeit without any observed increase in carcinogenesis.(7) With bodies composed of far more cells, and with a far greater post-treatment life expectancy, a small increase in chromal instability or authentic tendency toward malignant transformation that occurrs in the cells of telomerase-treated rodents would be expected to pose a greater risk of progressing into life-threatening disease in aging, TERT-treated humans."

http://www.sens.org/research/research-blog/tale-telomerase-lessons-and-limits-late-life-launch

And here's a related comment by the same author:

"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)."

https://www.fightaging.org/archives/2015/10/the-agelessness-of-anemones.php#comment-22124

Posted by: Florin Clapa at January 15th, 2016 3:06 PM

@Jim @Santi

''
"... True also. However, since in humans telomere shortening is strongly correlated with an increased risk of cancer it is also possible that it could increase chromosomal stability and slow the increase in cancer risk that comes with aging. "
A decrease in telomere length in humans is also correlated with age, which is correlated with cancer. Correlation does not imply causation when the correlated variables are co-factors of a third variable.
With regard to telomerase being perhaps a single silver bullet against aging, versus the SENS approach of a panel of therapies... I get the feeling that people are exhibiting some wishful thinking unfortunately.
''

A decrease in telomere length in humans is also correlated with age, and also not just correlated, but also causated. Telomeric DNA loss is Causal to aging, not just correlative. It is causal because it is linked by a mechanistic process that is ongoing due to telomeric damage (telomere end-problem replicative lifespan), it applies to all cells except a few (gonadal stem ones and transformed cancer ones) who use that telomerase or ALTernate telomere fusion recombination for their own immortality and eternal death evasion.

Santi is right that telomeric reductions is a big factor in cancers; it is not the only one but it plays a lot into that (because inflammation drives cancers and this inflammation is mostly oxidative stress rise-caused, creating either premature senescence or in certain telomeres that become low enough (at 2 kilobytes, cells efficiently 'tumorize' and immortalize at that M2 second 'final telomeric' low point; and stay on immortality frozen at that telomeric
2 kb size (thanks to telomerase or ALT recombination) never losing anymore telomeres).

Why I believe that Bioviva's telomerase therapy may not turn out as strong is because it was mostly tried in mice (as the previous comment said) and it had a rejuvenating effect; but as Steve says, it is alot of catch-up/patch-up/mop-up work; and I believe the oxidative stress in aging keeps the telomerase 'enough' at bay and one study showed that astragalus cycloastragenol increases 'only' the smallest telomeres but did nothing on the tallest telomeres; meaning telomerase targeted the shortest telomeres only (because of the urgency of small unstable telomeres and strong DDR signal activating p53 replicative senescence in these cells short telomeres). As such, it seems like a therapeutic effect (protection of health by increasing smallest telomeres) rather than a 'whole telomeres' lengthening effect (true biorejuvenation and age reversal because as said, telomere lengthening equals to cell cycling continuity and damage residues dilution during cycle).

Posted by: CANanonymity at January 15th, 2016 3:29 PM

@Florin

Hi Florin !

''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)''

It's true, there is a danger, large-size animals are very much more prone to cancer because of that fact and as such are nearly 100% somatic with no telomerase. But, there is a but, inflammation and unstability drives most cancers, high telomeres makes for less unstability and younger self. Stronger immune system with higher telomeres....
but here is one catch.....
mouse have Poor tumor prevention protection - we have Great tumor protection mechanism (of course we have no telomerase, so obviously it's easier said in us that in a telomerase-full mice with high telomeres; but, that's where the bucks stops, we have special p53 p16 variants, so does Naked Mole Rats, who live 35 years never get cancer...same goes for bowhead whales who live 200+ years, never get cancer, same for giant turtles of 150 years and again with red lobsters/marlings full of telomerase, barely get cancer....this means Telomerase - With p53 p16 (as that doctor says 'Super Senescence' 'to compensate' cancer risk) is viable; it's atricky thing but clearly humans and these long lived animals evolved tumor repression mechanisms that mice don't benefit of (as well at least); we always talk of oncogenic inhibitors p53 and tumor necrosis factor...it's just the tip of the ice, we have other genes that protect against cancer (studies found that in NMR and in old turtles who never get cancer that they have special tumor prevention genes). And yes, having no telomerase is one big reason why we would not have cancer...but it is Not the Be All end all of cancers...cancers highjack telomerase and make it a mutant hTERT form. The hTERT you got is not the same as the one cancers use themselves (it is an unstable dysfunctional form). I am very curious to see the cancer markers of Mrs.Parrish from Bioviva telomerazing her, have they changed ? or basically it does nothing ?

Astragalus kills cancers - and activates telomerase - at the same time...so yeah there is still much gray zones that are unknown but there is exaggeration too. Let's play it safe and we will see how strong that telomerase therapy is in Mrs.Parrish biopsy results soon and how cancerous like it is.

Posted by: CANanonymity at January 15th, 2016 3:42 PM

CANanonymity, I think we should be able to agree that it's an open question whether a partially-rejuvenated immune system and the partial rejuvenation of other tissue would outweigh the inevitable increase in cancer from pre-cancerous "rejuvenated" senescent cells. But (yeah, there's a big "but" in here too) if non-WILT cancer breakthroughs won't be able to completely cure cancer, telomerase induction will have to be taken off the table entirely regardless of its effects.

Posted by: Florin Clapa at January 15th, 2016 5:31 PM

@Florin

Perhaps the SENS senolyics therapy - combined with Bioviva telomerase would work ? Gradual removal of these senescent cells with increase of telomerase as a boost. I know SENS want to eradicate what little telomerase we have in certain cells (when in fact, telomerase is nearly 90+% absent in human cells except a few) because of telomerase highjacking by-cancer thus telomerase-causing-cancer problem. 'Low brow' astragalus it shall be then, at least it gives telomerase and it destroys cancers; I'm not expecting eternal life on astragalus alone though. Obviously, telomerase therapy may hit limits and be more harmful than hoped (I hope not), but it isn't, it has so much potential.
I truly can't wait to see the damage breakers, removers, etc that SENS has, we can talk about damage and repair, but until there is anything that removes them (I am not talking about senolytics, but more like AGE breakers and such) in near entirety...the mop-up/catch-up/patch-up game will apply also to the damage removal and repair stratagem; which translates to we could have great health effect but not much maximum lifespan extension just because the damages are too cumulative/numerous/varied/undegradable/irreversible, etc.

My saving grace is accelerated cell cycle dilution of indegradable residues as the real possibility to slow or freeze aging (because it make the cell cycle keep on going, and such translates into a 'telomerase-like' effect of making telomere bp loss nearly nullified (and thus blocking replicative senescence by telomere loss).

Posted by: CANanonymity at January 15th, 2016 7:33 PM

CANanonymity, yeah, killing off SCs plus increasing telomerase activity will probably work a lot better, but that still doesn't deal with the possibility that you'd still want to WILT all of your cells to prevent cancer arising from your non-SC cells.

Posted by: Florin Clapa at January 15th, 2016 9:24 PM

@Florin

It seems there are already humans with hyperactive telomerase due to variations in genes associated with hTERT and hTERC. Looks like they found it when searching for generic reasons why centenarians live much longer than everyone else.

Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868292/

I thought the OncoSENS's plan of telomerase inhibition on the way to WILT was already tried in mice through telomerase KO mice and found to accelerated aging, increased cancer, and shorten lifespan.
Do you have know of any studies of humans with mutations which makes it so that they do not have telomerase like normal people? I was looking but haven't found one yet. It seems highly likely that as there are people with hyperactive telomerase there would be people with natural telomerase inhibition due to mutations in hTERT and hTERC. Then instead of talking about theory people could actually compare humans with hyperactive telomerase to humans with natural telomerase inhibition and note the differences.

Posted by: Santi at January 16th, 2016 2:50 PM

@Florin

Found a study on humans with versions of genes associated with hTERT and hTERC that cause them to have less or no telomerase. Looks like if you inhibit telomerase in humans it would lead to bone marrow failure and possibly other disease states in a portion of the populace. Whether that would be a few thousand people due to other gene variations they have or the majority to everyone who has telomerase inhibition therapy is hard to tell from the study. With the way the media responded to one death and 5 brain dead in France in a stage 1 clinical trial this week I think it would be very difficult to get a whole body telomerase inhibition therapy FDA approved. Since anti-aging money is in short supply maybe another anti-cancer strategy should be employed.

My opinion is that liquid biopsy tech will mature over the next decade or two allowing us to be able to catch cancer at stage 1 which will dramatically reduce cancer deaths in those with the couple hundred dollars per year it costs to get it done once or twice a year.

Human diseases of telomerase dysfunction: insights into tissue aging

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190725/

Posted by: Santi at January 16th, 2016 6:01 PM

Santi, WILT proposes to eliminate the genes for telomerase (and ALT) in every cell AND periodically reseed the bone marrow, gut, lungs, and skin with stem cells which have normal telomeres but lack the genes for telomerase (and ALT). Your examples are of the absence or low activity of telomerase without stem cell replenishment and elimination of ALT, and unsurprisingly, the health outcomes aren't so great.

Posted by: Florin Clapa at January 16th, 2016 8:25 PM

@Santi @Florin

Removing telomerase and ALT recombination would indeed render most cancers inert. A great thing, but I'm just wondering how much stem cell replacement is going to work when mice injected with many stem cells (mesenchymal fetal like and adipose like ones, meaning freshest youngest stem cell injection thus stem cells with highest telomeres periodic injection, they never lived that much longer it was CR-like effect of health and average lifespan extension, and small MLSP increase or none Stem cell injection will be a rejuvenating health effect of organ tissues, not much for intrinsic aging. Damage and residue dilution/removal is the one that dramatically slow/freeze aging, as it will slow telomere loss when it is clear that telomerase is absent in most cells and itself, can't overcome damage accumulation making telomere loss - while it tries to add telomeric repeats on shortest most fragile telomeres.

This study here shows that people with leukemia cancer have increased oxidative stress and Lowered telomerase activity vs healthy controls (leukocyte white blood cells are one of the rare few cells (immune cells) that use telomerase unlike other somatic cells. Same goes for bone marrow cells, as you said Santi, they have low but active telomerase;bone marrow cells are immune cells too... The immune system uses telomerase. In this study, as leukemia cancer progresses they notice that telomerase levels rise - and the leukocyte telomeres shorten faster - at the same time. The cancer is highjacking the telomerase by increasing oxidative stress telomeres shortening rate, around 2Kb ultra short telomeres size, M2 crisis happens and the cancer immortalizes by 'getting' the full mutant Telomerase hTERT and hTERC free. So -at the start of the disease - Telomerase is - Lower. Bad thing to go aroung cutting telomerase in a frail state when your immune system depends on it to be strong and eradicate leukemia cancerous cells in the first place, which ironically these cancerous cells steal telomerase on their turn after sufficient inflammatory oxidative stress damage they caused. The irony is quite staggering and basically, it's a tug of war for who's gonna be the first to steal telomerase and render it 'loose' canon on hyper telomeres lengthening..
And, as you said Santi, certain centenarian Ashkenazi and their offspring have much higher hTERT leukocyte activity, meaning a young immune phenotype by high telomeres and thus a long life - cancer free - because high telomeres by telomerase = low oxidative stress burden = lower inflammation and cancerous transformation.
Plus, leukocyte telomeres length predicts replicative lifespan capacity and human MLSP. So cutting telomerase in immune system and specific telomerase-dependent cells
is like biting the hand that feeds you.

Telomerase activity in normal leukocyte and in hematologic malignancies
1. http://www.bloodjournal.org/content/85/9/2315?sso-checked=true

Posted by: CANanonymity at January 16th, 2016 9:31 PM

CANanonymity, WILT is only meant to prevent cancer, not to extend lifespan by other means such as stem cell replacement. Stem cell replacement is necessary to ensure that WILT doesn't kill you.

Posted by: Florin Clapa at January 16th, 2016 10:52 PM

@Florin

If WILT therapy is targeted only to cancerous cells it is of great use, if it intends to mess with the telomerase-dependent immune cells it can have unintended consequences (as you say WILT can kill you if not rejuvenated with combined stem cell therapy in compensation). Still, as said, cutting telomerase and ALT in cancerous cells will nullify them to inert state, immune system or not, and what little immune activity left will eradicate these, now telomerase/ALT-abrogated by WILT, non-invasive non-malignant benign cancer cells, making them for easy pickings and disposal by immune system.

On a side note, stem cell therapy, which won't slow intrinsic aging all that much, made me deepen further on what is intrinsic aging. Now I think I got it.

- Intrinsic aging is an accumulation of enlarged effete near-dead mitochondria (senescent) that produce ROS and are make for lipofuscinogenesis inside precisely ultra long-lived post-mitotic cells that never replicate (like neurons, cardiomyocytes and CNS nerve cells, these cells can be present an entire human lifespan or basically your born with your neurons and when you die it's still the same neurons at your birth, meaning these post-mitotic cells stay Decades and barely if ever replicate). Other extremely short-lived cells have a tiny lifespan of a few days and are immediately replaced through cell cycle self-replication.
Ironically, short-lived cell that are cycling/replicating don't have any time (they die very quickly and are replaced as quickly too) to accumulate lipofuscin and effete mitochondria in their lysosomes. As such, their proteasome is never hindered and junk-clogged. And, so doing, what little lipofuscin they accumulate is very easily diluted out because of the fact they continue to divide/replicate/
proliferate/grow/self-cycle; lipofuscin can only be diluted through cell cycling (undegradable nor ejectable by lysosomes' hydrolases and the cathepsins junk-degrading enzymes).
That means one big problem for ultra long-lived non-dividing post-mitotic cells who take the brunt of intrinsic aging, Because they don't self-replicate there is no cell cycling; no cell cycling means no lipofuscin cell cycling dilution going on. As such, these quiescent post-mitotic cells are The ones who accumulate lipofuscin and effete senescent mitochondria. By accumulating lipofuscin aggregate this hinders the proteasome and lysosome autophagy process. This junk produces ROS by quantity rise in lysosomes mass (iron catalyzed Fenton reaction of hydroxyl ROS by iron-rich lipofuscin and effete), destroying vesicules membranes and especially increasing oxidative stress by total junk deposition quantity in proteasome/lysosome/autophagosome/phages such as macrophage/endosomes and exosomes (excitatory endocytosis and exocytosis by excitotic neuron). Increased junk 'background' ROS accelerates telomeres loss by creating telomeric DNA damage specifically in these ultra long-lived post-mitotic 'dormant' undividing somatic cells. This, at some point, brings about M1 crisis point of replicative senescence (ironically these cells don't replicate so it is a 'figurative' 'replicative' senescence, they still senesce and lose telomeres, because of having no telomerase or ALT).

That is the intrinsic aging, post-mitotic cells in your body for your entire life who cannot dilute lipofuscin and causes telomeres loss replicative senescence in them. How are we going to circumvent that ? Lipofuscin and effete removal by nano robots, AGES/HNE/MDA/TBARS removal, increased macrophage and cathepsins lipofuscin uptake... I still don't know. At least, I know that the Redox controls proteasome and oxidative stress and correlates to lipofuscin levels, so altering glutathione process is something else that could retard proteasome hindrance and telomeres loss by lipofuscin accumulation.

Redox control of 20S proteasome gating.
1. http://www.ncbi.nlm.nih.gov/pubmed/22229461

Redox control of the ubiquitin-proteasome system.
2. http://www.ncbi.nlm.nih.gov/pubmed/21314436

Redox control of protein degradation.
3. http://www.sciencedirect.com/science/article/pii/S2213231715000750

Posted by: CANanonymity at January 17th, 2016 10:38 AM

Trying to convince people who have no interest in being educated seems like a waste of resources and I'm puzzled as to why 'advocates' simply regurgitate the same (fear or statistics based) arguments over and over and over again and then wonder why their strategies aren't as effective as they imagined they would be. (Could it be that those advocates have no structured materials to guide them?)

For now, perhaps a better use of time and energy would be to 'mobilize' those who already agree with the premise that aging is something that we can address in various ways. Give them something real, effective and FUN to do in order to help reach your goals.

You know, look at other advocate movements in other health-related areas and learn from them. Emulate them and use your marketing to give the impression that this cause is moving straight ahead with gusto and people can either help or get out of the way. It is happening. We don't need the permission from uneducated naysayers (distinctly separate from educated naysayers)

Stop wasting time arguing with people unless you know what you are doing ei. have experience in marketing, PR or some other public facing role in which diplomacy and empathy were instilled into your methodology.

Telling people that 100 000 people die each day from aging lends itself to their over-population argument, for one example of how we shoot ourselves in the foot by being pulled into these 'basic' round-about go-nowhere arguments. They feel productive but they are not.

Good luck!

Posted by: Sean at January 17th, 2016 12:23 PM

What Sean said!

Posted by: Steve h at January 17th, 2016 3:55 PM

Sean, I agree that many people can't be convinced. Talking to them is like feeding trolls. OTOH, there are other people that can read your discussion and that don't have yet an opinion on the matter. I myself knew nothing about SENS or gerontology one year ago, and I consider myself an educated man (I read science outreach books since 30 years ago, I have a PhD in math, read many news and papers about cancer since 10 years ago, etc.). There is a huge need of outreach.

Posted by: Antonio at January 19th, 2016 2:47 AM

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