The Challenge of Achieving Healthy Human Longevity

The big sea change of the past 10 to 15 years in aging research is that the scientific community is now near entirely behind the idea that aging is a viable target for therapy, and that we should be working towards greater healthy human longevity. Prior to this time, aging was near entirely a "look but don't touch" field, in which any talk of medical intervention in aging was strongly discouraged. Making this change come about was a battle of years of patient advocacy (such as by the SENS Research Foundation and Methuselah Foundation), argument, and incremental advances in the science funded by small sums of hard-to-find research funding. It is perhaps hard for people today to recall how opposed the culture was to the idea of extending healthy life spans.

The present challenge is different: to ensure that the now willing workers and funding institutions direct their attention towards projects that will make a meaningful difference. Near all present work on intervention in the aging process is intended to do no more than modestly slow aging, tinkering with metabolism to slightly slow the accumulation of cell and tissue damage, or slightly blunt the consequences of damage. But the research community can do far better than this; it is possible to repair the damage that causes aging in order to produce rejuvenation. That strategy should be the primary focus on the research and development community, and it is not.

The initiative mentioned here, the Health Longevity Global Competition, is an example of this problem. If one digs in to see what exactly it is that they are supporting, one sees that it near all consists of projects that will clearly make no meaningful difference to the healthy human life span. It is not enough to have the enthusiasm and support of the research community. The strategy must also be correct.

Achieving healthy human longevity: A global grand challenge

Over the past century, major advances in medicine, public health, and socioeconomic development have led to unprecedented extensions of life expectancy worldwide. Global population aging presents both new opportunities and challenges. The COVID-19 pandemic has challenged recent advances in science and medicine and underscored the vulnerability of older populations to emerging diseases, alongside existing age-associated susceptibilities to noncommunicable diseases. Without innovation and adaptation, societal aging is poised to strain health care systems, economies, and social structures worldwide.

Yet, these and other looming stressors are not inevitable and could be mitigated, if not avoided, by accelerating biomedical and technological advancements, as well as socioeconomic infrastructures and policies to keep people healthier throughout their lives. By extending the health span, defined as the healthy years of life, societies can benefit from the tremendous social and economic opportunities that come with an active and vibrant older population. Numerous studies have identified common cellular and molecular mechanisms underlying the aging process, demonstrating that biological aging is modifiable and in some organisms health span or life span can even be extended. Many of the genetic pathways underlying aging and age-related disease - such as the insulin/IGF-1 and mammalian target of rapamycin (mTOR) pathways - play a critical role in maintaining homeostasis in response to environmental modulators such as injury, infection, stress, or food availability.

Other emerging areas of aging research include cellular senescence and senolytic therapy, regenerative medicine, immunoengineering, and genome editing and silencing. Therapies targeting these mechanisms and biological changes associated with aging are now being investigated in clinical trials (1). For example, senolytic compounds that selectively eliminate senescent cells are being studied in human clinical trials for osteoarthritis, glaucoma, and pulmonary fibrosis (2). Likewise, researchers are studying the effects of caloric restriction (3); metformin, a first-line drug for the treatment of type 2 diabetes (4); and rapamycin, an approved drug that inhibits mTOR, on the biology of human aging.

A fundamental question that remains is how interventions that show promise in improving life span or health span in model organisms will be evaluated in humans, where a complex interplay of factors underlies the aging process. Indeed, biological age often differs from chronological age. Some older individuals are less likely to develop age-related diseases than their age would predict, whereas some younger individuals prematurely develop age-related conditions. Thus, scientists have searched for biomarkers or other biological changes associated with aging and age-related declines that might act as "aging clocks."

Despite recent progress, the current research and innovation ecosystem is not poised to deliver the transformative innovations needed to achieve healthy longevity. To achieve major breakthroughs, we need to reexamine our fundamental approach to aging research and innovation. The traditional biomedical research funding model continues to be largely risk averse. Typically, incremental and clearly feasible research is funded, whereas bold, high-risk but high-gain proposals are often less well supported. Similarly, we see a rather conservative approach to drug discovery, which is designed to target, manage, or cure one disease at a time.

For these reasons, the National Academy of Medicine (NAM) has launched the Healthy Longevity Global Competition to catalyze breakthrough research and generate transformative and scalable innovations by mobilizing action across disciplines and sectors - from basic research to technology, care delivery, financing, community development, and social policy. An important goal of this Global Competition is to stimulate worldwide interest from scientists and innovators, thereby creating a global movement to dramatically increase innovation and groundbreaking advances in aging research. In October 2019, NAM and global collaborators launched the Global Competition with the participation of 49 countries and territories. During the first phase of the competition over 3 years, more than 450 Catalyst Awards will be distributed globally, representing over US$30 million in seed funding to attract bold, audacious research ideas. In the second phase, "Accelerator Awards" will provide additional substantial funding or support for projects that have demonstrated proof of concept with potential for commercialization. In the third and final phase, one or more Grand Prizes totaling over US$4 million will reward breakthrough achievements with the promise of global impact.

Comments

Meaningful therapies which will take 10-15 years to go through all the clinical trials and FDA approval. Huge waste of time and money.

So it was "look but don't touch", now it is "touch but not too much". It will probably take another 20 years to go to "touch anything you want".

Posted by: Jonathan Weaver at October 23rd, 2020 4:54 PM

We need an Elon Musk mentality to shake things up.

Posted by: Robert at October 23rd, 2020 8:21 PM

I once heard a bright young man talking about how we can get the ~85% of the world which believes in God and an after life, interested in radical life extension.

His answer - "Stop calling them delusional idiots!"

I know the publisher of this site is wed to the belief that all we need to do is follow Aubrey de Grey and company into LEV - but this is delusional as well

LEV will never happen in a vacuum, and he needs to stop denigrating the thousands of good people and organizations contributing in some form to extending healthy life spans outside of the "club" - the same old people, showing up at every scientific conference, selling the same old narrative

The whole continuum of longevity biotech, age-tech, and supporting industries needs to be intact to make LEV happen - it's the only way you will get most everyone interested, including eventually, deep pocketed governments

So I say bravo to the NAM grants - 150 bright minds, many of them unknown, getting an additional push forward

Posted by: James Burnbrae at October 24th, 2020 6:29 AM

"The whole continuum of longevity biotech, age-tech, and supporting industries needs to be intact to make LEV happen."
Agreed. Sectarianism within the community is itself a hindrance to progress.

Posted by: Barbara T. at October 24th, 2020 6:38 AM

@James Burnbrae:

So... you demand us stop calling other people delusional while you call us delusional... Interesting.

"LEV will never happen in a vacuum, and he needs to stop denigrating the thousands of good people and organizations contributing in some form to extending healthy life spans outside of the "club""

... contributing in a very slow and minuscule way while there are much faster and bigger ways.

"the same old people, showing up at every scientific conference, selling the same old narrative"

Yeah, it's better to use the same old narrative that considers all ideas to be equally good because it doesn't go into the details.

"The whole continuum of longevity biotech, age-tech, and supporting industries needs to be intact to make LEV happen"

Nope, there is a huge amount of research that is not needed for LEV, like all the sirtuins stuff.

"it's the only way you will get most everyone interested, including eventually, deep pocketed governments"

Yeah, great idea, spreading the scarce funding available through a field as large as possible, so the small part that is really useful among all the junk gets more funding. Yeah, it makes sense!

Posted by: Antonio at October 24th, 2020 4:34 PM

@Antonio: why do you assume that James Burnbrae is talking about tinkering with metabolism when criticising SENS? To me it sounds like he's referring to integrating different approaches (likely including nanotech and reprogramming) and implementation strategies. It'd be nice if he clarified, but your take is certainly not how I interpreted his comment.
And since you are quoting:
"Yeah, great idea, spreading the scarce funding available through a field as large as possible, so the small part that is really useful among all the junk gets more funding."
Sure. Because SENS is the be all end all of rejuvenation despite its many archived failures. You've basically defined bigotry here.

Posted by: Barbara T. at October 24th, 2020 4:44 PM

In the unlikely event that SENS' damage repair approach fails, other approaches to achieve LEV would be even less likely to succeed, and life extension efforts would need to be refocused on cryonics and mind uploading.

Posted by: Florin at October 24th, 2020 8:53 PM

Where's the data showing that SENS is a better proposition than the Hallmarks of Aging or epigenetic reprogramming?
As things stand today, getting rid of amyloid in the brain has been shown to be useless, while de Grey himself lost faith in the foreseeable implementation of OncoSENS, favouring the very non-repair-based immunotherapy instead.
Ergo, SENS ain't SENS anymore - it has mutated.
People are getting too attached to their pet theories nowadays, which is a huge problem since dogma (like the fixation that aging is a one-way street) starts where the self-questioning stops.
Dogma = enemy of progress.

Posted by: Barbara T. at October 24th, 2020 10:56 PM

@Barbara: "why do you assume that James Burnbrae is talking about tinkering with metabolism when criticising SENS?"

Because he supports all antiaging research and it is included in it.

"Because SENS is the be all end all of rejuvenation despite its many archived failures."

What failures?

I agree with Florin.

"Where's the data showing that SENS is a better proposition than the Hallmarks of Aging or epigenetic reprogramming?"

That's like saying that we don't know whether man can go to Mars because nobody went there. Engineering, including medicine, it's not only a matter of trial and error, there is science behind it. The Hallmarks is a mix of root causes of aging and downstream consequences. The treatment of root causes will work well, the treatment of the others will be slow, expensive and quite inefficent. That's what we can say based on science. With no treatment in the market, we have only science to guide our selection of research to be funded and pursued.

OncoSENS, since the beginning, was recognized as the most difficult part of SENS and probably the last to be implemented. It requires a very mature stem cell medicine and a safe in vivo genetic engineering, that we don't have yet. That's why he favours CAR-T cell therapy now, because we have it now and it will be the best approach we will have for some time. All that said, CAR-T cell therapy is clearly not a cure for cancer, like oncoSENS can be. Even if it kills one cancer, a few years later other cancer will develop, an you have to continue creating new CAR-T cell therapies. If one of them fails or arrives too late, you are dead. With oncoSENS, you don't develop cancer at all, at least for current lifespans. Something will kill you before cancer does.

Posted by: Antonio at October 25th, 2020 2:02 AM

As for Alzheimer's, to me it's clear that it requires several kinds of treatments. Not only amyloid removal, but also tau removal and probably senescent cell removal and something to address blood vessel wear and tear (maybe glucosepane removal). At the moment, only amyloid removal alone and tau removal alone have been tried, with a small success with the first one (aducanumab). AdG always said that one of the 7 kinds of treatments alone probably would not have a great effect on lifespan. Indeed, he was surprised of the great effect of senolytics on mice when they were first tried.

Posted by: Antonio at October 25th, 2020 2:14 AM

@Barbara T - " de Grey himself lost faith in the foreseeable implementation of OncoSENS, favouring the very non-repair-based immunotherapy instead."

It was thought that the rising incidence of cancer with age was due to cells randomly accumulating several mutations until they became cancerous. Instead the evidence now strongly suggests that even a single mutation can cause a cell to turn cancerous and that the rising incidence of cancer with age is due to the decline of the immune system and immune-surveillance. Hence the removal of telomerase is unnecessary, restoring immune function via regrow the of the thymus, replacement of blood stem cells, ablation of old B and T cells, and perhaps defibrosis or replacement of some lymph nodes should be enough. Cancer immunotherapy to deal with any cancers that manage to escape a "young" immune system should be enough to deal with cancer.

That's obviously still a tall order, but a lot easier than eliminating telomerase (and ALT) from the body, then administering stem cells (where it is expressed) to ensure the body does not break down.

Posted by: jimofoz at October 25th, 2020 5:08 AM

AdG said WILT is overkill.

Posted by: Norse at October 25th, 2020 5:52 AM

@jimofoz: I agree with you. Also, there are promising complementary treatments on the horizon, like thermoablation with nanoparticles.
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@Antonio:
"Where's the data showing that SENS is a better proposition than the Hallmarks of Aging or epigenetic reprogramming?"
"That's like saying that we don't know whether man can go to Mars because nobody went there."
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I guess you didn't understand my question because that's not an answer to it.
If you want to show that A is better than B, you need supporting data (= Science 101).
If you don't have supporting data that favours either option, then you need to pursue both avenues.
If you don't pursue both avenues, you risk going down a blind alley.
We wouldn't have immunotherapy - current and future - if we'd listened to The Church of SENS.
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Also, pushing metformin is not the same as pushing OKSM, and it is nonsensical to lump all non-SENS approaches together. They aren't qualitatively the same.

Posted by: Barbara T. at October 25th, 2020 6:09 AM

@Barbara:

"I guess you didn't understand my question because that's not an answer to it."

You didn't understand my reply. It wasn't an answer to your question but an explanation of why your question is misguided.

I will try again... You asked for practical/engineering/trial data showing which approach is better. I pointed out that we have no such data and it's pointless to ask for them, because what we are trying to decide is where to put the money in order to produce the first antiaging therapy of any kind. So we have to reason from *science* data, not *engineering* data. And the science data clearly favours the repair of root damage instead of the dampening of downstream damage.

Again, we never travelled to Mars, so we have no practical/engineering data for the "can humans go to Mars?" question. But it would be totally silly to say that then we can only assign a 50% probability to either the YES or NO answer. We have a LOT of information: about rocket science, space suit design, avionics, Mars climate, etc. etc. Using that data we can obtain a pretty definite answer, with higher than 99% confidence.

Another example is cryonics. Some people say that cryonics is a scam, because nobody ever has been cryonized and then resurrected, so, since we don't know whether it's possible, cryonic services must not be sold nor promoted. That's absurd, it ignores a huge amount of biology, chemistry and physics, and treats the question as if we were dumb cavemen.

Posted by: Antonio at October 25th, 2020 3:51 PM

The problem with non-SENS approaches is that there's no theoretical reason to suppose that they could achieve LEV. For instance, is there any theoretical reason to suppose that a rejuvenated immune system plus immunotherapy, nanoparticles, or whatever-short-of-deus-ex-machina-nanobots could eliminate death from all cancer, all the time, forever? No. Could WILT? Yes. The same kind of analysis can be done for other categories of aging damage and the same results would be obtained. Could the proposed solutions in Hallmarks, Pillars, or whatever lead to LEV? No, I don't see how they can.

As for the claim that AmyloSENS doesn't work because efforts to get rid beta-amyloid have mostly failed, it should be kept in mind that AmyloSENS' primary target is beta-amyloid oligomers (not beta-amyloid plaques), something that no one has attempted to clear out. But OTOH, as Antonio pointed out (and Aubrey many times before), several SENS strands might need to work in the same organism to get a significant result. So, even though therapies that get rid of plaques are dead for now, they might get resurrected in the future.

Posted by: Florin at October 25th, 2020 3:57 PM

And, again, James Burnbrae was not advocating for OKSM funding vs SENS funding, or Hallmarks funding vs SENS funding. He was advocating for funding ALL antiaging research and treating ALL antiaging research as equally promising.

Also, about oligomers, see for example this:
https://www.alzforum.org/news/research-news/blunt-instruments-synuclein-antibodies-poorly-distinguish-forms
(Yes, I know it's about a-synuclein, but the same could happen for a-beta. Point is, trial failures don't neccesarily provide a clear answer at this stage.)

Posted by: Antonio at October 25th, 2020 3:58 PM

@Antonio:
First of all: "Engineering" data vs "science" data?
Excuse me?
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Second: Cryonics and trips to Mars are free associations. They have nada to do with clinical trials meant to compare the effectiveness of competing approaches.
Your example is the answer you may want to give to someone who doubts SENS on the grounds of treatments based on it not having rejuvenated anyone yet, which is light years away from what I am saying.
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Conclusion: You are talking about something that has zero bearing to the matter discussed and my question, which is:
Where is the DATA that shows that X approach is better than Z approach?
We have plenty preliminary data for plenty strategies, AND the preliminary data for non-SENS approaches looks good.
All you have are feelings, guesses, and hunches, which you use to deny the tons of encouraging data generated outside your Church.
Thank goodness scientists have an open mind.
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As for what James Burnbrae is advocating, I would rather hear his thoughts from him since you aren't inside his brain.
Either way, he's right that the whole continuum of longevity biotech needs to be intact for rejuvenation to happen. That is so commonsensical that I cannot fathom how someone can disagree with it other than for the sake of disagreeing.

Posted by: Barbara T. at October 25th, 2020 5:50 PM

@Antonio

That's right - To put all your eggs in the SENS basket, which have had no clinical success since their inception about 20 years ago, is indeed delusional

You are acting like the big pharma people who refuse to give up on b-amyloid - "just a few more billion and we'll get that positive result!"

We'll all be long dead with those strategies

Posted by: James Burnbrae at October 25th, 2020 5:51 PM

@Florin: "there any theoretical reason to suppose that a rejuvenated immune system plus immunotherapy, nanoparticles, or whatever-short-of-deus-ex-machina-nanobots could eliminate death from all cancer, all the time, forever? No."
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A pretty simple way to eliminate cancer in perpetuity would be to zap it with heat whenever it appears. Sure this would require regular (once a year, once every 5 years, whatever) visits to the nanomedicine clinic, but so would WILT. With the latter, you would need to get your telomeres amputated every 10 years or so and then hope that something doesn't go awry during reseeding. Basically, OncoSENS requires two complex solutions for one problem and the result is still temporary.
There's a reason de Grey shelved the project.
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Same for immunotherapy: if we train the immune system to recognise 100% of all cancers, then cancer is gone bye-bye. You wouldn't even need regular treatments aside from perhaps booster shots.
Sure, in practice some cancers may slip through the net, but who says that WILT would have 100% coverage? Not de Grey, who guessed a 50% problem resolution with the first few versions of all the 7 SENS strategies.
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So not sure why you think that there is no "theoretical reason" to support total eradication of cancer with means other than OncoSENS. On paper the two I mentioned are just as logical - as well as far more practical and easier to achieve.

Posted by: Barbara T. at October 25th, 2020 6:09 PM

There's no reason to think that heat can be targeted to kill every single cancer cell. You'd need something to successfully target every single cancer cell and we already know that they can evolve to deal with any targeting scheme you throw at them. Unless someone comes up with something full-proof that's not based on magic, this heat cure-all won't work.

The same reasoning can be applied to immunotherapy; there's no reason to think that immunotherapy can get rid of every single cancer cell. Some cancer cells might evolve to counter whatever immunotherapy tricks you can come up with. How do you know they won't? After all, immunotherapy isn't 100% effective today and what reason do you have to assume that it will ever become completely effective? But even if immunotherapy could really kill all cancer, how do you know that the side effects wouldn't kill the patient before it kills their cancer? There's no way to now any of this ahead of time. This is fatal flaw #1. And there are even theoretical reasons to think that it might be physically impossible for immunotherapy to be a cure-all. For instance, we already know that some types of cancer cells have no surface markers for the immune system to target. But maybe the immune system has some other mysterious way to target those types of cells. Yeah, maybe, but again, we don't know. But but but, what if it does? Then how do you know that targeting system could be improved to be good enough? You don't. This is fatal flaw #2.

All of these cancer cure-alls are like trying to build a giant cannon to launch a rocket to the moon. Yeah, it might able to launch a rocket, but it probably won't get you where you want to go for reasons that we can know ahead of time.

As for WILT, I don't see any fatal flaws that we can know about ahead of time. If there's any theoretical reason you can think of that WILT won't be able to get 100% coverage, I'd like to know about it. If WILT can get to 50% coverage, why won't it get to 100% coverage?

Posted by: Florin at October 25th, 2020 7:54 PM

Is SENS correct? I guess the only thing to do is raise the money and carry out the experiments to find out.

People talking trash about SENS should remember that it correctly predicted that Senescent Cell removal would extend animal lifespans and healthspans over 20 years ago. It hasn't been shown to be definitely benefical in humans yet... so what, very few therapies translate from animals to humans without a bit of back and forth and further innovation.

I think if you are writing off senolytics, that is a pretty bold move, and if you are still posting comments on this blog 5-10 years from now you be eating your hat. Gene therapy, RNAi, CAR T cells, even antibodies were written off by some commentators initally.

Posted by: jimofoz at October 25th, 2020 8:50 PM

@Barbara T.: You didn't understand anything that I said, so I'll not repeat it again.

@James Burnbrae: You dismissed all my arguments presenting no arguments, so I will apply Hitchen's Razor and stop wasting my time.

Posted by: Antonio at October 26th, 2020 2:42 AM

We need a complete flood of money going to the pharmaceutical industry & the publicly funded research organizations. Let them have enough money that they can be doing all kinds of research including all sorts of crazed radical ideas, including radical ideas that in hindsight turn out to be sort of stupid ideas to try.

In a $20 trillion dollar economy I think its about $500 billion a year is currently going to the pharmaceutical industry and the publicly funded research. It can easily go to $1 trillion a year and still not remotely be spending too much on it.

Posted by: aa3 at October 26th, 2020 4:42 AM

@Florin: by the same logic there's no reason to think that cancer won't mutate to bypass WILT and regrow telomeres. On the other hand, heat is brute force and you can't evade that. It's the laws of physics.
The tricky part is finding micrometastasis, but as long as you have a treatment often enough (every one year? three years) you'll keep the problem in check. Also, you'll zap emerging cancers before you even know they are there.
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Things can go wrong with immunotherapy just as things can go wrong with WILT.
Also: why assume that the side effects of immunotherapy will kill you? Tune the system well enough and the problem is solved.
In other words, there is no "theoretical reason" why one approach should fail and the other work - it's all guesswork at this stage.
Not knowing that a "targeting system could be improved to be good enough" is as much as a "fatal flow" as not knowing if reseeding will work across all cell types.
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As for why de Grey said that the first few generations of his therapies won't work perfectly, ask him!
My guess is simply that the lab is not the clinic and the first prototypes of anything are far from perfect. We are seeing it with senolytics: people hoped that one or two drugs would kill senescent cells across the board and that would be that. Alas, being senescent is not a specific enough target to make one single approach work in all tissues.
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In conclusion, I am not saying that WILT wouldn't work, but given where we are with the technology, even if all resources were channelled to that goal it would take many decades to get perfect results. In the meanwhile, millions would die of cancers that could be cured or kept in check with immunotherapy and nanomedicine.
Focusing on WILT now is not rational from an economic (where the currency is lives) perspective. WILT's inventor pretty much said that himself.

Posted by: Barbara T. at October 26th, 2020 6:00 AM

@jimofoz: I am speaking for myself only here, but I am not trashing repair strategies at all.
What I am trashing is some people's dogmatic faith in SENS as a ready made package that will be the solution to all our problems.
SENS is being treated as a religion whereas it is simply a problem-solving tool amongst emerging others. Some parts of the package may work soon, a few may take decades, others may never work.
I am thinking about writing a PhD on how scientific theories acquire such a cult-like following, until the lines between science and religion get blurred.
Lots of material to draw on in the comments section of this blog.

Posted by: Barbara T. at October 26th, 2020 6:12 AM

@Antonio

Your arguments are vapid and worthy of dismissal

You are an acolyte and a cheerleader for sci-tech you obviously do not understand

Posted by: James Burnbrae at October 26th, 2020 7:32 AM

@Barbara
The SENS approach had the benefit that at least it tries to address all the issues. It goes to far in the future, probably. For example WILT looks like madness at the current technological level. Even if achieved the cure might be worse than the disease itself. Transferring genes from mitochondria to the nucleus also seems like a gargantuan task which of implemented most surely will be causing metabolic difficulties.

On the other hand, we know what will not bring exciting advances. All the treatments that are targeted at the end results of metabolic pathways dysfunction will only bring marginal benefits. The higher up the disrupted chain we can bring the fixes there better results were can expect..

Of course it implies we have understood well enough the damage for cause and affected pathways.

Posted by: Cuberat at October 26th, 2020 9:57 AM

"A fundamental question that remains is how interventions that show promise in improving life span or health span in model organisms will be evaluated in humans, where a complex interplay of factors underlies the aging process"
"The traditional biomedical research funding model continues to be largely risk averse. Typically, incremental and clearly feasible research is funded, whereas bold, high-risk but high-gain proposals are often less well supported."

IMO there appear to innumerable research projects already in existence that show promise of achieving major progress towards better health/life span but only for animals. The problem is moving forward to applying these applications to humans which I feel NAM recognise as well - see quotes above. For me it is disappointing that they are applying the bulk of their funding to creating even more "initial" research avenues & little funding to moving on to human research. I feel what they will achieve is to have even more projects halted at this "animal to human" research barrier.

Posted by: Trevor Bingley at October 26th, 2020 6:27 PM

@Antonio
This gene migration is a remarkable feat, however even if all the genes can be migrated even in a human cells it doesn't mean that the whole organism will be healthy.

It is meddling in such a profound level that for sure will affect the metabolism. And even small mutations that affect only speed of transcription can lead to closing diseases. Let alone such big a change. Au least it is not impossible but will take at least 3 decades to achieve it in middle organisms and when is feasible for humans there will be some other option like medical nanobots

Posted by: Cuberat at October 26th, 2020 8:47 PM

It will be like the type 2 diabetes market has developed. Over time more drugs are developed, both drugs which have the same mechanisms of action as previous drugs, yet are different enough that they are very useful.. and new classes of drugs will be developed.

Over time we find out which classes of drugs are the best, and which combinations of drugs work well together. The growing variety of drugs gives doctors options to try for drugs that don't work well with some patients for whatever reason.

With polypharmacy, having say 5 different classes of drugs that act on different pathways for one disease, there is additional benefit in adding drugs for the patient. If 1 drug isn't enough to bring the disease under control.

It will be the same with something like Senolytics. At some point when we have a better understanding of it, we need blood tests where we can determine the level of Senolytic cells in the various organs for the patient. There will be some amount of Senolytic cells that are not harmful - eg.. in young adults.

So the person can start with 1 drug and see if that brings the number of Senolytic cells in that organ under control. If not, additional drugs can be added, there will be guidelines to follow based on the results of the blood tests, and how the patient is feeling on the drugs.

Posted by: aa3 at October 27th, 2020 2:29 AM

@Barbara T.

There are currently no known showstoppers for WILT. There's no chance that cancer could ever "reinvent" the genes for telomerase or ALT in order to defeat WILT. It's too complicated, and no cancer would have enough time to evolve those genes even if it could. As for reseeding, there might be showstoppers, but we should assume that there aren't until a showstopper shows up.

There are actual and potential showstoppers for any other cancer cure-all you care to mention. It doesn't matter what kill vehicle you pick (heat, chemo, immuno, whatever); if it can't target every single cancer cell, it will fail. And we already know that it's probably impossible to a build a perfect targeting system, as I've explained before. That's a showstopper. We already know that immunotherapy can kill patients, and there's no reason to think that you can tune the system just right to avoid fatal (or otherwise intolerable) toxicity for all cancers forever. This is likely to be another showstopper. So, we shouldn't expect that any current cancer therapy could ever be perfected.

At best, stuff like immunotherapy will help some people live long enough to benefit from WILT. So, mainstream funding for that stuff should continue. The SRF doesn't have the resources to fund everything, and that's a major reason why it cut funding for WILT. Another reason might be that there's decent mainstream support for WILT-relevant research. I'd like to see the mainstream start to get all of the parts of WILT working together. That's probably unlikely to happen, so the SRF will have to step in again at some point in the future.

A review of cancer immunotherapy toxicity
https://doi.org/10.3322/caac.21596

Posted by: Florin at October 27th, 2020 6:41 PM

Hey there! Just a 2 cents. TL DR: Achieving Healthy Human Longevity is a Challenge, and so is getting along.

If we fight, we'll never defeat aging; it requires all; it is why we end up with more roadblocks; funding is oftenly dependent on big numbers/people with 10-digits bank account balance; the more fighting (between each other) vs fighting aging Fight Aging.Org...the less money there will be because people don't invest in something that is not certain or with enough assurance; they can lose their investments; when they see chicanerie and negativism, this does not help out; it makes people think : ''the field is wack...full of raging, phony, crazy, angry, bitter and what not..
Nope.''. We should not spend too much energy on in-fighting but in-'getting along (despite our differences of opinions)'. The more we remain individualistic and the less we are socialistic/community, the less it will happen. Aging is the affair of all, because we all age.

An Individual alone can invent the next best thing; but after pouring zillions dollars to solve aging...and still not there...it is safe to say that this individual, alone, solving aging, is probably not existing in the next 50some years (AdG is close to being that one because he spearheaded/kickstarted the whole thing). Thus, it requires the entire planet to solve aging. From every country and every researcher; despite their divergences of views on medical science/(un)progress (so far). SENS so far has been one of the best things, because it is sound and makes sense (pun/had to do it), yet, it's only a small drop in the ocean..it's true that lots of the stuff out there probably will do jack...on lifespan...but SENS is only one thing...we will have to combine several things. Let's not dismiss everything so quicjkly.... it's understandable...after so many studies with low results..it kind of makes one pessimistic on the 'outlook of things'; I mean billions of dollars and no cancer cure...so, it's understandable to be a bit worried/wary/ wondering/less optimistic about things. Even doubting of 'the rest' out there.

Doubting & using critical thinking are important; but shouldn't let them stop our attempt of defeat aging; and by any Other means (than SENS or other therapy); (nearly) any thing is good, if it Does do something beneficial in terms of solving aging. I understand also the point of ''if we put the money on all these 'useless' other ones (that possibly do nothing much on lifespan)..it leaves none left for the Real Therapies That Matter (like SENS, that Will do something)''...(put all your eggs in the same basket)... It's understandable, to want to maximize the funding Towards the more relevant and efficient (use of funsd) therapies that give us the best chance...nothing wrong there. But aging is so complex, it is possibly doubtful SENS, alone byitself, will solve it all; we need the whole gamut of what's out there...aging may require all of that (since, after all, we did pour trillions of dollars and still no answer; SENS seems the answer, but, it could end up, partly, the answer; not the full answer). LEV is an immense undertaking, and will likely require a mega pitstop/tuneup composed of several therapies - done at once and in several rendez-vous medical appointment visits.

WILT is something that could end up quite powerful at stopping cancer; but there is also the danger of reducing telomerase activity (it would have to be targeted to cancer cells) in dividing cells/stem cells; which all make use of some small telomerase activity; even certain immune cells use telomerase - ironic...since cancer hijack it. Thus, WILT, would have to be temporary thing that would do once per whatever number of years to minimize any possible problems from telomerase cutting. Quite a few cancer cells would die from that since no more telomerase lenghtening and no more ALT neither; or any other type of lenghtening of telomeres. In that sense that is pretty efficient. I just fear that is equal kind of to the chemotherapy or radiation of cancer cells; it might kills cancer cells; but, you too. It's the 'Fight Fire with Fire'; you get burned in the process/double-edge sword of damocles. Toxic to cancer cells, but could be toxic to healthy ones 2. If all our cells were postmitotic nondividing cells/organ tissue that no turn over no division of cells..then it would be lots safer; but we have several tissues that are have high turn over/cell replacement...thus, it means it'S there the danger. These tissues and niches may depent on telomerase for renewal; cut that, and it could be costly (even if we only target it to cancer cells). It would have to be very short time/short burst and done with (not like 'long term chemo or radiation'). Heat could also be great..it is already used with laser heating, which kills the cells quickly...but, cancer cells could developp better anti-heat capability...they are quite sturdy...we need to fry them at extreme temperature, extreme cold (cold azot gaz) can also destroy them, by rendering them 'inert'. But, just like, chemo or radiation, they can cause permanent damage to the surrounding healthy cells. IT needs extreme/precise targetting and 100% accurate targetting is not always easy/feasible.

In my point if WILT never happens, the other thing is the epigenetic aspect; all cancers are epigenetic in nature (dysregulation), epigenetic methylome tells us cancer long in advance; these changes Drive cancer; cancer Cannot continue/form if 'ordered' by the methylome/epigenome; cancers are often mutations in nucleotides (in DNA), which cause cancer (T -> U, thymine to uracil change (or D -> L (aspartic racemization of aminos))); these purine/pyrimidine nucleotide 'swaps' are the mutations; which will then accumulate sufficiently and compromise the cell; it will then adopt a cancerous disposition once too many of them. These mutations accelerate the epiclock/change its landscape towards 'chronic inflammation/oxidation damage' and accelerate the oxidative lesions burden/DNA oxidation and chromosome unpacking/loosening/uncoiling (which will form progeria related toxic amyloids, like prelamin-a/progerin; these end up contributing to junk burdern and accelerate chromsomal/transcription/splicing/epigenetic drifting, proteostatic loss, protein aggregation, mitochondrial ROS overproduction, etc). In fact, I'm even surprised there is not much on the whole genetic compoenent; it's because 'we tried in the past - genetic' (and failed) to solve cancer....that'S because not looking in right spot; we need to dig deeper in DNA/and especially our methyl clock (which is upstream/causal to cancer).

After all this money, you would tink more research on that; but, most cancer research was observation of genes; not so much the episwitch that activate/deactivate them. It scares me that I can read 1980s studies about epigenetics...it's been sleeping in with the fishes, (and I worry, possibly forever). Sometimes, it takes 1000s of years for an invention 'to be/become'...it was already invented thousand years before...but people, slept on it/decided - no, not worth our time (Only,....a 1000 years later to do people 'wake up' and realize..'we needed it all along, (just) Now is The (Right) Time')...a thusand years later... I so hope that does not happen with the future of biogerontology/epigenetics/reprogramming. We don't have a 'spare 1000 years' to wait.

But it's the reality, things advance fast but it's a Mirage-like fast/it seems fast but when you look deeper, it's not That fast//not enough. When you can read studies dating nearly 50 years old and they were talking about the stuff today, it puts a damper on your spirit/hopes (sure, back then progress was slow, but...we are half-a-century later, and no cure for aging; is this the future, in fifty years..people 'of the future' reading studies that 'happened in the year 2020'...2070...still no cure/'we were doomed all along/a futile attempt, we tried', and most of us could be gone in 2070s). But what else can we do, but (continue) trying. Our lfe depends of it (otherwise, it's giving up and that is the end of us).. We all want to be there in 2070; still... ..&going (analogically, like that energizer bunny, 'going going going and going...Never 'Gone'). Rechargeable batteries, never run out of juice/energy; ..still going.

For now, if WILT, does happen it could be the best cure...immunotherapy is the other one, immune system needs telomerase, and WILT is about stopping telomerase (of cancers); thus we would compatibility problem (WILT might cause brief immune depression, it is safer in postmitotic quiescent cells), we would need to do them 'in separate times' to avoid doing therapies that 'cancel each other'...that's not better/could be fatal or highly damaging.

There is a timing (for everything...... - except a timing, to die; this timing, has to not be, anymore).

Just a 2 c.

Posted by: CANanonymity at October 28th, 2020 2:10 AM

@Barbara T.

Hallmarks is one step forward, two steps back. It doesn't mention crosslinks, intracellular junk like lipofuscin and lipids like 7KC, or damaged elastin. And it's proposed interventions won't help out that much in reaching LEV.

Posted by: Florin at October 29th, 2020 12:30 AM

@Florin: it's easier to figure what may go wrong for therapies that are in the clinic already than for something on paper like WILT.
Implementation - let alone successful implementation - is too far away in the future.
Targeting issues may affect WILT too, because who says that we will manage to interdict telomeres from all cells and tissues?
Mess up just one gene and you may end up with a fatal disease.
On the other hand, perfect targeting isn't necessary with heat-based approaches as long as you keep tumor burden under a certain threshold. Cancer cannot develop resistance to heat (assuming that targeting doesn't require drugs) and people can live healthily for many years with cancer that refuses to disappear but neither does it progress.
I am not saying that WILT will never work, but I don't expect to see it eradicate cancer before I am 90.
As for Hallmarks and what's missing... that's only true if your premise is that SENS is the correct paradigm. See it from the perspective of Hallmarks and it is SENS that's missing stuff.
But these are opinions, not fact.
Time will tell which one of these approaches will yield the best results. My bet is that'll be a combination of many different ones.

Posted by: Barbara T. at October 29th, 2020 4:16 PM

The strength of SENS is not in its specific proposed interventions into the aging process. I assume a few will work but most will fail, or at least need to be tweaked significantly. The strength of SENS is in its overall damage repair strategy that aims to rejuvenate an already-old organism instead of just slowing down aging.

Posted by: kel at October 29th, 2020 7:35 PM

@Barbara T.

Yes, every single cell will have to be WILTed correctly. It might be really hard, but there's nothing working against you like it is with cancer. And there isn't any showstopper that I know of.

And yes, it might take a long time to WILT every single cell. I've heard that it might take more than a century. But I anticipate that most cells will be WILTed a lot sooner, so the chance of cancer developing before every last cell is WILTed will be quite low.

Again, heat (or any other method of killing cells after they've turned cancerous) will require perfect targeting, something that's unlikely to ever be developed. Cancer will simply inactivate or evade your targeting vehicle just as it's done numerous times in the past. If you throw a fancy nanoparticle at a cancer cell and it spits out a bunch of decoy targets, how are you going to deal with that? And for certain kinds of cancer, there's almost nothing to even "target."

It's fairly well-established that damaged lipids is what causes athero, but Hallmarks ignores this fact. On the other hand, it's not a well-established fact that epigenetic change causes any age-related disease or condition, and this is why SENS ignores it.

Posted by: Florin at October 29th, 2020 7:40 PM

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