Karl Pfleger - Why I'm cautiously optimistic on rejuvenation progress (Reddit)

#1

The following is from Karl Pfleger, former Google AI engineer and now the leading SF Bay Area Longevity Biotech angel investor. He maintains this website: About AgingBiotech.Info

The aging/longevity field’s goal is best-possible health for as long as possible for as many people as possible. High level approaches are SLOW aging rate or REJUVenate (reverse) each of aging’s molecular changes (damage). Backup strategies are CRYOpreservation, mind UPLOADing, & whole-body REPLACEment (brain transplant). Many who favor the backups have pessimism for SLOW & REJUV. Contingency plans are good but hard ones divert time+$ from primary plans.
I’m most optimistic for REJUV.

Here’s why:
The field understands many causally pathological aging changes (damage types) at the molecular level & already has feasible plans & proof-of-concept demonstrations for reversing them. We know most exacerbate others. Which should we expect progress on in coming decades? A list:

  • Accumulation of persistent senescent cells: Progress seems achievable w/in 5-15yrs given preclinical data & # efforts eg Rubedo slice&dice, Oisin & Deciduous systemic plus half dozen others & some groups working on diagnostics. Ongoing supplement trials might even partly succeed.
  • Telomere shortening: Expressing telomerase is pretty straightforward. Rejuvenation Tech is in late preclinical via now-easier RNA but others working on it too. Some data suggests doesn’t lead to more cancer even in cancer-prone mice. Progress seems very plausible in 10-15yrs.
  • Epigenetic changes: Some success w/ in- or ex-vivo partial reprogramming seems almost likely in 5-15yrs (esp of things like HSCs or other stem cells) given preclin data, huge funding, & # companies eg Altos, Retro, NewLimit, Turn, Life, Shift, Junevity, …
  • ECM: Breaking crosslinks at least in easy-access areas (arteries, eyes) prob just enzyme engineering (eg Revel Pharma, Lento Bio). Targeted chelation, ECM growth factors, & ECM injection in preclin too (eg Elastrin, Elastin Bio, XM Tx). 5-15yr progress certainly possible.
  • Cancer: Oncology making big gains. Survival up. CAR-T improving fast. MAIA’s THIO pan-cancer weaponization-of-telomerase in phase 2 w/ 2 variants at ph1. Early detection improving. A decade or so prob won’t see 100% cure but big decrease in total burden believable.
  • Mitochondria changes: 20+ biotech. 20+ trials, many ph2-3. Much positive preclin data. Much evidence of importance to many areas esp neuro. At least 2 acquisitions so far (Mitobridge, Mitokinin). Many diff MoAs eg mito transfusion (Cellvie, Mitrix). 5-15yr progress seems likely.
  • Atherosclerotic plaques: CVD is #1 killer. Actual reversal of plaque build up in late preclin at 2 companies: Repair, Cyclarity. ECM stuff above may also help w/ CVD. Could take a big chunk out of #1 killer in a decade or so.
  • Aging, less functional stem cells: Lots of preclin data showing stem cell rejuvenation via injection of young stem cells or their secretions eg Juvena, Immunis (ph1/2a). Other approaches being researched too inc drugs. Progress seems achievable in 5-15yrs.
  • Intracellular junk eg lipofuscin: Also mostly understood enzyme engineering plus delivery. Eg Lysoclear (part of Ichor in late preclin). Just maybe this approach could handle microplastic accumulation too. Progress conceivable in 10-20yrs for at least some tissue/cell types.
  • Misfolded proteins: Despite Aβ mAb fails, improvements w/ less side effects being studied eg catalytic antibodies, endocytosis clearing. 1st drug exists for ATTR (top 110+yo killer). Other neuro approaches eg BBB, glymphatic may reduce misfolding. 10-20yr progress possible.
  • Muscle degeneration frailty/sarcopenia: (Overlaps w/ stem cells above.) 8+ companies in various stages preclin to ph3 trials. 4+ in ph2+. Lots of $. Increased big pharma interest due to GLP1 muscle loss. Progress seems quite likely w/in 5-15yrs.

REPLACEment strategy really a continuum of amount/granularity w/ total-body the nuclear option. Partial replacement: organs, tissue, cells, mitos, ECM should be considered part of REJUVenation too & are part of my optimism that backups may be slower/unneeded for most alive today. Eg: Organs: liver eg Lygenesis (ph2), kidney, thymus eg Thymmune, Thymofox. Whole cells eg stem cells: many companies, wild-west-ish but some legit/progress. Mitochondria: see above. Tech for supplies: 3D bioprinting (many biotechs), xenotransplants, synthetic embryos eg Renewal Bio.
Above covers 7/7 SENS areas, ~7/9 orig Hallmarks, 4+ top aging diseases. Predicting progress hard. Big confidence intervals. Skeptics will say no good evidence any above will succeed in humans, but OTOH also no data nor strong reasons to suggest any, let alone all, will fail.

Any combo of several above areas in 10-20yrs would greatly benefit most now<60yo humans, prob enough to unlock several years of further breakthrus (basis of LEV concept Aubrey+others discuss, a clearly rational idea). Would also unlock huge funding increases for the field.

After some success in most areas above I think we’d finally be at point where healthy lifespan increased more than via optimal lifestyle and/or lifestyle mimetics, prob enabling ~10-20% of humans to get to 130-140yo. But as said above CIs big. Others will disagree.

After success in most/all of above, which slow molecular changes of aging will be top limiting factors that kill? This will be easier to judge w/ successful therapies for above avail, making targeting the new limiting damage types easier.

https://www.reddit.com/r/longevity/comments/1buc1so/why_im_cautiously_optimistic_on_rejuvenation/

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#2

The issue that needs identifying is what the underlying mechanism of aging is. As people know I think it is a genomic failure (driven by the shortage of metabolites).

If you fix that then everything else very slowly starts working properly.

There will be other issues relating to things like DNA damage, but those are much less of an issue.

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#3

Definitely much more research needs to be done to dig down under and reveal the causes of the hallmarks of aging. But many people aren’t willing to wait for that and are developing therapies to target some many of the key factors thought to be involved in aging, and the hallmarks of aging. Time will tell if this is a fruitful strategy, but I don’t think they are at all independent.

As progress continues on the root causes of aging, more scientists and longevity biotech entrepreneurs will start new companies to address these also. In the meantime interest is growing rapidly in the field:

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#4

I think there always has been interest in the field. Sadly some of the papers written in the 1940s got forgotten as they had some useful information in them.

The real difficulty in ignoring mechanism is that without that it is really hard to work out what has synergistic effects and what cancels out effects.

Still I think I know what the mechanism is. Hence I will plod on with my experimentation (including intermittent rapamycin) and time will tell.

Responding specifically to the chart we should be told the absolute numbers.

In any event considering aging without considering DNA is IMO a mistake.

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#5

It would be tremendous if / when that is done - and there may be many, many and just one.

But I don’t think it’s correct the say that “the issue” is that we have to do that.

The whole idea with replacement is that we can shortcut past (a) a complete identification of what causes aging in tissues AND (b) being able to solve / reverse all of those causes and their compounded effects.

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#6

I accept my thinking may be biased because I think I understand the basic mechanism(?s) of aging and to some extent how to fix it. However, I think that although replacing mitochondria may itself be a good thing, generally the replacement of organs will get a worse outcome than fixing the main aging process.

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#7

Thanks @John_Hemming

What about replacing old people’s entire body with their own identical 16 year equivalent body?

(From a clone that never had a head and hence never was “human” and never had any ability to become conscious nor sentient)

Seems like that within an instance would reverse the age of the majority of that old person…

For example,

  • Virtually no cardiovascular risk for decades - so biggest killer of cardiovascular disease and risks of biggest disablers of strokes and heart attacks basically off the table.

  • The vast, vast majority of cancer risk goes to almost to zero for many decades

  • Ultra young metabolic health for decades

  • For decades a perfectly rejuvenated immune system

  • No frailty, not risk of osteopenia for decades

  • Replacement of 95%ish percent of one’s mitochondria and stem cells to optimally youthful ones.

  • And so and so forth.

—

(And increased abilities for youthful adventures, sports, sex life, etc, would increase healthspan in profound ways and also likely help with mental health)

—

We still have to work on the brain of course - but off the bat, the youthful environment and all of above would make our brain much better off in the 16 year old body than in an aging 70, 80 year old one.

Seems like the totally of all the things like above could be a huge way to give people some (or many) extra decades of life and survival for you and others to figure out other ways to reverse aging through understanding aging mechanisms and also figure out solutions for all/enough of those mechanisms?

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#8

What about the blood vessels in the brain and alzheimers.

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#9

To help provide my thoughts for an answer in a good way can you help me understand one thing:

  • Do you by and large agree that then part in bold below is a likely/good conjecture (or if not why not)?

We still have to work on the brain of course - but off the bat, the youthful environment and all of above would make our brain much better off in the 16 year old body than in an aging 70, 80 year old one.

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#10

I don’t think it would reverse Alzheimers.

What you need are more efficient mitochondria in the brain, fewer senescent cells, and for this to have improved cellular function more generally.

Attaching the brain to a new body even if practical and ethical will not sort those things.

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#11

Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell–Derived Cardiac Spheroids

Open access paper:

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.064876

#12

Excuse me sir, I don’t want a young body and an old head

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#13

Can you help me understand?

In general I think we’d want as much health and disease-freeness as possible?

#14

What about the brain itself?

There are a couple of pillars to a complete answer but here is a sketch

  • if your own head/brain is moved onto/into a genetically identical, but young version of your own body that will itself almost certainly lead to some form of rejuvenation. I will be like young plasma exchange/parabiosis on steroids (and parabiosis has shown massive health effects on the older animal, including against neurodegeneration)!!! It would be like a continuous systemic stem cell therapy, it would be like optimal GFD11, klotho, etc therapies and there will be additional benefits from each of your organs having perfect young function without any of the impairments from age - from your kidneys, to your microbiome, to even having a young and fresh spinal CNS to help cleanse and provide a healthy environment for your brain. This argument might be even stronger than just based on those mechanisms, see a post I will come back with.

  • above will likely increase the time that your brain will last and those extra years or (many) decade(s) will enable more time for you to access more medical advancements

  • and if body replacement becomes widely used, there will be much less need to study most non-brain disease processes - as most of them can be solved by a body replacement. Perhaps that is too extreme, but it would absolutely shift the incentives and funding and market dynamics to reward work focus on neurological health and neurological aging - probably by several orders of magnitude

  • Think about it…. no need to invest in liver, pancreas, colon, breast, prostate cancer… no need to invest in type 1 and 2 diabetes…, no need to investment organ impairment of kidney, liver, pancreas, lung and heart…, no need to invest in things like Crohn’s or any other digestive tract type of disease…, no need to invest in thing like sarcopenia, osteoporosis…, and so on and so forth…

  • Above is further accelerated by the fact that people will (a) be living longer lives and (b) care much more about their brain specifically, so the willingness for both the government and individuals to invest in brain health would go up by a lot

  • So beyond a mass shift in resources, government founding, investor and industry funding to Alzheimer’s and other dementia, etc, etc, any of the other longevity therapies that show promise, like partial reprogramming, CRISPR editing - your stuff - can now in a more focused way target brain health and rejuvenation without having to be diluted towards every other system and disease process in our body

And it might be that none of above is needed, because as I laid out elsewhere on the forum:

We could even gradually replace parts of the brain in a gradual, continuous way such that you still are you even after we over say a decade or so have replaced your entire brain with healthy young neuron and other brain tissue.

See for example:


https://www.nature.com/articles/s41536-017-0033-0

And

Neuroscience News – 21 Jul 23

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Rejuvenating the Brain: Healthy Cells Replace Diseased Ones - Neuroscience News

Transplanted healthy glial cells can outcompete and replace diseased or aged brain cells, potentially restoring normal brain function.

And

$1B dollar investment with successful phase 1 data of iPSC derived neural transplants in humans, about to enter phase 2 trials: https://www.bayer.com/en/us/news-stories/clinical-trial-for-parkinsons-disease-continues-to-show-positive-trend

Similar, younger company: https://innovation.ucsf.edu/news/neurona-therapeutics-raises-120m-advance-groundbreaking-pipeline-regenerative-cell-therapy

And a third example from this month: Aspen Neuroscience Announces First Patient Dosed in First-in-Human Phase 1/2a Clinical Trial of Autologous Neuronal Cell Replacement Therapy for Parkinson's Disease

There is an arms race of biotechs working on these types of things. They focus on epilepsy, Parkinson’s, etc, but the approach can be broadened to any aging related brain disease.

For a complete roadmap of how we could gradually replace parts of the brain in a gradual, continuous way such that you still are you even after we over say a decade or so have replaced your entire brain with healthy young neuronal and other brain tissue.

https://www.amazon.com/Replacing-Aging-Jean-Hébert-Ph-D/dp/1513663763?
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#15

Hi @John_Hemming - any thoughts/feedback on my last reply to you in the post directly above?

Btw - I am by no means saying this is the only approach that should be pursued instead of other approaches. Just sayin that it has a good chance of actually being impactful and that it would be good if the world did pursue it for real.

#16

Given that I think I know the answer using biochemistry I am not inclined to analyse potential alternatives involving mainly transplantation to work out whether if the biochemistry didn’t work i would suggest trying those.

#17

Ok. Re your work. What do you think the impact of your approach will be when/if fully implemented in an optimal way?

(10-20 years slowing down of aging type of magnitude or a full reversal type of magnitude or what? Just your rough estimate.)

#18

A lot of this quantatively depends on how much progress can be achieved with mitochondria.

In the end I fumble around doing the best I think I can with the biochemistry. The testing results point to progress, but I cannot honestly identify a destination.

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#19

Zardoz was a 1974 cheesy sci-fi film that posited essentially a version of this this approach. In spite of low production values and poor ratings it asked an interesting question about life extension. The most interesting aspect of the film (to my young mind at the time and still remains so) was that pursuing a goal could be preferable to achieving it.

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#20

Will see if I can find it.