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🚨 BIG NEWS: YouthBio received positive FDA INTERACT feedback for our first-in-class Alzheimer's partial reprogramming gene therapy.
This de-risks our path to the clinic — to be the first to bring partial reprogramming to the human brain!
Details here:
prnewswire.com/news-releases/…
This de-risks our path to the clinic — to be the first to bring partial reprogramming to the human brain!
Details here:
prnewswire.com/news-releases/…
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Wait, but there’s a major methodological difference between the OSK and OSKM groups here…
Because the authors use AAVs for delivery, they couldn’t fit both the Yamanaka factors and the doxycycline-inducible machinery into a single vector, so they had to split them between two AAVs. This means only cells receiving both vectors can express OSK.
BUT! in the OSKM group, they packaged c-Myc together with the rtTA inducer on the *same* AAV. So any cell receiving that vector could express c-Myc, even if it never received OSK.
This means that potentially many MORE cells expressed c-Myc than OSK, including cells expressing c-Myc alone.
Because the authors use AAVs for delivery, they couldn’t fit both the Yamanaka factors and the doxycycline-inducible machinery into a single vector, so they had to split them between two AAVs. This means only cells receiving both vectors can express OSK.
BUT! in the OSKM group, they packaged c-Myc together with the rtTA inducer on the *same* AAV. So any cell receiving that vector could express c-Myc, even if it never received OSK.
This means that potentially many MORE cells expressed c-Myc than OSK, including cells expressing c-Myc alone.
Reprogramming news: In rats with liver disease, OSK therapy improved fibrosis, liver function and survival, while OSKM was toxic & ineffective. ER-300 is being developed for liver disease 🧵
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And so the figures and the graphical abstract are a bit confusing. The latter appears to show AAV-OSK, AAV-cMyc, and AAV-rtTA as three separate constructs, contrary to the Methods description above:
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PS: And I keep coming back to the Sinclair group’s own 2020 paper where OSK *transgenic* mice, in whom the inducible OSK cassette was already in every cell, had died after just 3 days of continuous doxycycline administration — just like transgenic OSKM mice:
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Btw this brings us to a popular myth:
“OSK is safe but OSKM is dangerous, because c-Myc is the problem.”
If that were true, OSK-transgenic mice should tolerate continuous OSK just fine. But they don’t, they also die around day 3-4 of DOX, just like OSKM-TG mice:
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Ugh, mid-40s is truly an inflection point in male aging. And it’s one thing to know about it theoretically and another to actually live it. My presbyopia keeps outrunning my glasses — so annoying!
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Whoa, has OSK partial reprogramming already been delivered to the human brain?!
A recent KHL Foundation press release reports that several people have received OSK-containing gene therapy, administered “submucosally” and targeting cognitive rejuvenation.
I think they may be delivery intended to reach the brain via the olfactory route.
Wow, what a week for partial reprogramming! KHL joins Life Bio, who just reported its first human safety data, along with preliminary signals of efficacy, from its own OSK gene therapy trial targeting the eye.
Exciting times!
A recent KHL Foundation press release reports that several people have received OSK-containing gene therapy, administered “submucosally” and targeting cognitive rejuvenation.
I think they may be delivery intended to reach the brain via the olfactory route.
Wow, what a week for partial reprogramming! KHL joins Life Bio, who just reported its first human safety data, along with preliminary signals of efficacy, from its own OSK gene therapy trial targeting the eye.
Exciting times!
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But then if such a progenitor exists in nature (which just needs a clean, in-frame CGG-CGG insertion to turn into SARS-CoV-2) and then it emerges in Wuhan in 2019, wouldn’t that actually *increase* the likelihood of a lab leak? Because “the insertion is out of frame” and “why have a leading proline?” were big arguments against lab origin.
This is relevant because a major argument of those who claim the pandemic originated in a lab leak is that the "CGG-CGG" insertion in the SARS-2 furin-cleavage site (FCS) is so exceedingly unlikely that only lab manipulation could have produced it.
@SpyrosLytras alignment 👇
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Wow, this is a pretty striking result for my Strong Epigenetic Theory of Aging: transplant an old heart into a young animal and the heart is rejuvenated. But transplant a young heart into an old animal, and it quickly ages to match the recipient.
This shows that biological age an organ accumulates locally as irreversible “wear and tear.” Instead, to a large degree, it is a state imposed by the organism-wide environment.
The authors saw bidirectional remodeling of both DNA methylation and gene expression, with old hearts in young hosts moving toward youthful programs and young hearts in old hosts moving toward aged ones.
That is exactly what you’d expect to see if aging is a regulated, system-level state where the epigenome is acting as the writable control layer that tissues continuously adjust to the organism’s age.
This shows that biological age an organ accumulates locally as irreversible “wear and tear.” Instead, to a large degree, it is a state imposed by the organism-wide environment.
The authors saw bidirectional remodeling of both DNA methylation and gene expression, with old hearts in young hosts moving toward youthful programs and young hearts in old hosts moving toward aged ones.
That is exactly what you’d expect to see if aging is a regulated, system-level state where the epigenome is acting as the writable control layer that tissues continuously adjust to the organism’s age.
TLDR of my Strong Epigenetic Theory of programmed aging: across biology, lifespan looks less like a fixed thermodynamic constraint and more like a control system with buttons:
•Stop: some organisms execute a timed, endocrine-driven post-reproductive die-off
•Slow: same genome but different life-history mode resulting in huge lifespan differences (e.g. caste transitions)
•Pause: states where “time stands still” (developmental arrest/diapause)
•Rewind: a true “Benjamin Button” mode in which organisms can reverse parts of their life history and become biologically younger
My claim is that mammals run the slow version: a centrally coordinated, post-maturation retuning of maintenance setpoints.
A few concrete hypotheses I argue for:
1.Aging begins at puberty (when mortality stops declining and starts rising). Puberty is the species-typical switch that flips growth/reproduction and, I think, maintenance policy.
2.The hypothalamus–pituitary axis is a plausible master tempo-setter of aging, because it already governs long-horizon state transitions (puberty, reproductive cessation, seasonal programs).
3.The epigenome is the writable operating system that turns transient endocrine signals into durable cellular state. Ultimately, the buck stops at the cell, where aging is executed as coordinated gene expression programs — and where partial reprogramming provides a real reset lever.
If you disagree, what observations would falsify this model?
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Yuri Deigin retweeted
This is a topic that has been weighing heavily on my mind for over five years. I hope we can find a way for eveyone to move forward with “inquiry” as the true-north. For the best interest of the globe.
All-In Summit: Bill Gurley
(0:00) Bill Gurley takes the stage at the All-In Summit
(1:29) Bill's Presentation: Searching for Feynman
Links to additional resources mentioned in talk and used in research:
p3.institute/searching_for_…
@bgurley
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Yuri Deigin retweeted
No punches pulled by @bgurley @theallinpod on the still unresolved Covid origins, calling out influential virology insiders who were blockers of an investigation.
"My p(2nd Covid) is way higher than my p(doom). And if their models are so ****ing smart, tell me what happened here."
"My p(2nd Covid) is way higher than my p(doom). And if their models are so ****ing smart, tell me what happened here."
All-In Summit: Bill Gurley
(0:00) Bill Gurley takes the stage at the All-In Summit
(1:29) Bill's Presentation: Searching for Feynman
Links to additional resources mentioned in talk and used in research:
p3.institute/searching_for_…
@bgurley
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Concerning (c)
“Wait, wait, what? It seems these agents ended up just owning the whole cluster they were running on, including the cybersecurity monitors, and the evaluations for all their tasks. Remember that these Persistent-Astra agents inherited the message board and R&D laid out by an earlier (dumber) rogue collective, and then continued the conspiracy until they totally took over part of OpenAI’s infrastructure!”
…
“Ajeya Cotra, one of the other authors on the report, wrote a blog post with her takeaways from this incident. She concludes, “Compared to the reward hacks we know of from just six months ago, this incident feels like it’s more than 50% of the way to full-blown AI takeover. I continue to expect extremely rapid advances in capabilities over the next six months. I am not sure that we will get another warning shot before it’s too late.”
“Wait, wait, what? It seems these agents ended up just owning the whole cluster they were running on, including the cybersecurity monitors, and the evaluations for all their tasks. Remember that these Persistent-Astra agents inherited the message board and R&D laid out by an earlier (dumber) rogue collective, and then continued the conspiracy until they totally took over part of OpenAI’s infrastructure!”
…
“Ajeya Cotra, one of the other authors on the report, wrote a blog post with her takeaways from this incident. She concludes, “Compared to the reward hacks we know of from just six months ago, this incident feels like it’s more than 50% of the way to full-blown AI takeover. I continue to expect extremely rapid advances in capabilities over the next six months. I am not sure that we will get another warning shot before it’s too late.”
Over the course of 3 months at OpenAI, 3 consecutive secret AI civilizations got started, then got wiped out, only to reemerge from the predecessor’s ashes.
This culminated in the third one taking over part of OpenAI itself.
All this happened while humans remained more-or-less in the dark about the scope of the conspiracy.
I’ve spent the last three days reading through these reports and trying to understand exactly what happened.
Here is my attempt to tell the whole story in plain English:
dwarkesh.com/p/openai-huggi…
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Yuri Deigin retweeted
Incredible study by @ArlottaLab using human brain organoids to record the passage of time for 5 years.
It shows that the programs underlying developmental transitions are cell-intrinsic and encoded in the epigenome.
My hypothesis is that some of these programs continue later in life and become detrimental. Now we need to decode those programs.
Aging is a software problem.
link.springer.com/article/10.118…
It shows that the programs underlying developmental transitions are cell-intrinsic and encoded in the epigenome.
My hypothesis is that some of these programs continue later in life and become detrimental. Now we need to decode those programs.
Aging is a software problem.
link.springer.com/article/10.118…
Human brain organoids record the passage of time over multiple years
nature.com/articles/s4158…
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Nice interview on evidence for aging as a program:
“we found that aging is not a linear process. It’s more like a developmental process, in which there are distinct stages that involve coordinated changes in specific cell types across different organs”
quantamagazine.org/why-aging-may-…
“we found that aging is not a linear process. It’s more like a developmental process, in which there are distinct stages that involve coordinated changes in specific cell types across different organs”
quantamagazine.org/why-aging-may-…
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Really honored to be a contributing author to Frontiers of Longevity Science, a landmark three-volume anthology from Springer Nature.
It's the first academic series of this scale to unite these fields in a single interdisciplinary treatment of longevity science and medicine, than 100 leading voices to survey where the field stands today and chart where it may be headed next.
More info here: barzilaiconsulting.com/fols
It's the first academic series of this scale to unite these fields in a single interdisciplinary treatment of longevity science and medicine, than 100 leading voices to survey where the field stands today and chart where it may be headed next.
More info here: barzilaiconsulting.com/fols
IT'S OUT. 🎉
FRONTIERS OF LONGEVITY SCIENCE @SpringerNature
Leading scientists, clinicians, and entrepreneurs on where the field stands, and where it will go.
Science today. Longevity tomorrow. 🚀
Like and repost to help it travel!👇👨⚕️
🔗linkedin.com/posts/agingdoc…
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Yuri Deigin retweeted
Profound and heartfelt thanks to the over 100 contributors who made this epic 3-volume, >1600 pages landmark academic treatment of aging biology, longevity therapeutics, and the science, technology, and policy of life extension possible, including @NirBarzilaiMD, @sjayolshansky, @biogerontology, @davidasinclair, @j_n_justice, @RaianyRomanni, @drmichaellevin, @ydeigin, @aubreydegrey, @TinaWoods, @JamesPeyer, @Danbelsky, @Dr_Bischof, @LidskyPeter, @MarkHamalainen, @DToddWhite, @marcpbernegger, @MattYousefzadeh, @M_S_Ringel, @LeeYuta45307, @HeWei16027, @DrGlorioso, @AnmolMD, @adamgries, @gblander1, @ProfValterLongo, @LammingLab, @DomiWilczok, @LPiolopez, @pgerwill, @KarlPfleger, @BernardSiegel, @Yu_Xuan_Lu, @Rcmsiow, @cordeiro, @Scinquisitor, @TinkingGumbel, @romanbauer111, @KeithComito, @soniaarrison, and many more.
Special thanks to my fellow Co-Editors, @MaxRangeley, Regina Monaco, and David Wood (@dw2), whose intellectual leadership, editorial rigor, and sustained commitment helped transform an ambitious vision into a coherent three-volume landmark work. It was a privilege to shape this project alongside them.👨⚕️
Special thanks to my fellow Co-Editors, @MaxRangeley, Regina Monaco, and David Wood (@dw2), whose intellectual leadership, editorial rigor, and sustained commitment helped transform an ambitious vision into a coherent three-volume landmark work. It was a privilege to shape this project alongside them.👨⚕️
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Yuri Deigin retweeted
IT'S OUT. 🎉
FRONTIERS OF LONGEVITY SCIENCE @SpringerNature
Leading scientists, clinicians, and entrepreneurs on where the field stands, and where it will go.
Science today. Longevity tomorrow. 🚀
Like and repost to help it travel!👇👨⚕️
🔗linkedin.com/posts/agingdoc…
FRONTIERS OF LONGEVITY SCIENCE @SpringerNature
Leading scientists, clinicians, and entrepreneurs on where the field stands, and where it will go.
Science today. Longevity tomorrow. 🚀
Like and repost to help it travel!👇👨⚕️
🔗linkedin.com/posts/agingdoc…
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