I’m assuming that the mice still die from various cancers even if most of their tissues have been rejuvinated.
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I think Rick said that they’ll have results at the end of the summer. It sounded as if the mice were all perfectly healthy, but then they just stop. I wonder whether organisms might have a built in ‘expiration’ date. That it doesn’t matter how healthy the body is, we’re programmed to have a specific amount of time.I know there’s been some talk of the hypothalamus being a potential universal clock. It’ll be really interesting to see what the result is. If there is a hard limit, it’s an exciting problem to work on.
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It could also be related to the thymus shrinking with age, in which case I would love to see a trial using Yamanaka factors + HGH + empagliflozin.
Or it’s an issue with the extracellular matrix which the treatment does not affect. This is one of the reasons why naked mole rats live much longer than regular old rats and basically never get cancer.
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nikney
#14
yes it is really interesting. If the organs turn into the organs of a young mouse, which he says, he even says that old mouse skin becomes like young mouse skin and when you make an incision, it starts to heal the next day, then why do these mice die? I wonder if a single dose only extends life by 25%? Or are some tissues or organs less affected by these factors? This is a really interesting but very exciting development.
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HGH shortens lifespan, so I’m not sure that would be helpful. It’s possible that the EM could play a factor, maybe the mice hearts become so stiff, they simply stop beating. I do think immune aging has a huge effect. I seem to remember reading somewhere some centenarians have effectively exhausted their T cells. My feeling is that it might be programmed and all reprogramming is doing is resetting the cells to live out their maximum capacity. I’m sure there’s plenty of reasons why that isn’t the case. Fascinating stuff, and I can’t wait to hear what they find.
ng0rge
#16
I think he’s talking about TRIIM and TRIIM X which directly address the T cell problem and immune aging. A complete examination of the mice when they die should give us some answers.
See this thread:
https://spotify.localizer.co/t/first-hint-that-body-s-biological-age-can-be-reversed/1021?u=ng0rge
And posts here:
https://spotify.localizer.co/t/rapamycin-vs-hgh-as-longevity-therapies/11674/33?u=ng0rge
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I think there are better thymus treatments on the horizon. They’re are at least three or four companies developing immune regeneration treatments. I think TRIIM is really interesting but I have a feeling it’s a bit of a blunt instrument. It does seem as if HGH shortens lifespan, so it may just be offering healthspan improvements in the people they’re testing it on, but I think it’s probably shortening lifespan. That’s probably not a bad thing if you stay healthier and then decline more quickly at the end. There was an interesting talk at the Dublin Longevity Conference on it on the effects of HGH. Worth a listen.
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In a sterile lab environment, HGH is probably detrimental for lifespan. But what about the outside world teeming with pathogens?
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Neo
#19
Can you talk more to Empa in this context?
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Neo
#20
I’m with you on this from a medium to long term, chronic shift in GH and IGF-1 axes perspective
But I think TRIIM is only a short pulse once or perhaps a 2-3 times during an entire lifetime
Not saying whether TRIIM is/will work, just that the HGH shortens lifespan logic might not apply for a few short bursts, if the generated thymus and immune system then is better for decades each time
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Neo
#21
New Altos Labs paper in one of the Science journals with the guy who opened up the entire field of partial reprogramming as senior author:
Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging
Editor’s summary
Partial cellular reprogramming via cyclic expression of octamer-binding transcription factor 4, sex-determining region Y-box 2, Kruppel-like factor 4, and cellular myelocytomatosis oncogene (OSKM) improves health and life span in mouse models but may lead to tumor induction or organ damage. Here, Sahu and colleagues used adeno-associated viruses to deliver OSKunder the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically target stressed and senescent cells in a mouse model of Hutchinson-Guilford progeria syndrome. Treatment extended life spans and improved overall fitness, associated with a shift in the transcriptome toward that seen in younger mice. Similar effects occurred in aged wild-type mice and treatment did not increase tumor occurrence, suggesting that targeting partial cellular reprogramming to specific cell populations may be a more viable rejuvenation strategy moving forward. —Melissa L. Norton
Abstract
Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSKin aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.
https://www.science.org/doi/10.1126/scitranslmed.adg1777
@AnUser or anyone else able to access the paper?
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Replacement for metformin
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ng0rge
#24
Good catch! Yes, I’d love to see the whole paper, too.
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Neo
#25
Do you feel Empa has better longevity data than Cana or what are your thoughts on that?
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argonaut
#26
I’m probably missing something, but this appears to be similar to, if not a replication of, work David Sinclair did a few years ago.
I like the selective nature for the SGLT2 pathway of empa more than the dual nature of cana. It’s just a personal preference. Either drug works perfectly fine in humans.
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Neo
#28
The senior author on this paper was the first person to show breakthrough results of this concept (the person some people think might get the next Nobel prize in something related to aging)
After that, Sinclair and - many others, including the $3B funded Altos Labs, have since all done of lot of work on partial reprogramming
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Neo
#29
Got it. Just trying to understand if there is something with SGLT1i that you don’t like?
argonaut
#31
Human trials beginning next year. We don’t know if they’ll be using OSK, OSKM or some other mix.
ng0rge posted an article above. It doesn’t specify which of those factors it refers to in the portion pasted here, and I’m too lazy to dig further, but it does say this: “However, it is crucial to note that cellular identity states of these cells post-partial reprogramming are not identical to those of their parental cells.”
Will a trial participant become copy of a copy of a copy? Probably not. They’ve probably resolved that. Still, I’m not volunteering.
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