#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?

5 Likes
#23

Replacement for metformin

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#24

Good catch! Yes, I’d love to see the whole paper, too.

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#25

Do you feel Empa has better longevity data than Cana or what are your thoughts on that?

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#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.

#27

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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#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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#29

Got it. Just trying to understand if there is something with SGLT1i that you don’t like?

#30

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Whole thread:

x.com?

See also above

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#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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#32

There’s some interesting info in this other thread about a presentation by Juan Carlos Izpisua Belmonte.

Including these 2 links:

https://www.technologyreview.com/2023/06/17/1075097/got-rejuvenation-better-call-security/

https://www.science.org/content/article/two-research-teams-reverse-signs-aging-mice

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#33

Great new interview on Partial cell reprogramming posted by @RapAdmin here:

https://spotify.localizer.co/t/the-new-levity-podcast-on-radical-life-extension/14635/3?u=ng0rge

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#34

Recent tweet from him here:

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