NewLimit Launches, Another Well Funded In Vivo Reprogramming Venture

Following on the heels of the formation of Altos Labs, NewLimit is another well capitalized project focusing on in vivo reprogramming as a path to rejuvenation therapies. Given the sizable funding involved, it seems that reprogramming will be quite extensively explored in the decade ahead. Most of the questions we have now will likely be answered: can the risk of cancer be managed; how will reprogramming be conducted safely and efficiently in tissues consisting of different cell types with different reactions to the Yamanaka factors; will rejuvenation be largely limited to mitochondrial function, or will other sizable changes emerge as a result of resetting epigenetic marks; and so forth. I don't think that there is any expectation that reprogramming will do well with metabolic waste, and localized excesses of metabolic waste are a major component of degenerative aging. But we shall see.

NewLimit will start by deeply interrogating epigenetic drivers of aging and developing products that can regenerate tissues to treat specific patient populations. We will start by using primary human cells and reference species to develop machine learning models on what chromatid features change with age, which of these changes may be causal to the aging process, and finally develop therapies that could slow, halt, or reverse this process.

You can take a skin cell from an old mouse and clonally turn it into a newborn mouse with an entire life ahead of it. Remarkably, to accomplish this magic, you only treat the cells with four types of proteins. In a system as complex as mammalian biology, with billions of DNA base pairs and tens of thousands of proteins, all it takes is dosing four proteins for a couple weeks to completely change what the cell "is". NewLimit plans to initially focus on this mechanism: epigenetic reprogramming. Put simply, we want to figure out a way to restore the regenerative potential we all had when we were younger, but somehow lost.

We've raised $105 million initially from the founders to help get the company off the ground, with additional funding available upon reasonable progress. We expect capital will not be the limiting factor for the next few years. We may raise external funding as well down the road.



It's good to see that there will be lots of capital pursuing epigenetic reprogramming. I know that damage theory purists are skeptical that epigenetic erosion represents a form of age-related damage, but this objection should be challenged. If I told you that your old Pentium laptop hardware was fine, but it was failing because the program contained on the hard drive was corrupted, you wouldn't bat an eyelash. So why is it that people object to the idea that a form of age-related damage might be corruption of the programming of our cells?

Yes, epigenetic reprogramming may be a sledgehammer when it comes to correcting the damaged programming. Yes, it may only be kicking a small number of cells into more of a stem-like state. But the real litmus test here should be a rigorous testing of the impact of reprogramming on every single hallmark of aging.

I'll take this opportunity to mention my preferred version of the Hallmarks found in a recent article on their evolution:

It does appear that reprogramming will be getting lots of attention. I just hope they will address critical questions about its nature in addition to going after therapeutic intervention. Hopefully this work will get through the peer review process eventually, too:

It'd be good to know if this model for epigenetic aging passes peer review, as it would tie a form of damage to the observed loss of epigenetic information. I don't know that we can do anything to prevent it, but it would be valuable to know if it is indeed a significant driver of mammalian aging.

Posted by: Robert Cargill at December 13th, 2021 5:44 PM

@Robert Cargill
Like all other things in biology we will know for sure only when we can implement it fully. I can name a whole bunch of conditions that could easily kill us even if every single cell in the body was working as 20 years old. Examples: kidney and other stones, progressive scarring due to wear and tear, cholesterol plaques, overgrowing tissues, elastin loss. Arguably, all those things can be corrected with simple operations.

And then we have all kind of genetic damage in the somatic cell lines. If the DNA is corrupted, no amount of mutilation reprogramming will fix that.

Pouring all that skepticism I would still say that if we are lucky, whole body cell reprogramming could slow down and even revers a whole bunch of age-related issues and can probably increase the health-span by a couple of decades.

Posted by: Cuberat at December 14th, 2021 1:15 PM
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