A Short In Vivo Reprogramming Treatment Modestly Slows Accelerated Aging in Progeroid Mice

Progeria, caused by loss of function mutations in the lamin A gene, is not accelerated aging. It is an example to demonstrate that many forms of cellular damage and disarray, when present to a greatly exaggerated degree, can in some ways mimic manifestations of aging. Aging is, after all, a process of cellular damage and disarray. It is, however, a specific balance of various forms of damage. Change that balance radically, or employ other forms of damage, as is the case in progeroid mice, and the outcome can no longer be called aging. It becomes a challenge to determine whether interventions that help ameliorate the harms of progeria would help meaningfully with normal aging; that depends strongly on the details of each case.

There is a growing interest in applying cellular reprogramming as an in vivo treatment. The goal is to deliver enough of the reprogramming factors to make a significant number of cells become more functional, by improving mitochondrial function and reversing a range of age-related epigenetic changes, but without forcing cells to abandon their roles to become induced pluripotent stem cells. A small number of such conversations is probably acceptable, given the outcome of stem cell therapies, but at some point too much of that will produce cancer or outright tissue failure. Thus initial explorations of reprogramming as a therapy are focused on short or otherwise limited exposure to the reprogramming agents.

A single short reprogramming early in life improves fitness and increases lifespan in old age

In 2006, it was shown that mouse somatic cells can be converted into pluripotent cells (iPSCs) by inducing the expression of four transcription factors: OCT4, SOX2, KLF4, and c-MYC (OSKM). This process of cellular reprogramming induces a global remodeling of epigenetic landscape to revert cell identity to a pluripotent embryonic-like state. Exploiting cell reprogramming offers an alternative route for cell therapy to restore organ and tissue function. Somatic cells can be reprogrammed into iPSCs, then modified or corrected in vitro before being re-differentiated into cells, tissues or organs for replacement in the donor or an immune-compatible patient.

Previous experiments using a reprogrammable mouse model demonstrated that a cyclic induction of OSKM two days a week, over the entire extremely short lifetime of a homozygous accelerated aging mouse model, increased longevity, through a potential chronically unstable epigenetic remodeling. These mice have a mutated Lmna gene that produces high level of the natural aging protein progerin.

In this study, we investigate a single short period of in vivo OSKM induction as pre-clinical proof of principle for a potential usage in clinic to prevent aging defects. We focused on heterozygous animals, which have moderate lifespan and levels of progerin, as these heterozygotes might be extremely sensitive to anti-aging therapies. As a short OSKM induction, was described to ameliorate immediate tissue regeneration after experimentally induced tissues injuries, we wondered whether a short period of OSKM genes induction might improve lifespan and tissues aging of heterozygotes mice.

Surprisingly, we found that many health measures, and longevity itself, were ameliorated in elderly mice, by a single two and a half weeks treatment earlier in life, at two months of age. This outcome was associated with a differential DNA methylation signature, suggesting that a "memorized effect" initiated by our short induction protocol early in life might be involved in a more juvenile physiology.

Comments

I think progeroid mice will stop being a research topic very soon. Since this year, lamin A gene can be edited very efficiently in vivo (using a CRISPR-derived technique) and effectively cure progeria:

https://pubmed.ncbi.nlm.nih.gov/33408413/

Posted by: Antonio at May 28th, 2021 7:10 AM

"I think progeroid mice will stop being a research topic very soon."
Research on these mice is not primarily done to find a treatment for progeria but because you can see the results of your intervention much faster and therefore you can publish sooner.

Posted by: Michael at May 30th, 2021 2:19 PM

"you can see the results of your intervention much faster"

Yes, as someone who comes to longevity tech by way of the semiconductor industry, access to good models is everything! Models, models, models!!! Progress accelerated dramatically when the machines that could be built using the current silicon allowed quick, predictive simulations of the next generation of silicon.

Trivial treatments of an artificial model are useless. Showing you can restore normal lifespan by adding an exogenous antioxidant to a mouse that has a component of its native antioxidant defenses genetically damaged says little about the ability to extend lifespan. On the other hand, if a mouse model has a defect in a certain pathway, but an intervention achieves improvement without targeting the immediate pathway associated with that gene, then it likely has merit. Showing that you can improve several hallmarks with an intervention directed at a single one is promising, and it's a reason why I'm particularly optimistic about in vivo epigenetic reprogramming. Although it can't fix DNA point mutations, It seems as though it improves almost all the other hallmarks: stem cell viability, mitochondrial bioenergetics, proteostasis, lysosomal function, senescence, injury repair, and of course, epigenetic drift as measured by epigenetic clocks.

That said, medicine generally, and the longevity industry doubly so, would benefit dramatically from greater investment in better, faster models. "Better" here means "more predictive." How many failed $100M clinical trials could have been saved with better preclinical or early phase trials that could have detected the lack of efficacy sooner? And that's just the financial cost. What about the opportunity cost of continuing to hope for five additional years that a failed approach will work?

I'm hopeful that organoids will begin to help with this, but I think it would be well worth our time to invest more in human-in-a-dish or human-on-a-chip test benches. Mice are not small humans. There remain ethical constraints manipulating human embryos, but I wonder if iPSC is far enough along to build actual miniature organs having standard cell type and structure at a 1/10th scale. As long as we leave out the neocortex, it should avoid the biggest ethical concerns, and I could see this having a great deal of predictive value.

For some therapies, I think we could take advantage of organ donations that aren't suitable for transplantation. If you die at 95, it may not be worth it to place your organs in the body of someone in need of a replacement, but if you can show that a certain therapy produces engraftment of stem cells, boosts muscle fiber strength, clears lysosomal debris, promotes repair of a bone fracture, or eliminates senescent cells in an ex vivo organ setting, that might have much greater predictive value than showing it works in mice, without triggering some of the concerns of working with non-human primates.

I also think we need to revisit research animal protections. There are 93 million cows and 71 million pigs being raised for meat in the United States. They face a rather ignominious ending. However, I had to pay nearly $100,000 to test a biosensor in TWO pigs for a single year, mostly because of the astronomical regulatory burden of complying with government regulations. I could've raised and processed two hundred pigs for meat at that price! We could use a system that employs local animal IRBs that allow non-threatening animal research to take place in a lower regulation environment.

Would love to hear others' thoughts on improving models for longevity research!

Posted by: Robert at May 30th, 2021 8:20 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.