Perspectives on David Sinclair anti-aging Cell pub & in vivo reprogramming

About twenty years ago a science story made big news of a so-called anti-aging Methuselah gene.

methuselah mouse, anti-aging
Old Methuselah mouse character fan art.

Methuselah gene and anti-aging

The claim was that this DNA conferred long life on people. Hence the name Methuselah, which refers to a man from the Bible who reportedly lived 969 years.

The so-called Methuselah gene was at first not a specific gene. Just a big stretch of DNA. Later some claimed to have found the key gene within it. A gene related to insulin signaling, in one case.

As best as I can tell, now twenty years later nothing human-related has come of that buzz. The last paper with Methuselah gene in the title was published eight years ago and that was Drosophila work. I appreciate fly research but it’s not always directly tied to what’s going on in people.

Overall, you might say it was a stretch to claim this DNA, the supposed Methuselah gene, made a big difference for human aging.

More generally anti-aging research remains a super hot area.

Methuselah mice?

Now much of the emphasis is on making Methuselah mice. For instance, what if you could make a mouse that lived 50% percent longer than typical?

Cool, right? In fact, researchers already have been able to make mice that live significantly longer than usual.

But is that a major step on the road to significantly increasing the average human lifespan? Does it get us anywhere?

Incidentally, I didn’t even realize before I wrote this post that the anti-aging research group the Methuselah Foundation gives a Methuselah Mouse Prize or MPrize. Also, there’s a fictional character called Old Methuselah who is a mouse (see image above).

stem cells aging
A stem cell theory of aging. The purple “sand” represents the number of stem cells a person has as they age.

Mice vs. humans

An old friend of mine was fond of dinging mouse cardiovascular studies as often having low relevance to human heart disease. I wonder what she’d think of the new studies aiming to extend the lifespan of mice or even de-age already old mice. I bet she’d be skeptical of the relevance to reversing human aging.

Don’t get me wrong, mouse studies can have great relevance to human development and disease. I’ve been doing mouse genetics myself for more than twenty years. However, on the human anti-aging front, I’m not so sure the murine data live up to the buzz so far in some cases.

In today’s post I’m digging into this exciting area. Part of the reason it’s on my mind is the buzz about Bryan Johnson’s extreme anti-aging measuresHowever, recently there have also been high-profile research papers on aging in mice.

Methuselah gene therapy? Reprogramming with OSK

One type of push to extend lifespan in mice has been to use adaptations of pluripotency reprogramming. Basically it’s turning back the developmental clock on cells. If you do this just right in enough cells in an organism, maybe you can de-age the whole animal?

A relatively new preprint and a Cell paper, from two different teams, have revisited the idea of in vivo reprogramming. 

In both cases, they used a three-factor cocktail version of Yamanaka factors (Oct4, Sox2, and Klf4) or OSK to try to fight aging in mice. In the Cell paper by a team led by Harvard’s David Sinclair, they first artificially aged mice in fast forward using a novel method and then gave them a boost of OSK. It seemed to reverse elements of the induced aging.

This is cool and encouraging, but is the artificially induced aging reflective of natural aging?

Also, the main reprogramming idea isn’t new.  I first wrote about a mouse in vivo reprogramming paper about a decade ago in 2013.

Sinclair’s team also published an in vivo reprogramming paper in Nature in 2020.

Teratoma or other tumor surveillance?

One key thing that seems missing from some recent published studies is a thorough analysis of possible side effects of in vivo reprogramming.

Do you see teratomas or pre-teratoma-like masses? Pre-cancerous lesions? Small proliferative nests of immature cells?

Based on looking over the recent studies, I’m not sure they checked carefully.

For example, the Cell paper didn’t even use the word “teratoma” once. Not even in the Intro or Discussion, despite those tumors having been observed in previous in vivo reprogramming studies. The omission is very surprising, especially considering the media coverage of this paper talked extensively about possible applications of this tech in humans down the road. Sinclair did say in a Harvard Gazette interview that they haven’t seen safety concerns so far with the OSK protocol, but the interview wasn’t too specific.

The preprint from the other team did mention not seeing teratomas, which is good, but I wonder how rigorously they looked and if they looked for pre-cancerous lesions or early teratoma.

Note that one or more of the OSK cocktail are overexpressed in many human cancers even beyond teratomas. That’s a huge hurdle to any translation of this approach.

I  recommend the video above from Eleanor Sheekey that does a nice job of going over the Sinclair paper. One thing she mentioned, which also struck me, is that the Sinclair paper does not report actually extending mouse lifespan. That’s a surprising gap too just like the lack of mention of teratoma or precancerous lesions one way or another.

Hitting a bullseye with a canon ball?

Note that one of the other challenges with tackling aging with reprogramming is the possibility of overshooting. The original 4-factor approach of OSK plus Myc is more powerful at making iPS cells, but OSK alone can do that as well under specific conditions too.

The OSK approach is powerful. How do you make already functionally defined cells (cardiomyocytes, kidney cells, lung cells, brain cells, blood cells, etc.) just be younger and healthier without turning them into primitive stem cells?

For instance, if after OSK activation your brain suddenly becomes half full of neural stem cells instead of just younger versions of pre-existing neurons then things are going to turn very ugly health-wise. Same goes for other essential organs becoming mostly stem cells instead of functional cells.

Incredible precision is needed to just turn back the dial on cells’ ages the right amount, whatever that means. Teams have tried to address this with transient OSK expression but it’s very challenging.

Information-related aging isn’t the whole story

In the bigger picture, I like Sinclair’s idea of an information theory of aging. I especially like the novelty of the information theory as explaining an important component of aging. Note that I don’t think it explains the main cause of aging though.

As we age, the idea goes that our cells and tissues become phenotypically older primarily because of “software” and data problems, in part related to DNA repair mechanisms. Our epigenetic storage, retrieval, and use of cellular information get increasingly goofed up. Witness how cellular reprogramming, with its basis in epigenetic rebooting, can turn an ordinary cell like a fibroblast into a “new” iPS cell. It’s an epigenetically and functionally young cell but without genetic changes being needed.

Combo theory: epigenetics, genetics, & stem cells

Epigenetic “information” dysfunction seems likely to be an important contributing factor to aging. However, I believe aging is due to a combination of both software and hardware problems. As to the latter, think of mutations, accumulations of toxic, misfolded proteins and other substances, etc. These changes are at least as important or more so than information problems.

Also, what I and others have called the stem cell theory of aging is likely at work. In the stem cell theory of aging, a major contributing factor to human aging is running low or out of stem cells. The depletion of stem cells could be downstream of the events invoked in the information theory or downstream of mutation elements. Some stem cells with aberrant information systems plus or minus certain mutations probably die, depleting their overall pool.

It’s never going to be just one thing or theory. For that reason, I’d favor a combo theory, but maybe combinations aren’t as fascinating as arguing for just one cause?

Young blood for anti-aging?

There are other research approaches to anti-aging as well. Some of you are likely familiar with another push in this space: the “young blood” work or parabiosis.

It turns out that if you stitch a young and an old mouse together so they share a circulatory system, the older mice start to seem younger. And vice versa for the young mice. This apparently is a fairly consistent phenomenon in mice.

It’s unclear if there’s any relevance to people though. Even so, there has been so much hype about it that a firm called Ambrosia started selling (well offering to enroll you in a maybe kinda sorta “clinical trial” for $8,000) experimental young blood transfusions. The FDA wasn’t so happy.

The core hope seems to be to find a powerful “youthifying” substance in young blood that could be used as a drug in people. It hasn’t made major progress that I’ve seen. There have even been some big missteps and hype along the way.

Of course, there are many other important areas of anti-aging research as well.

The future of anti-aging research

More broadly, looking ahead we need to keep somewhat sober in this space. It’s too early to be talking about curing many serious and complex aging-related diseases like Alzheimer’s with reprogramming.

So after all this discussion in today’s post, again if groups can make Methuselah mice, does that mean anything for people? Will there be a Methuselah gene therapy to safely and effectively counteract human aging?

The short answer is that nobody knows for sure so far.

What’s needed here are good data that are more relevant to people, but that’s much harder to get than studying mice. Sinclair has moved into non-human primate studies. In the same interview mentioned earlier, he took an appropriately cautious tone I thought:

“GAZETTE: What is the next step? You’ve begun experiments in nonhuman primates. How far is this from the clinic?

SINCLAIR: Things look promising in the primate studies. If those are successful, then the first humans will be treated just a couple of years after the studies have finished. Does that mean it’ll work? No. But if it works to cure blindness in a monkey, I am optimistic it’ll work in a patient. And if we’re not successful in the next few years, somebody will be, because there has been about $5 billion invested in aging drug development just since our Nature paper came out in 2020. There are many companies now working on this. So, while we’re at the forefront, there are many others who should succeed if we’re not successful first.”

I agree with the general optimism that someone is likely to make a dent in human aging in long run. If reprogramming is a key area then it will likely have to be achieved via drug cocktails that target key elements of OSK-related pathways rather than genetically.

Unfortunately, this kind of research takes decades. At age 55, I’m also not getting any younger. So far.

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