Reprogramming Alone is Not Sufficient

Epigenetic reprogramming is a process of exposing cells to the Yamanaka factors for a long enough period of time to shift their epigenome towards that found in youthful tissues, but not for so long as to cause any meaningful number of them to change state into pluripotent stem cells. It is an attempt to reproduce aspects of the cellular rejuvenation that occurs in the initial stages of embryogenesis, without harming the functional specialization of the cells so altered. It works surprisingly well in animal studies, considering all of the very reasonable a priori objections as to why we should believe that such an embryonic process would be harmful and cancerous (at the very least) in the very different, structured environment of adult, aging somatic tissue.

There is a school of thought-slash-marketing-to-investors regarding mechanisms of aging that suggests epigenetic reprogramming of cells in vivo will be sufficient to produce comprehensive rejuvenation, addressing near all issues. That reprogramming the epigenetic landscape to a youthful configuration will provoke tissues into repair and clearance of enough of the damage of aging that further therapies would be superfluous. This really doesn't appear to be the case, however.

Based on the animal studies to date, reprogramming will produce significant benefits, just like, say, clearance of senescent cells, but it won't be the whole of the picture. There are forms of damage that a young body cannot repair. Many forms of persistent molecular waste, such as components of lipofuscin or some advanced glycation endproducts, cannot be broken down effectively by our cells. Nuclear DNA damage won't be repaired once present. Localized excesses of cholesterol, such as that found in atherosclerotic lesions, would overwhelm the macrophages responsible for clearing this damage even in a young person. And so on and so forth.

SENSible Question: Wouldn't Cellular Reprogramming Be Enough?

Cellular reprogramming turns an old person's cells young again. So can't we fix aging by just reprogramming a person's old cells with reprogramming factors? This is a tantalizing idea that's on a lot of our supporters' minds these days. On the one hand, it's certainly true that we lose cells with aging and that other cells become dysfunctional. And on the other hand, the cellular reprogramming experiments have in some senses rejuvenated cells in a way that can and should spark excitement - first and foremost, because the technology will greatly enable cell therapy of various kinds, which will be critical to the medical defeat of aging. But the quite rational enthusiasm for a specific technology can sometimes spark a kind of irrational biomedical exuberance so great that even some very prominent geroscientists seem to have begun to fall into a kind of fallacy of composition: the body is made up of cells; therefore, if we rejuvenate all our cells, we will rejuvenate our entire bodies.

People making this intuitive leap are in for an inelegant crash. We simply are not composed entirely of cells, and replacing lost cells and restoring the original differentiation of cells with epigenetic changes won't do anything to remove or repair aging damage to the many other functional units that are lost or damaged as we age and that contribute to diseases and disabilities of aging.

For one thing, there's aging damage to the extracellular matrix (ECM). The ECM is the lattice of proteins that provide both physical structure and signaling cues for our cells and tissues, and that also have important roles of their own in the body's movement and plumbing. In addition to damage to the ECM, another critical kind of aging damage that would impair the youthful function even of pristine reprogrammed cells is the various extracellular aggregates ("amyloids") that accumulate outside cells. These are damaged proteins that either physically impede cells' ability to carry out their function, or cause cellular dysfunction in other ways.

We've been thinking about using reprogramming technology either to create replacement cells for those that have been lost to aging processes, or to reprogram cells already in the tissues in order to (as advocates would have it) rejuvenate their function. These applications could in principle deal with cells that are either missing entirely, or that are still present but behaving badly due to reversible changes in their epigenetics - but they can't do anything about cells that survive, but have suffered certain other kinds of aging damage.

For instance, cells overtaken by mitochondria with large deletion mutations (which are the most problematic kind of mitochondrial damage in aging) almost certainly can't be restored to normal functioning through reprogramming. In all probability, the presence of mitochondrial mutations and other aging damage (such as intracellular aggregates, the abnormal splice protein lamin A, and some mutations and epimutations) is one of the main reasons why only a tiny fraction of cells exposed to reprogramming factors ever actually get reprogrammed. And in addition to not repairing all aging damage, reprogramming itself causes other kinds of damage to some cells that make them useless for rejuvenation biotechnology, such as the newly-created mitochondrial DNA mutations, or abnormal numbers of chromosomes, or the paradoxical mixed bag of reprogramming-induced senescence (RIS).

And there are even narrowly cellular forms of aging damage that you can't or wouldn't want to "repair" using reprogramming. Yes, you can reverse cellular senescence by reprogramming, and with a few additional tricks you can even reverse reprogramming-induced senescence, but is that a good idea? Remember, the cellular senescence machinery is a kind of emergency brake, which the cell pulls when it is in danger of careening out of control, such as by progressing to become a cancer or by laying down excessive collagen after an injury, leading to fibrosis.

Comments

Let's face it, 20 years of the SENS (damage repair) approach didn't produce any noteworthy results. On the other hand, the reprogramming technology is relatively new and already produced amazing results in mice (Belmonte, for instance) which proves that cellular reprogramming results in systemic rejuvenation. And even it if turns out that some age-related systemic and cellular changes (I wouldn't call this damage) cannot be fixed with cellular reprogramming, we can then try to find ways to solve these few remaining issues.

The fact that currently almost all research money goes to cellular reprogramming and cellular senescence (which is about the same topic because senescent cells essentially reprogram the age of nearby cells) shows that the majority of leading scientists believe in reprogramming. Just count the number of Nobel laureates who work for Altos Labs.

Instead of sulking, SENS should concde that their approach failed and that it is time to try something fundamentally new. It is no shame to admit that a theory has been falsified by new data. However, it is a shame if scientists kling to the old theory desperately trying to defend their lifetime work (just as Thomas Kuhn predicted).

Posted by: Michael at November 19th, 2022 6:01 AM

We're planning to have a daughter with embryo selection and we want to chose a girl because they live longer but also want it to have genes for longevity. Someone here can compile a list of genes or knows whiwch labs I can get the service.

Posted by: peggy at November 19th, 2022 8:21 AM

also seems plausible that "overwhelmed by garbage" sorts of disease like arteriosclerosis is caused / enhanced by misread genes? As a 49 year old, I can tell you there definitely seems to be a point when the pace of aging quickens noticeably. Maybe this is when the epigenome starts to wear out.

Posted by: matt at November 19th, 2022 9:15 AM

@Michael: SENS may be taking too long for some of us, but if its approach is correct, then I expect that it should be continued even in light of cellular reprogramming. These other things that cellular reprogramming can't fix may well fall under SENS, so, let's just keep everything in our toolbox here and remember that all of it may be useful on the way to our goal.

@Peggy: Sorry, I have no idea about specific genes, although my understanding is that this is still being sorted out. Pre-genetic testing is a great idea though, so good on you for looking into it.

Posted by: Sadi K. at November 19th, 2022 5:49 PM

I fully support this article. Moreover, i personally work on improving elasticity of the extracellular matrix, removing various junk from the ECM and from inside the cells (lipofuscin), and last but not least on mitogenesis and mitophagy. Reprogramming cells sounds very scientific and attracts a lot of money for the research but how is it different from the stem cells thechnology? Moreover, our body can itself reprogram cells to become senescent cells or stem cells. All depends on environment, stresses, and various signals from blood and lymph. SASP is just one example, and rejuvenation by young blood transfusion is another. However, it looks boring, and not supported enough. Instead, people try to find a magic tool to extend their lives. So, it is good to see a very reasonable article on the FightAging website.
BTW, i am getting quite good results myself while following this strategy. A problem, sometimes it take very long to see improvements. Also, i cannot talk yet about lifespan extension. It will take a hundred years to prove.

Posted by: Oleg at November 19th, 2022 10:55 PM

@matt I strongly disagree! Once a theory has ben falsified and a new theory is available that fits much better to the data it is just a waste of time and resources to try to save the old, dying theory. This reminds me of the great Albert Einstein who wasted most of his career in trying to refute quantum theory. Hard to imagine what this genius could have accomplished if he simply accepted the overwhelming evidence for the new theory.

The comparison lags a bit because in geoscience the most brilliant minds are already on the right track. This is probably due to the fact that only until recently serious research in geoscience has begun. Thus, many of those scientists working on aging now, don't have to defend their previous publications and can just start fresh with the new theory.

Posted by: Michael at November 19th, 2022 11:16 PM

Like Oleg above, I am starting to follow the Rejuvenation Strategy. However, I do not expect such rejuvenation to work on turning might white hair back to my natural brown because all of the pigment cells have long since died. Also, for those who are bald will likely not be able to rejuvenate hair when all of their hair cells no longer exist.

Posted by: Brian at November 20th, 2022 7:56 PM

Forgive me, Michael, but when you say SENS has been falsified, what on earth are you talking about?

Posted by: Ben at November 22nd, 2022 1:53 AM
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