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.