Cell biologists are within striking distance of “partial reprogramming”.  Already, technology has arrived to turn an old cell into a young cell in a Petri dish, and researchers (Turn.bio) are looking intensely for ways to safely rejuvenate cells within a living body. Is this the breakthrough that we in the human rejuvenation movement have been waiting for, or is it a sideshow? 

Partial Reprogramming

In nature, aging is part of a one-way street.  A germ cell becomes a stem cell becomes a differentiated cell, and then the differentiated cell grows old.   

In the course of nature, cells change their epigenetic state from left to right.  Nature must have a mechanism for resetting the cellular aging clock, going all the way back to the left. If this didn’t exist, then all cells would be on a one-way path to extinction.  At some point in the life cycle, nature needs to take a mature cell and turn it into a germ cell (sperm or egg). But, in the process, epigenetic programming is wiped clean. Two things happen simultaneously: memory of the cell’s functional differentiation is lost, so it becomes again a pluripotent stem cell; and the age of the cell is reset to zero.  

It never happens in nature that the cell’s epigenetic age is reset to zero, without also erasing the cell’s functional identity.  Nature has no need for this process. But for cellular rejuvenation, this is what we would like to be able to do. If all the cells in your bones became young again, you might lose the calcification and brittleness of old bones and regain the springy resilience of a 10-year-old.  But if all the cells in your bones became stem cells, your bones would lose their structural integrity and your body would collapse like a mass of jelly.

In theory, we might learn enough about hundreds of epigenetic changes that take place with age, and use CRISPR or analogous process to reset each one of them individually.  This would be cellular rejuvenation “by hand”. If we are really, really lucky, then this Herculean biochemical task might be avoided by some accidental pathway by which the cell resets these hundreds of epigenetic markers on command.  But we have no reason to expect that a mechanism exists to do this, because in the normal course of a life cycle, nature has no need for it.

Thirteen years ago, Yamanaka [2006] found that differentiated cells (specifically skin cells) could be induced to revert to stem cells by exposing them to just 4 proteins, which have come to be known by their initials as OSKM, the Yamanaka Factors.  This was akin to what nature does, resetting the cellular age and erasing the cell’s function.  Then, three years ago, a study from Juan Carlos Belmonte at the Salk Institute gave us hope that de-aging a cell might be possible without loss of its identity.  They used the same OSKM, but exposed the cells for just a few days, then turned off the exposure. They reported that the cells were made younger without erasing their function. Mice with the rejuvenated cells lived longer.  This was a proof of principle, but there were big caveats. First, they worked with progeria mice, genetically programmed to age unnaturally fast. Second, the mice were genetically prepared with OSKM grafted into their DNA, and pre-coded with a chemical switch so that OSKM could be turned on and off at will by injecting the mice with doxycycline.  For mice that are not genetically modified before birth (or for normal people), delivery of OSKM to individual cells and timing that delivery poses a substantial challenge.

Then, in a preprint posted to BioRxiv just this spring, Vittorio Sebastiano and his Stanford group took another step forward.  They added two more ingredients to the Yamanaka recipe (OSKMLN) and succeeded in rejuvenating human fibroblasts in cell culture, as reported by the methylation age of the cells.  This experiment had neither of the two limitations of the Belmonte group, and it was human cells rather than mouse — three steps forward.  But it was done in vitro only — one big step backward.

Turn.bio is a biotech startup that is seeking to develop and capitalize on the technology.  Steve Hill of the Life Extension Advocacy Foundation (LEAF) interviewed Sebastiano about his discovery and the path forward.  Hill provides more background in this article.  Over at FightAging!, Reason reviewed the subject.

Is epigenetic reprogramming a driver of aging, or a response to cellular damage?

Hill asked Sebastiano this question, and he hedged in his response:

My personal opinion is that I can’t really decide whether the epigenetic changes are the cause or the consequence. I cannot decide what theory is right in the sense that some people suggest it’s a developmental program of aging and some people say it’s a consequence of damage accumulating. What I really care about, at the end of the day, is that, regardless, epigenetic changes explain aging. The epigenetic changes are what, at the nuclear level, triggers this dysfunctionality of the cell. 

— Vittorio Sebastiano

The logic in this answer is incoherent.  I suspect that Sebastiano is not confused, but he knows what he has to say to keep his funding flowing, and to keep from being distracted by philosophical arguments.  There is a prejudice in the field that he has chosen to skirt, rather than confront it head-on. Look at his last sentence, “The epigenetic changes are what, at the nuclear level, triggers this dysfunctionality of the cell.”  He recognizes that altering the epigenetic program is going to make the cell younger, but he avoids saying that the body has arranged the epigenetics to make the cell older.

Aging as an epigenetic program

The core truth here is that alteration of gene expression is the way the body functions.  Gene expression is different from cell to cell, from tissue to tissue. The way the body changes its strategies from minute to minute and also from decade to decade–also gene expression. Epigenetics = gene expression is the heart of the way the body’s metabolism and the core of the developmental program by which we grow arms and legs and bones and muscles.  It is also the core of the aging program, but you can run afoul of funders, decision-makers, journal editors and other gatekeepers if you say so. Better not to say so.

We know the cells of nearly every tissue are epigenetically reprogrammed as we get older.  Is the purpose of this reprogramming to resist the damage, which is the primary cause of aging? (standard theory)  Or are the epigenetic changes implemented as a self-destructive program for the express purpose of weakening and then killing the body? (programmed aging theory, to which I subscribe)   

This is no abstract question for theorists–it has fundamental implications for practical anti-aging research.  If the epigenetic changes are there to resist aging as best the body knows how, then we shouldn’t be tampering with them. But if the epigenetic changes exist only to create damage and stymie the cell’s repair mechanisms, then restoring the epigenetic program of the cell to a younger state looks like a promising anti-aging strategy.

Reason on Cancer

The response at FightAging! to Sebastiano’s experiments with cellular rejuvenation starts with a presumption that this kind of intervention must raise the risk of cancer.  Where does this presumption come from? His thinking is based on general principles of evolutionary theory. Theory says that the body is trying to live as long as possible, and if the body has made the decision to permit cells to senesce, it must be from a self-interested calculation that it is better to allow certain but slow death in the guise of cellular senescence than it is to risk the possibility of near-term death from cancer.

I believe the evolutionary theory is wrong, and if so, there is no a priori reason to think that cellular rejuvenation will increase cancer risk.  In fact, we might hope that cancer risk decreases, as the body’s immune system is restored to a younger state and systemic inflammation is quelled.  (Of course, we will still want to experiment with animals and then humans to assure ourselves that the treatment does not increase cancer risk.) 

I have staked my professional career on the theory that aging is programmed self-destruction, that the body is not trying to live as long as possible, but rather is aiming for a predictable lifespan, and if we thwart that program, we won’t have hell to pay.*  

 

Clear logic of programmed aging

Aging is an epigenetic program, honed by natural selection for the sake of the community over the individual.  The one-line proof is that genes regulating aging have been preserved in the genome since we were descended from single-celled ancestors 1 billion years ago.  A longer version is in this blog five years ago, and the 300-page version is in my book.

Once you accept that aging is programmed, it follows that aging must be coordinated system-wide.  We can look for one or several clock mechanisms, and for signals that transmit the age-state of the body through (almost certainly) the blood plasma.  The quickest path to rejuvenation technology is not “repair of damage” — a daunting challenge of bioengineering — but only a modification of the signaling environment, or, perhaps, direct manipulation of the body’s aging clocks.

Cellular Rejuvenation: The Path Ahead

When the treatment matures, what will be our strategy for the body as a whole?  Is there a central clock (perhaps in the hypothalamus, a neuroendocrine region of the brain) where the treatment must be targeted, after which the rejuvenation signal will be transmitted to the body without further intervention?  Or would we have to reprogram every cell in the body?  

What about inflammation?  Presumably, systemic inflammation is controlled by signal molecules that will revert to youthful levels after reprogramming.

What about arterial plaques?  Will they be cleared up by a rejuvenated metabolism?  Same question for beta amyloid in the brain?

What about oxidative damage?  Would the body know how to pick up the ball that it dropped when we were much younger?  What about cross-linking? Accumulation of lipfuscin?

At times like these, I’m shaken awake to realize how little I really know about the aging metabolism, and the signal transduction that drives it.

————-

 

Perspective

For me, this is a case where the technology has gotten ahead of the science.  

The big picture is that from the 1950s, evolutionary biologists have handed the medical researcher a mistaken framework.  Medical researchers have done their best to ignore the theory and forge ahead with a practical program that addresses the changes that are observed to take place with aging.  This agnosticism is a lot better than sticking dogmatically to a flawed theory.

But we could do so much better — we will do so much better — when we embrace the correct theory.  A clear theoretical framework will be extremely helpful in guiding lab experiments toward the most important questions.

Here’s what I mean, specifically:  Evolutionary theory offers the clear message: the body cannot have organized programs of self-destruction.  This implies that aging is a disorganized process. It must be damage. It must be random and it must be local.  It makes sense to learn about the cellular biology of aging, and develop ways to heal the aging cell. Aging will be remediated from the bottom up.

But the theory is wrong.  In fact, aging is coordinated systemically. It is a top-down process, directed by signal molecule in the blood.  The most efficient way to remediate aging is to study the signaling mechanism, to understand it well enough that we can alter the signaling environment, telling the body that it is young.  We don’t have to repair damage in every damn cell in the body. All we have to do is to re-adjust the levels of hormones and transcription factors that circulate in the blood to youthful levels.

Once we think this way, it is obvious where the focus of our research ought to be.  

  • We need to understand how the system is coordinated.  It is not yet known whether the clock that controls aging is in a specific location, probably the hypothalamus deep in the center of the brain, or whether the clock operates as a consensus among many distributed sites (e.g., telomere lengths and methylation states in many tissues).  In this latter picture, the transcription factors that circulate in the blood and dictate epigenetic state are generated throughout the body, contributed by every cell in every tissue.
  • Even more important, we need to catalog the thousands of signal molecules in the blood, proportions of which change with age.  It is likely that some of these are more important than others, and if these few are reset to youthful proportions, the rest will follow.  How many? Is there a manageable list of signal molecules that can be re-balanced in the bloodstream, and it will reprogram all the rest? Or must we manipulate hundreds of separate hormone levels in order to turn back the aging clock?  The answer is yet unknown. A related question: How long must the blood levels of these compounds be artificially maintained before the body is reprogrammed to a youthful state, and the intervention is no longer necessary? We might imagine people lined up for a once-every-decade trip to the rejuvenation clinic with an IV drip for two days.  But if the treatment has to be sustained for months at a time, it will be prohibitively expensive, uncomfortable, and disruptive.  

Here’s an example that comes from this kind of thinking — an experiment we might start with: Take a sample of blood plasma from an artery going into the brain of a young mouse (or human), and catalog the proteins and RNAs.  Do the same with the blood plasma emerging from the brain. “Subtract” the two profiles with a computer comparison to see which elements are changed.  Any significant differences might tentatively be imputed to the hypothetical hypothalamic clock. Repeat the two measurements and the differencing with an old mouse.  The difference of the differences is a good first guess as to what molecules in the blood control aging.

Back to Cellular Rejuvenation and Partial Reprogramming

Cellular rejuvenation may turn out to be a crucial technology for us to master, or it may be something we don’t have to understand in detail, because the body does this by itself once we rebalance the signal molecules in the blood.  Or — a third possibility — it may be that cellular rejuvenation in the hypothalamus is sufficient to reset the body’s global aging clock.  We could be addressing these questions experimentally.