{"id":861,"date":"2019-07-30T12:53:29","date_gmt":"2019-07-30T12:53:29","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=861"},"modified":"2019-08-01T02:50:32","modified_gmt":"2019-08-01T02:50:32","slug":"rejuvenation-at-the-cell-level","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2019\/07\/30\/rejuvenation-at-the-cell-level\/","title":{"rendered":"Rejuvenation at the Cell Level"},"content":{"rendered":"

Cell biologists are within striking distance of \u201cpartial reprogramming\u201d.\u00a0 Already, technology has arrived to turn an old cell into a young cell in a Petri dish, and researchers (<\/span><\/em>Turn.bio<\/a><\/span>) 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?\u00a0<\/span><\/em><\/p>\n

Partial Reprogramming<\/strong><\/p>\n

In nature, aging is part of a one-way street.\u00a0 A germ cell becomes a stem cell becomes a differentiated cell, and then the differentiated cell grows old.\u00a0\u00a0\u00a0<\/span><\/p>\n

\"\"In the course of nature, cells change their epigenetic state from left to right.\u00a0 Nature must have a mechanism for resetting the cellular aging clock, going all the way back to the left. If this didn\u2019t exist, then all cells would be on a one-way path to extinction.\u00a0 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\u2019s functional differentiation is lost, so it becomes again a pluripotent stem cell; and the age of the cell is reset to zero.\u00a0\u00a0<\/span><\/p>\n

It never happens in nature that the cell\u2019s epigenetic age is reset to zero, without also erasing the cell\u2019s functional identity.\u00a0 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.\u00a0 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.<\/span><\/p>\n

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.\u00a0 This would be cellular rejuvenation \u201cby hand\u201d. 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.\u00a0 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.<\/span><\/p>\n

Thirteen years ago, Yamanaka [<\/span>2006<\/span><\/a>] 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 <\/span>Yamanaka Factors<\/span><\/a>.\u00a0 This was akin to what nature does, resetting the cellular age and erasing the cell\u2019s function.\u00a0 Then, three years ago, a <\/span>study<\/span><\/a> from Juan Carlos Belmonte at the Salk Institute gave us hope that de-aging a cell might be possible without loss of its identity.\u00a0 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.\u00a0 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.\u00a0 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.<\/span><\/p>\n

Then, in a <\/span>preprint<\/span><\/a> posted to BioRxiv just this spring, Vittorio Sebastiano and his Stanford group took another step forward.\u00a0 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.\u00a0 This experiment had neither of the two limitations of the Belmonte group, and it was human cells rather than mouse — three steps forward.\u00a0 But it was done in vitro<\/em> only — one big step backward.
\n<\/span><\/p>\n

Turn.bio<\/span><\/a> is a biotech startup that is seeking to develop and capitalize on the technology.\u00a0 Steve Hill of the Life Extension Advocacy Foundation (LEAF) <\/span>interviewed Sebastiano<\/span><\/a> about his discovery and the path forward.\u00a0 Hill provides more background in <\/span>this article<\/span><\/a>.\u00a0 Over at <\/span>FightAging!<\/span><\/a>, Reason reviewed the subject.<\/span><\/p>\n

Is epigenetic reprogramming a driver of aging, or a response to cellular damage?<\/strong><\/p>\n

Hill asked Sebastiano this question, and he hedged in his response:<\/span><\/p>\n

My personal opinion is that I can\u2019t 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\u2019s a developmental program of aging and some people say it\u2019s 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.\u00a0<\/span><\/p>\n

— Vittorio Sebastiano<\/span><\/p><\/blockquote>\n

The logic in this answer is incoherent.\u00a0 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.\u00a0 There is a prejudice in the field that he has chosen to skirt, rather than confront it head-on. Look at his last sentence, \u201cThe epigenetic changes are what, at the nuclear level, triggers this dysfunctionality of the cell.<\/em>\u201d\u00a0 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.<\/span><\/p>\n

Aging as an epigenetic program<\/strong><\/p>\n

The core truth here is that alteration of gene expression is the way the body functions.\u00a0 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\u2019s metabolism and the core of the developmental program by which we grow arms and legs and bones and muscles.\u00a0 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.<\/span><\/p>\n

We know the cells of nearly every tissue are epigenetically reprogrammed as we get older.\u00a0 Is the purpose of this reprogramming to resist the damage, which is the primary cause of aging? (standard theory)\u00a0 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)\u00a0\u00a0\u00a0<\/span><\/p>\n

This is no abstract question for theorists–it has fundamental implications for practical anti-aging research.\u00a0 If the epigenetic changes are there to resist aging as best the body knows how, then we shouldn\u2019t be tampering with them. But if the epigenetic changes exist only to <\/span>create<\/i><\/b> damage and stymie the cell\u2019s repair mechanisms, then restoring the epigenetic program of the cell to a younger state looks like a promising anti-aging strategy.<\/span><\/p>\n

Reason on Cancer<\/strong><\/p>\n

The response at <\/span>FightAging!<\/span><\/a> to Sebastiano\u2019s experiments with cellular rejuvenation starts with a presumption that this kind of intervention must raise the risk of cancer.\u00a0 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.<\/span><\/p>\n

I believe the evolutionary theory is wrong, and if so, there is no <\/span>a priori <\/span><\/i>reason to think that cellular rejuvenation will increase cancer risk.\u00a0 In fact, we might hope that cancer risk decreases, as the body\u2019s immune system is restored to a younger state and systemic inflammation is quelled.\u00a0 (Of course, we will still want to experiment with animals and then humans to assure ourselves that the treatment does not increase cancer risk.)\u00a0<\/span><\/p>\n

I have staked my professional career on the theory that aging is programmed self-destruction, that <\/span>the body is not trying to live as long as possible<\/i><\/b>, but rather is aiming for a predictable lifespan, and if we thwart that program, we won\u2019t have hell to pay.*\u00a0\u00a0<\/span><\/p>\n

 <\/p>\n

Clear logic of programmed aging<\/strong><\/p>\n

Aging is an epigenetic program, honed by natural selection for the sake of the community over the individual.\u00a0 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.\u00a0 A longer version is in this blog<\/a> five years ago, and the 300-page version is in <\/span>my book<\/span><\/a>.<\/span><\/p>\n

Once you accept that aging is programmed, it follows that aging must be coordinated system-wide.\u00a0 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.\u00a0 The quickest path to rejuvenation technology is not \u201crepair of damage\u201d — a daunting challenge of bioengineering — but only a modification of the signaling environment, or, perhaps, direct manipulation of the body\u2019s aging clocks.<\/span><\/p>\n

Cellular Rejuvenation: The Path Ahead<\/strong><\/p>\n

When the treatment matures, what will be our strategy for the body as a whole?\u00a0 Is there a central clock (perhaps <\/span>in the hypothalamus<\/span><\/a>, 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?\u00a0 Or would we have to reprogram every cell in the body?\u00a0\u00a0<\/span><\/p>\n

What about inflammation?\u00a0 Presumably, systemic inflammation is controlled by signal molecules that will revert to youthful levels after reprogramming.<\/span><\/p>\n

What about arterial plaques?\u00a0 Will they be cleared up by a rejuvenated metabolism?\u00a0 Same question for beta amyloid in the brain?<\/span><\/p>\n

What about oxidative damage?\u00a0 Would the body know how to pick up the ball that it dropped when we were much younger?\u00a0 What about cross-linking? Accumulation of <\/span>lipfuscin<\/span><\/a>?<\/span><\/p>\n

At times like these, I\u2019m shaken awake to realize how little I really know about the aging metabolism, and the signal transduction that drives it.<\/span><\/p>\n

————-<\/b><\/p>\n

 <\/p>\n

Perspective<\/strong><\/p>\n

For me, this is a case where the technology has gotten ahead of the science.\u00a0\u00a0<\/span><\/p>\n

The big picture is that from the 1950s, evolutionary biologists have handed the medical researcher a mistaken framework.\u00a0 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.\u00a0 This agnosticism is a lot better than sticking dogmatically to a flawed theory.<\/span><\/p>\n

But we could do so much better — we <\/span>will<\/i><\/b> do so much better — when we embrace the correct theory.\u00a0 A clear theoretical framework will be extremely helpful in guiding lab experiments toward the most important questions.<\/span><\/p>\n

Here\u2019s what I mean, specifically:\u00a0 Evolutionary theory offers the clear message: the body cannot have organized programs of self-destruction.\u00a0 This implies that aging is a disorganized process. It must be damage. It must be random and it must be local.\u00a0 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.<\/span><\/p>\n

But the theory is wrong.\u00a0 In fact, aging is coordinated systemically. It is a top-down process, directed by signal molecule in the blood.\u00a0 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.\u00a0 We don\u2019t 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.<\/span><\/p>\n

Once we think this way, it is obvious where the focus of our research ought to be.\u00a0\u00a0<\/span><\/p>\n