A Popular Science View of the Road to Partial Reprogramming Therapies

Reprogramming via expression of the Yamanaka factors slowly transforms somatic cells from tissues of any age into induced pluripotent stem cells that are essentially identical to embryonic stem cells. Along the way, aged epigenetic patterns are reset to a youthful configuration, and age-related decline of mitochondrial function is reversed. This approach recapitulates the cellular rejuvenation that takes place in early embryonic development.

Interestingly, temporarily exposing old animals to Yamanaka factors produces improved health and far less cancer than one might expect. It appears that it may be possible to build therapies for aging based on partial reprogramming, meaning exposing cells to expression of the reprogramming factors for long enough to obtain epigenetic rejuvenation, but not so long as to create pluripotent cells that can go on to generate cancer. The animal data is promising, but it may still turn out to be challenging to establish that point of balance sufficiently well to convince regulators to approve treatments.

An aging research initiative called Altos Labs recently launched with $3 billion in initial financing from backers. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research into epigenetic reprogramming. In December, NewLimit was founded, an aging-focused biotech backed by an initial $105 million investment.

The discovery of the 'Yamanaka factors' - four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state - transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cells (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research.

So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle, and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. These results have spurred interest in translating insights from animal models into anti-aging interventions.

Even though Life Biosciences and several other startups are investigating Yamanaka factors with a view to reversing human aging, the biology of rejuvenation by reprogramming remains enigmatic and opaque, at best. "These first papers make some astonishing observations. But much more research is needed to dig into the molecular and mechanistic processes that are occurring." Given that fully reprogrammed iPSCs readily form tumors known as teratomas, scientists must determine whether the cellular clock can be wound back safely in humans - which means the race to the clinic will likely be a marathon rather than a sprint.

Link: https://www.nature.com/articles/d41587-022-00002-4


When there is an error in a DNA repair gene & subsequent copies receive that error, then how can epigenetic reprogramming fix that?

Is aging due more to epigenetic or to genetic errors?

Posted by: Matt at January 31st, 2022 7:54 AM


Great question - and the short answer is....it can't

And this is the major gap in the whole "rejuvenation by Yamanaka reprogramming" story - there is a significant amount of difference between "cellular reprogramming" and "whole organism reprogramming"

As some background, Dr. Yamanaka did NOT discover rejuvenation factors - he discovered "lineage gateway factors" - Big difference - During development, when locked down, cells are guided down select lineage pathways to help guide proper morphogenesis - Unlocking them, per de-differentiation experiments, allows terminally differentiated cells to re-explore lineage possibilities - and occasionally (<0.01% of the time in the petri dish) one of those paths is de-differentiation leading to a "pseudo-rejuvenated cell"

Yamanka's discovery links back decades to the original 1952 cloning experiments by Robert Briggs and Thomas J. King, modified by John Gurdon (the "other" Nobel winner with Yamanaka in 2012), Beatrice Mintz, Rudolph Jaenisch, and many others etc. into the current day

Organism rejuvenation via reprogramming, is NOT the same thing - it is a much more complex set of events, but which can be summed up as such:

Organisms (such as amphibians, planarians, echinoderms, hydrozoans, etc.) that have the ability to "turn back biological time", to regenerate / repair / rejuvenate most (or all) of their bodies, possess two inherent capabilities that they use in synergy:

1) The ability to re-establish the "embryogenic" potential of their cells / genomes / gene regulatory networks (per inherent cellular reprogramming dynamics - like above),

AND, of equal (if not greater), importance,

2) ...the ability to re-establish the "morphodynamic" architecture of their tissues / organs / limbs / body segments

The latter involves many other things beyond just cellular reprogramming including: ECM histolysis and remodeling, activation of components of the innate immune response, supression of components of the adaptive immune response, membrane potential changes, morphogenetic gradient formation, and a long additional list of other stuff that I won't take up space with here

But the point is, it is in the context of the regenerative micro-environments that RESULT from this reprogrammed cellular flexibility that the really neat stuff happens in nature - not just the complex regeneration and remodeling in these "lower" non-human species, but also in mammalian embryos - this is why you can "dump" all sorts of "junk" into a mammalian embryos (normal somatic tissues, cancer cells, viruses, etc.) and it all gets "organized out"

Below are some links to nice reviews on the general theme of regenerative micro-environments and their ability to "organize in / out" stuff they don't need, and well as modify the diseased phenotype. As a subset of this re-organization theme, here are also papers on the topics of revertant mosaicism (primarily seen in tissues with an active regenerative niche) and cellular competition (seen in both development and the maintenance of tissue fitness)





The seminal work on embryos and teratocarcinoma was done by Mintz et al in Philadelphia in the 1970s:


Similar dynamics also occur in the plant kingdom:


But the major point is that for whole organism human rejuvenation using such tools, especially for complex tissues and organs, we will need to go well beyond just "pulsing" some Yamanaka factors and walking away - that is far from how the process works in nature

Now people will then say, well what about David Sinclair's amazing optic nerve regeneration study from last year?

In Dr. Sinclair's very controlled acute optic nerve damage model, he is essence "loosening up" the potential lineage flexibility to allow new neurogenesis to occur, versus say scar tissue formation.

This is potentially useful for stimulating some certain targeted regeneration events in-vivo - but must be balanced with appropriate re-differentiation signaling to avoid establishing inappropriate lineages, or uncontrolled proliferation

But this is far from a technology which on it's own can make your body younger

The optic nerve is very unique tissue micro-environment, especially this animal model

But in say an aged, chronically damaged human heart, made up of cardiomyocytes, fibroblasts, endothelial cells, peri-vascular cells, pacemaker cells, etc. etc., things are quite more complicated and unlocking cells to explore the wealth of lineage "state space" with a blast of Yamanaka factors on their own, is potentially a recipe for disaster

But there is tremendous potential with these tools if used correctly in the right "bio-dynamic" context....

Posted by: Ira S. Pastor at January 31st, 2022 11:14 AM

"The primary challenge in bringing this class of therapy to the clinic will be the long-term safety questions, how to assess (and then minimize) the risk of cancer via unwanted pluripotency of cells, when the consequences of that risk might take years to become visible in humans."

-from an earlier post a few days ago.

After reading that and thinking about it.... I would be much more willing to take a senolytic treatment than I would an epigenetic treatment.

But... meh, gotta test it. Especially if you are giving these treatments to people in their 80s/90s, the risk of cancer (which is going to happen anyways) might not be such a factor compared to potential immediate benefit of the therapy.

Posted by: GREGORY S SCHULTE at January 31st, 2022 11:30 AM
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