Thursday, July 20, 2017

Senolytics and allotopic expression

Aging and Cell Senescence


The pursuit of an indefinite healthy lifespan, or healthspan, is the most noble challenge put before mankind. To get there, many bold technologies have been proposed and explored. Among them are two approaches that have already achieved some preliminary measure of success. In particular, they are the elimination of cellular senescence by drugs or immune activation, and the so-called ‘allotopic expression’ of mitochondrial genes into the nuclear DNA. Regrettably, neither of these methods stand a chance, for reasons I will detail in this essay. Fortunately, at the confluence of these seemingly isolate approaches there is a way forward. This interface -- namely, the mitochondrial control of cellular senescence -- offers deep promise.


Senescence
                                  
Cellular senescence refers to cells that can no longer divide. Neurons and heart cells are senescent, but they are not a threat. Rather, they are the most important cells in the body. In terms of the standard cell cycle, these quiescent cells exist in the resting or ‘G0  growth phase’. By contrast, there are many other senescent cells in the body that have outlived their useful lifespans and linger on in a crippled limbo. When things are working properly, such cells have built in programs to bow out gracefully -- they safely self-destruct in a process called apoptosis.


However it is often the case, that cells are damaged to the extent that they lose this self-regulating capability and become a liability. Sometimes, cells end up senescent as a result of too much replicative power, as in cancer. Here, the cell (often with highly damaged DNA) manages to halt its runaway replication, but fails to deploy the full apoptotic program. The rapidly exploding new field of ‘senolytics’ aims to eliminate these cells with senolytic drugs.


Allotopic expression


The other approach to strike at the heart of the aging process is take the genes normally expressed in mitochondria and put them into the nucleus. The logic behind this is that here they would be immune to corruption from the free radicals that saturate the mitochondrial interior. The success of this strategy depends on the ability to re-target the proteins made by these genes back to the mitochondria where they are assembled into various subunits of the essential respiratory complexes. Proponents of this philosophy fancy this endeavor as a natural completion of a long evolutionary process of naturally off-loading the genes of our mitochondrial endosymbionts to the nucleus for safe keeping.


High-tech billionaires
These two anti-aging schools of thought have drawn ample attention both from established corporate biotech, and from those individuals most naturally disposed to command them -- namely, the high tech billionaires. One place that has figured prominently in the development of both plans is the SENS (Strategies for Engineered Negligible Senescence) Foundation. Its primary founder, Aubrey de Grey, has been the most influential proponent of these technologies for the last 15 years. Multi million dollar care packages have been donated to SENS by the likes of Peter Thiel, Larry Ellison, and many other high tech luminaries. In turn, SENS oversees both in-house experiments as well spinning these funds off to other outside researchers that apply to them for grants. See recent profile on Aubrey by the editor in chief of Billionaire Magazine;
http://www.billionaire.com/people/peter-thiel/2875/could-human-beings-live-for-1000-years

Some successes


Research in senolytics has so far hinged on several assumptions. The main one is that senescent cells possess something in common which can be used both to identify them, and also target some therapy towards them. Typically this would be expression of a specific protein that marks them, or a defined pathway of protein operations would render them uniquely susceptible.


Problems


The first problem with senolytics is that the assumptions made have in the fullness of time proven to be largely invalid. There simply is no unique marker only expressed by senescent cells, and there is no pathway that can be uniquely targeted. The second problem is that the drugs that have been promoted are actually highly toxic. The only reason that any of them have managed to gain any traction in the anti-aging community is by virtue of the fact that they have been previously approved by the FDA as chemotherapy or anti-viral drugs. That is no small feat in today’s regulatory pipeline. The kicker though, is that these drugs are now being promoted as senolytics simply because were too toxic to continue to justify their use in killing tumors and have therefore become unemployed. But change a small functional group here or there and you have a different drug as far as historical baggage -- albeit one with largely the same functionality in the body. This is madness.


With allotopic expression, the main problem is that the field has failed to distinguish in any tangible way between what I would call ‘soft’ and ‘hard’ allotopic expression as it pertains to aging. Soft expression would be simple putting a copy of single gene into the nucleus. There is ample evidence from nature that this might in theory be made to work. There are also recent results from companies like GenSight and Foundations like SENS indicating that individuals who have massive functional deficits in these particular mitochondrial genes might be improved.


While most mammals and other higher-ups typically retain around 13 mitochondrial genes, nature doesn’t always use that mold. Other species like drosophila and many single celled protists can get by with less. Some have even offloaded all their tRNAs or mRNAs to the nucleus and import them as well.They do this however, only by making qualitative sacrifices in those particular genes jettisoned off the nucleus. Typically for proteins, this involves making them less hydrophobic so that they manage to get imported back to mitochondria.


If we want to stretch things a bit, one could even include expressing a few copies from a small set of genes from a particular respiratory complex into the nucleus under the umbrella of soft expression. However, things would rapidly go downhill from there. Hard expression -- putting copies of all the mitochondrial genes into the nucleus -- would be a PR disaster for mitochondria. Their reason to be would vanish.


What the SENS supporters have thus far failed to appreciate is that in the decade or so since the major tenets of their anti-aging strategy were formed researchers learned a lot about how respiratory complexes are actually assembled and deployed. Regarding allotopic expression, my sentiment is simple -- mitochondria aren’t built like that. As genetic hybrids, mitochondria are organelles that exploit two separate transcription and translation systems in what we might call a meta-genetic cooperative. In other words, the seemingly massive and disproportionate overhead of carrying nearly twice as many tRNAs as proteins is actually their primary feature rather than a bug.


Two uniquely optimized translation systems, one on the outside membrane of the mitochondria facing the cytosol, and one on the inside membrane simultaneously working in tandem in the mitochondrial matrix, painstakingly construct the electron transport complexes with precision clockwork. These are in turn positioned with particularly stoichiometries into larger supercomplex geometries within the cristae. What that means for us is that although one might have some success in rescuing gross genetic deficits by allotopically saturating ailing mitochondria with a missing protein, one is not going to meaningfully improve normally aging individuals with these nuclear enticements.
Solutions


A curious thing has unfolded in aging research that seems to have caught many off guard. That thing is the realization that free radicals (like dual genetic systems) are actually features rather than just bugs. What was the response of the SENS Foundation to this newsflash as it would pertain to the rationale underlying allotopic expression? I have not heard.


I would argue that rather than trying to allotopically diminish our mitochondria, what we should be doing is trying to enhance them. In other words, give them more genes and more powers. This is something we can already do. For example, one group has reported the ability to optically control membrane potential in mitochondria by giving them special proteins.
(ref)


Charlie Gard was made famous this past July after Donald Trump and Pope Francis made compassionate pleas to an English hospital which was for all intents and purposes holding him as a medical prisoner. When the parents wanted Charlie to see an American doctor and try a seemingly rational (if a long shot) therapy to replace the nucleosides his mitochondria could not make, a court had to intervene to stop the English hospital from pulling the plug on his respirator. Both copies of Charlie’s RRM2B genes were already expressed from the nucleus but both copies he inherited were mutated. What Charlie really needed was an infusion of good mitochondria.


Unfortunately, you can’t really just inject mitochondria into the blood like you would in a transfusion. For one thing, mitochondria are highly immunogenic by virtue of their bacteria-style formylated peptides and undermethylated CpG islands (regions of their genome that frequently given extra methyl group tags via special epigenetic regulatory enzymes). In fact our immune system exploits mitochondria by ejecting them to self-activate. For the all the recent hype regarding the special functions of the so-called microbiome -- the sum total of gut, skin, or other bacteria that lives on and in us -- it should probably just be said that the ‘real’ microbiome is our mitochondria. The mitochondriome being all the unique variants of mitochondria that heterogeneously unfold and exchange within our differentiated tissues.


Notwithstanding this unassailable conventional wisdom, a Chinese group testing this out in mice and found evidence that brute force injection can have some success in the acute phase. They reported no immune activation for in the first 2 hrs after injection, however when I asked if they found any later on, they said they will need to look further. Intriguingly the researchers found that cells from many different organs had taken up apparently functional mitochondria.  
(ref)


I suggested that they might try injecting mitochondria directly into the ventricular system of the brain and this is something they hope to investigate. If the mitochondria can pass the blood brain barrier, or alternatively can be supplied more directly to different nerve access points, then many new possibilities open up. For example, it is now understood that many cancers are directly controlled by not only by their own mitochondria, but also are transformed by donation of mitochondria from other cells.


It is also known that the many cancers are controlled by the nervous system (gastric cancers, skin cancers, etc). Similarly, various stem cell populations, cell senescence, and regeneration of tissues, organs, and limbs are also all under tight control of the nervous system. The one other key fact we need to tie together these elements is that nerves take the donation and absorption of mitochondria to an extreme. It is their bread and butter. Perhaps even the reason nervous systems first evolved and then later rectified themselves into polarized circuits transmitting from dendrite to axon. (It is not too difficult to imagine mitochondria seeking refuge in the small proto-appendages of cells where they could escape predation and degradation by the lysosomes in the locale of the nucleus, with the fully arborized neuron later evolving as a selector of mitochondria).


The full Monty is now laid bare;
The nervous system controls the body, the many cell niche populations in various states of senescent and proliferation by apportioning mitochondria.


I first published some of the evidence supporting these claims here https://medicalxpress.com/news/2017-03-nervous-tumor-growth.html
And many related comments regarding the nervous system earlier in a previous article for Inference.


In this light cell senescence is not quite so irreversible as one might assume.

The immediate task ahead would be to better identify the best access points to add or siphon off new or obsolete mitochondria, and even modified super mitochondria, as needed. To do this we would essentially need some kind of circuit diagram or principles which reflects how mitochondria are transmitted throughout the body. Much of this diagram is already quite inferable from existing literature.

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