Alternative Approaches to the Treatment of Mitochondrial Aging at the SENS Research Foundation
The primary approach to the prevention and treatment of mitochondrial aging undertaken by the SENS Research Foundation is allotopic expression, putting backup copies of mitochondrial genes into the nuclear genome. This prevents mitochondrial DNA mutations from degrading mitochondrial function in ways that can become pathological. This isn't the only approach on the table, however, and here some of the others are outlined.
Mitochondrial mutations - and above all, large deletions in the mitochondrial DNA - accumulate in long-lived cells over our lifetime. And until we can do something to repair or bypass that problem, the overtaking of this small fraction of our cells by deletion-bearing mitochondria will continue to drive diseases of aging. Long before there was a SENS Research Foundation - even before a "Strategies for Engineered Negligible Senescence" (SENS) platform existed - our founding CSO Dr. Aubrey de Grey surveyed the possible solutions for this problem, and the only one that seemed viable was allotopic expression (AE).
So why - after making great leaps forward with the science - are we now breaking ground on entirely new MitoSENS strategies? A few reasons. Considered at the most fundamental level, AE itself is an inherently difficult biotechnological challenge. Then there's the additional hurdle of delivering it to those cells that are vulnerable to mitochondrial mutations with age. Thus scientists in our MitoSENS lab are now working on two of these alternative strategies - both of them also thought up or endorsed by Dr. de Grey. You might think of them as backup strategies for the backup copies.
One of these strategies is to use a form of mitochondrial transplantation to replace the cell's mutation-bearing mitochondria with healthy ones. For mitochondrial transplantation to work as a rejuvenation biotechnology, we need a way not only to get the transplanted mitochondria into the cells, but to enable them to bypass the selective advantage of the native mitochondria, and especially of the powerful advantage of mutation-bearing mitochondria. This is where the relatively new biotechnology of "gene drives" come in. Engineered mitochondria would use restriction enzymes designed to target one of the several restriction sites that are naturally present in the host's mitochondria. The restriction enzyme would quickly go to work eviscerating the cell's original mitochondrial DNA, thereby clearing space to allow the new, transplanted mitochondria to take over.
We can't say much about the second strategy the MitoSENS team is exploring because it's a very early-stage project, and we want to be sure we're on the right track before making any announcements. All we'll say for now is that our scientists have identified a drug that may potentially "unmask" deletion-bearing mitochondria, attracting the attention of the mitophagy machinery and allowing it to cull them. Under some circumstances, such "unmasking" is sufficient to keep deletion-bearing mitochondria at bay when they haven't yet overtaken the cell. If the drug we're testing (or a similar one) could do that, we might be able to keep many cells operating normally by holding deletion-bearing mitochondria down to a minority of the population, and keep other cells free of deletion-bearing mitochondria entirely by catching the first one and sending it to its grave.
Link: https://www.sens.org/mitosens-new-strategies-gene-drive-mitophagy/
Hello, I have a question which I hope isn't too far off-topic...
There was a time when SENS and Aubrey de Grey were very identified with a seven-part strategy for overcoming aging. It's still there on the SENS website:
https://www.sens.org/our-research/intro-to-sens-research/
It shows the folly of the human race, that this research program was not swiftly adopted or imitated or debated by national and international healthcare systems and medical research plans, but instead was regarded with indifference, mild curiosity, or worse.
But I'm sure the readers of this blog have already noticed the peculiar indifference of the human race to the idea of curing the aging process.
Anyway, a few years ago, de Grey separated from the SENS Research Foundation, and now heads a new "Longevity Escape Velocity Foundation". I am trying to understand what this means for the old SENS plan, and longevity research in general, intellectually and philosophically.
Tentatively, I see a possible division of labor between SENS and LEVF, in that SENS is doing the reductionist thing of identifying sub-processes of the aging process and trying to cure them, whereas LEVF is doing more integrative things - above all, using mice as a model for combining the best of available techniques in order to keep a single organism alive and young, and thus as a model of overall rejuvenation. (LEVF's other big project is about the use of cryopreservation in organ banks, so maybe there's a possible crossover with cryonics there.)
Does this idea, that SENS is doing reductionist work, and LEVF is integrating the fruits of that work into a single holistic practice, bear any relationship to reality?
Also, is there, by now, anything better than the original sevenfold plan of SENS, as an overall blueprint for defeating aging? Or is that still the apex of systematic approaches to the problem? Does that plan need to be amended in any way, e.g. were other fundamental sub-processes of aging ever identified as deserving their own additional streams of research? Is there anything wrong with the sevenfold plan, conceptually or methodologically?
Hey Mitchell, I'm no biologist... but....
"Does this idea, that SENS is doing reductionist work, and LEVF is integrating the fruits of that work into a single holistic practice, bear any relationship to reality?"
Not totally clear on what you mean in this question, but I know ADG has repeatedly said that tackling aging will have to be a divide and conquer approach, and that fixing 6 problems out of the seven will only get you so far. ALL the problems he laid out need to be fixed in order to put a dent in the problem of aging.
"Also, is there, by now, anything better than the original sevenfold plan of SENS, as an overall blueprint for defeating aging? Or is that still the apex of systematic approaches to the problem? Does that plan need to be amended in any way, e.g. were other fundamental sub-processes of aging ever identified as deserving their own additional streams of research? Is there anything wrong with the sevenfold plan, conceptually or methodologically?"
ADG has also repeatedly said that he has been very happy that no fundamental new problem has risen up beside the original 7 he laid out. You can categorize them in different ways and divide them and count more and so on, but fundamentally, no, the original 7 seem to be "it".
the devil is in the details though...
LEVF is very exciting, because it's the first major organization that is combining multiple anti-aging treatments in one big experiment. Everything so far has kind of led up to this. The goal of LEVF (and also the first major goal laid out in "Anti-Aging") is to take a mouse who's aged to mid-life, and get that mouse to live 2x as long as it normally would via medical treatments. The LEVF
experiment is the first attempt to actually reach that goal. ADG has often said that doing this (which he refers to as Robust-Mouse-Regeneration or 'rmr') will create a tipping point for the industry as far as attention and funding....and now they are actually going for it. So, yes, it's pretty damn exciting.
Urolithin A for mitothagy? Thoughts?
LEV Foundation lists the treatments they plan to include here:
https://www.levf.org/projects/robust-mouse-rejuvenation-study-1
Rapamycin
Hematopoietic Stem Cell Transplant
Telomerase Expression
Senescent Cell Ablation
then:
plasma dilution
t cell rejuvenation
next-generation senolytics
It would be nice to know how to simulate these treatments at home, without the need of vectors or a crisper machine.