Why is there not an immortal(ish) mouse yet?

By now we have all heard about epigenetic reprogramming and its successes. More than one lab has achieved epigenetic age reversal in mice. The epigenetic age of mice can be manipulated using various combinations of Yamanaka factors, reversing and accelerating the age at will. Very notably, the Sinclair lab demonstrated that reversing epigenetic age in the optic nerves of mice enabled them to regrow and restore vision in mice that had been completely blinded.

Yet we still have not seen an actual mouse that has lived more than 10-20% longer than average using these techniques. Why not?

In theory, if you can reverse the epigenetic age, and epigenetic age seems to control the phenotypic age of cells, why are we not seeing mice that live 2,3,5,100x longer than average? What is the disconnect?

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We have seen it with injected or fed DNA/RNA mix. Less with RNA alone. Maybe someone should ask well-known aging researchers if they know about the six rodent studies and why no one is trying to discover the mechanism. A 50:50 DNA:RNA mix should be a top priority for ITP to see if these old studies can be validated.

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Only half joking:
Some well respected scientists believe we may be living in a computer simulation, Sim City, as it were.

Lisa Randall at Harvard
Sabine Hossenfelder of the Frankfurt Institute for Advanced Studies
David Deutsch at Oxford
Zohar Ringel
Dmitry Kovrizhin
and many others, along with Elon Musk.

Dr Melvin Vopson published the research in AIP Advances which suggests that the universe behaves just like a computer, ordering and deleting unnecessary information

As we approach the speed of light it becomes harder and harder to go any faster. The speed of light of course is probably the maxispeed the computer can process the simulation.

As we approach the absolute maximum limit of the life the computer simulation allows, the harder it will be to get any older. Fewer and fewer people are near the limit. Maybe no one has achieved the absolute limit yet, but if we live in a simulation, there is surely a limit. :stuck_out_tongue_winking_eye:

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The Sinclair group has only been able to rejuvenate discrete organs/tissues (optic nerves), not the whole body. Perhaps, it is because different organs age differently.

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It’s much more difficult than one might think to epigenetically rejuvenate cells. In vitro, when applying reprogramming coctails, you often see just a tiny fraction of the cells being reprogrammed. Delivery is a major problem and also controlling the exact reprogramming. What Sinclair did was far from whole body epigenetic rejuvenation. His research is overhyped in the media.

Even if you could epigenetically rejuvenate all the cells of a mouse, I don’t think it would result in the mouse living twice as long. Epigenetic rejuvenation only fixes some aspects of aging. There are plenty of things it doesn’t fix.

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What are some of the things that are not fixed by epigenetic rejuvenation? Would epigenetic rejuvenation of immune cells allow them to again (as in youth) address more of the hallmarks of aging?

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@Joseph_Lavelle Think it might be that we as organisms are

  1. much more than the sum of our cells
  2. not all damage to cells is due to epigenetic issues

Would love to hear @Olafurpall thoughts here too. Below is a non complete sketch of some reasons:

Beyond being a collection of cells, we are structures among and around our cells, we are a complete “environment”.

Those structures and that environment also age and accumulate damage and gunk as we age.

  • Changes to extra cellular matrix
  • glycation,
  • accumulation of beta ameloid,
  • build up of tau
  • build up of soft and hard plack in the arteries,
  • scarring,
  • etc, etc.

Those structural issues that increase exponentially with age are not solved by reprogramming per se that is a cellular process and operates at the levels of cells.

We also lose extremely important cells and cell types. Think Parkinson’s as one example. Again reprogramming helps restore/reset cells to a healthier state and not really help create new cells (this one is a bit less clear in some citation is you actually reprogram stem cells).

And while epigenetic damage can perhaps be reversed or re-set via partial reprogramming that does not include damage at the DNA level (think mutation and some cancers) won’t be solved per se with partial reprogramming.

Having said above, I think partial reprogramming has the potential to be truly transformational. Just that it won’t be enough to fix all types of disease and aging related decline.

For a good summary of some of this see the few minutes starting at 21 min, 15 sec here

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@Neo mentioned some good examples above. Some of the main things that will not get fixed with epigenetic reprogramming are the stochastic damages that occur to the extracellular matrix, including glycation, racemization and isomerization of proteins. We have no mechanisms to significantly reverse these kinds of damages.

Some other examples that I think would either only be partially fixed or not at all are DNA damage, nuclear pore complex damage and cell loss.

A main take home point is that the body never evolved to be able to fix all damages because it never needed to do that to pass the genes on to the next generation. In that sense, it makes perfect sense that epigenetic reprogramming won’t fix everything.

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@Olafurpall @Neo Thanks. The piece I am particularly interested in is the possibility of revitalizing the immune system (via reprogramming or otherwise) so that the immune system can perform its maintenance processes well again. Killing off cancers, eliminating senescent cells, not being overly activated by self or no harmful proteins, etc.

This is one of the benefits I thought rapamycin would provide. Yes? How else to do this?

Thanks.

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I think the solution to radically extending lifespan is rather simple based on the disaccordance in lifespan between rats who live a couple years at most and naked mole rats who can push 40.

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Rejuvenating the immune system is going to require the combination of a lot of approaches because there are so many different components that change with age like myeloid bias, clonal expansion, thymus involution. You would likely need, among others, to rejuvenate the thymus, rejuvenate the hematopoietic stem cells/bone marrow, deplete lots of B cells and more. Rapamycin doesn’t do any of this AFAIK, at least not directly, although I think it helps indirectly slow down aging of the hematopoietic stem cells somewhat and possibly some other parts of the immune system, but I doubt it’s going to actually rejuvenate any parts of it significantly.

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I think the solution is clear as the problem is a sinple one in the main. Cells atop functioning properly and that function needs reinstating.

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I think it’s a misunderstanding to think it’s simple just because two species of rats have very different lifespans. Science is nowhere close to being able to modify one species of a higher order animal to be more similar to another distantly related animal, not to mention that it’s much harder to extend the lifespan of humans than of shorter lived animals.

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Why do flying creatures live longer?

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There are lots of reasons for that, some known, most unknown. The same can be said about why naked mole rats live longer than other strains of rats.

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@Olafurpall Thats a bummer. Why do you suppose rapamycin improves vaccine response (Levine study) and seems (anecdotally) to reduce sensitivity to allergens (airborne at least), if it isn’t rejuvenating the immune system?

And thoughts on how to reduce the rate of aging of the immune system? Some guesses…

Rapa to reduce the SASP burden while boosting autophagy to clean up the system?

HGH (with metformin and dhea) for thymus rejuvenation?

Lower ectopic fat deposits: get fat deposits out of bone marrow, get fat out of organs causing high blood sugar / insulin resistance causing CVD and reduced brain blood flow, stop poor blood flow of nutrients to over-full fat storage causing chronic inflammation?

Reduce iron overload to reduce oxidation and inflammation?

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I would argue flying creatures live longer because they need more efficient mitochondria to be able to fly. Having more efficient mitochondria also gives them a longer life as the cellular function has a longer way to drop because it becomes too bad to maintain life.

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That could be one part of the several reasons they live longer. Another possibility is that they don’t have more efficient mitochondria but instead just have greater number of mitochondria per cell. I actually think that birds are on average likely to have less efficient mitochondria than other mammals, because they need to maintain a very high body temperature and one major way in which they do that is by increased mitochondrial uncoupling. The increase uncoupling acually reduces the efficiency of ATP generation in the mitochondria and makes more of the energy instead go to heat production which is what occurs when protons leak through the mitochondrial membrane instead of going through ATP synthase to produce ATP.

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I will have a rummage through the literature at some point when I have more time. A cursory glance did not provide an answer. One argument put by Nick Lane is that there is an optimal ratio of mitochondria, capillaries and muscle fibres. Increasing the number of mitochondria would only mean larger cells and would not impact on the ability to fly.

I think you’re missing the fact that any such optimal ratio of mitochondria would differ greatly between animals of different body sizes because the larger the animal the smaller the ratio of body surface area to volume. One of the requirements of a small animal relative to a large one is that they have higher relative body surface area and therefore lose more heat and need to make up for that by having faster metabolism and sometimes increased uncoupling to generate heat.

Then there is the metabolic scaling problem, but differences in metabolic scaling are actually caused in part by the fact that nutrient delivery is slower in larger animals because the delivery route (the body surface area) is smaller relative to the tissues that need the nutrition (represented by the volume of the animal). So a part of the reason the larger animals have slower metabolism is because you can’t deliver as much nutrients to their cells as you could with a smaller animal. These factors heavily influence differences between animals of different sizes, but of course if we’re talking animals of similar size/body surface area, then other things will matter more.