SENSible Question: How Secure a Mitochondrial “Backup” is Allotopic Expression?

But still, our AE copies of mitochondrial genes are likely to suffer disabling mutations at some point in the future, even if that point is many times further away than anyone alive today has yet lived. What can we anticipate our future options to fix the problem to be?

The most obvious approach is a “simple” do-over: put another set of AE mitochondrial genes in the nucleus of our cells. If we were to again deliver all 13 AE genes together for this second round of therapy, we would face the same challenges of delivering gene therapy for mitochondrial genes as we did the first time around, with two differences.

First, as we’ve just noted, a very long time would likely have to pass after a person’s first round of AE gene therapy before they would be due for a round of maintenance treatment. This would give scientists decades — perhaps even centuries — to either develop improved versions of the AE genes themselves, or new gene therapy technologies that do a better job of delivering them, or entirely new MitoSENS strategies to supersede AE. Indeed, SENS Research Foundation scientists are already in the early stages of developing a mitochondrial “gene drive” rejuvenation biotechnology that would replace all mutated mitochondrial genomes directly, without making any modifications to the nuclear genome. Long before anyone needs a second round of AE gene therapy, this “gene drive” approach might render AE obsolete.

Another difference between a person’s first round of AE gene therapy and subsequent rounds is that while a person has no existing AE genes in any of their cells when they undergo their first round of AE, in later rounds they would still have some intact AE genes left over from their first round of therapy, even if other AE genes had mutated. In the great majority of cases, any such mutations would occur in one or a few AE genes rather than as large deletions. And those localized mutations would not impact the production of the proteins encoded in non-mutated AE genes as happens in mitochondria with the “common deletion.”

Thus, while it wouldn’t make sense for a person to undergo a new round of AE gene therapy until he or she had lost a sufficient number of AE genes from a sufficient number of cells, the fact that most people would likely still have several of the AE genes from previous rounds still intact might make it unnecessary to repeatedly deliver the entire set of 13 mitochondrial genes at once, as would be the case for the first round.

Instead, people’s pre-existing AE copies and the slow rate of nuclear mutation might allow us to perform an “AE topup” of just those AE genes that had mutated. More likely, it would give us room to set up a protocol in which people receive successive rounds of partial AE gene therapy. Each round would deliver a single AE gene or a small number of them; the regimen would work through all 13 AE genes in turn over the course of years or decades and then start over again at the beginning. One feature of this approach is that delivering these smaller packets of genetic material would not require the very large payload capacity of phage integrases, which would allow us to use gene delivery systems that we can’t use to deliver the full 13 for the first round of AE.

A second, entirely different way to address the long-term risk of mutations in AE genes is to replace the cells entirely. We will need to replace cells anyway on an ongoing basis to keep up with losses due to aging, trauma, and other causes (RepleniSENS). Additionally, systematically replacing each tissue’s adult stem cells and/or its mature cells is at the core of the WILT defense against cancer. We can both screen cells used for cell therapy or for WILT to make sure that their mitochondrial genomes are pristine, and also pre-engineer AE genes into such cells, which is a lot easier than delivering AE genes into the existing cells in a person’s body.

Bottom line for this section: no single cell in the body has to last indefinitely for us to last indefinitely, so the AE copies of mitochondrial genes in any given cell don’t have to last indefinitely either.

When you combine the dispensability of individual cells with the ability to perform maintenance rounds of AE, the much lower rate of both oxidative damage to and actual mutations in mitochondrial versus nuclear DNA, the additional defenses against mutations and their consequences in the nucleus versus the mitochondria, and incipient rejuvenation biotechnologies to slow the spread of mitochondrial DNA deletion mutations, we can be confident that “backing up” our mitochondrial genes via allotopic expression from the nucleus will secure our cells’ ability to fuel themselves and maintain normal metabolism beyond our current horizon.