Fight Aging!

Hundreds of mitochondria can be found in every cell in the body. Their primary purpose to create adenosine triphosphate (ATP), a chemical energy store molecule necessary for cell function. Mitochondria are the distant descendants of ancient symbiotic bacteria, now fully integrated into the cell. As such, mitochondria have their own circular genome, the mitochondrial DNA, and despite being a component of the cell still behave very much like bacteria: dividing, fusing together, swapping component parts. Over time, near all mitochondrial DNA has migrated into the nuclear genome, the result of unlikely mutational accidents. On a long enough timescale, even the unlikely becomes frequent. Still, some critical mitochondrial genes have proven resistant to this process, and they remain in place, in the mitochondria, to make up the small mitochondrial genome.

The problem with the existence of mitochondrial DNA is that it is (a) essential to mitochondrial function and (b) both far more prone to damage and far less well guarded and repaired than is the case for nuclear DNA. Deletion mutations in mitochondrial DNA can produce dysfunctional mitochondria that outcompete their undamaged peers, creating a malfunctioning cell overtaken by disruptive mitochondria, a cell that becomes actively harmful to surrounding tissue. The accumulation of lesser forms of mitochondrial DNA damage, repeated countless times throughout the cells of the body, is still thought to contribute to the age-related loss of mitochondrial function.

Researchers have given considerable thought as to how to fix this issue. Replace the mitochondria with new ones harvested in bulk from suitable cell lines; tinker with the mitochondrial quality control system of mitophagy to make it more efficient; cellular reprogramming to recreate the processes of early embryonic development that appear to clear out malfunctioning mitochondria; and of course allotopic expression. Allotopic expression is the goal of completing the work carried out to date by evolution by creating copies of the remaining mitochondrial genes in the nuclear genome, suitably altered to ensure that proteins are delivered to the mitochondria where they are needed. In effect, producing a backup source of vital proteins to ensure that mitochondrial DNA damage doesn't lead to dysfunction.

How Secure a Mitochondrial Backup is Allotopic Expression?

Doesn't the existence of mutational damage in nuclear DNA undermine the concept of nuclear backup copies as a solution to mitochondrial DNA damage? In fact engineering backup copies of the mutation-prone mitochondrial genes into the safe harbor of the nucleus is our strongest strategy for protecting the body from large mitochondrial deletion mutations. It's these deletions - particularly one that is found in so many cells that it is literally called "the common deletion" - that are most tightly linked to aging and diseases and disabilities of aging like Alzheimer's and Parkinson's diseases and the loss of functioning muscle fibers and strength with age. The concept of these engineered backup copies (technically, allotopic expression (AE)) was in fact the first of the proposed Strategies for Engineered Negligible Senescence (SENS) rejuvenation biotechnologies.

There are several things about the nature of the problem and the tools we have at our disposal that make AE not just viable but an enduring solution for mitochondrial mutations, even though nuclear DNA is also susceptible to free radical damage just like mitochondrial DNA is. The first is the sheer amount of oxidative damage in mitochondrial versus nuclear DNA. The mitochondrial DNA's exceptional vulnerability to free radical damage results, first and foremost, from its being located so close to the mitochondrial energy-production machinery, which is one of the major sources of free radical production in our bodies. We can now say with great confidence that the impact of mitochondrial free radicals on the nuclear DNA is negligible.

Even when mutations do occur in the nuclear DNA, the consequences are less likely to be harmful than those in the mitochondrial DNA. This is true in a couple of different senses. First, most mutations in the nuclear DNA are self-contained, causing defects in the proteins produced by one or a small number of genes that are directly damaged. By contrast, the "common deletion" mutation in mitochondrial DNA not only wipes out several genes that code directly for proteins, but also the genes that encode some of the machinery that the mitochondria need to assemble the proteins coded for by any gene in the mitochondrial genome. Without this machinery, the mitochondria can't produce any of the proteins encoded in the mitochondrial genome, including proteins whose genes are completely intact. There is no parallel catastrophic failure in garden-variety nuclear mutations.

A second way that mutations in the nuclear DNA are less likely to cause problems than mitochondrial DNA mutations derives from how much less of its nuclear DNA a given cell type needs to carry out its function. The mitochondrial DNA is a very lean operating system: almost every letter in its code carries essential instructions for producing some machinery that the mitochondria require for their function throughout life. By contrast, each cell houses lots of DNA in its nucleus that it can do without, or that can suffer a significant amount of mutation without harming the cell.

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. Those mutations might even spread into tissue if they occur in stem cells. 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. A gene therapy given once can be given again.