Fight Aging!

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/