The cellular machinery and higher-level structures of our bodies inevitably damage themselves as part of keeping us alive. While our bodies have mechanisms to prevent and repair some aspects of this damage, the repair is never complete. Over time, damage to our cells and tissues accumulates in our bodies, causing them to become increasingly dysfunctional with the eventual endpoint of aging and its many diseases.

At SENS Research Foundation, we work to develop the https://www.sens.org/our-research/intro-to-sens-research/  seven practical repair strategies into rejuvenation biotechnologies that can prevent, defang, or remove this damage to restore the health of our cells and tissues and thus maintain or restore youthful health and vigor.

The https://www.sens.org/mitosens/  MitoSENS program at SENS Research Foundation is working to develop longevity therapeutics to repair or render harmless the damage that drives the age-related decline in the function of our cellular power plants — the mitochondria. The most important kind of age-related mitochondrial damage is large deletions in the mitochondrial DNA, which are the ultimate result of the toxic byproducts of cellular energy production. Such large deletions are prime culprits in multiple specific age-related pathologies, such as Parkinson’s and Alzheimer’s diseases, as well as sarcopenia — the loss of mass and disproportionate loss of power in aging muscles. Such mutations also drive broader pro-aging effects across the body.

Using a biotechnology called allotopic expression, the Boominathan Lab at SENS Research Foundation is engineering “backup copies” of the genes normally harbored in the mitochondria into the safe environment of the nucleus, separating the damage-causing molecules in the mitochondria themselves from the genes that are essential for cellular energy production.

In 2015, SRF launched a crowdfunding campaign for the allotopic expression of mitochondrial genes with the help of Lifespan.io, which enabled us to ramp up our efforts. This additional funding was instrumental in establishing proof of concept for this strategy. In collaboration with renowned mitochondrial scientists Dr. Martin Brand and Dr. Birgit Schilling of the Buck Institute, the MitoSENS team showed that the allotopic expression of two mitochondrial DNA genes restores critical metabolic functions in cells derived from a patient with a severely disabling mutation in the mitochondrial ATP8 gene.

Subsequently, to validate the gene therapy product in a living organism, they teamed again with Lifespan.io for a second crowdfunding campaign” the Mitochondria Repair Project 2 . Using the maximally modifiable mouse model, the researchers at SRF placed a single copy of ATP8 in a safe harbor locus in the nucleus. They then crossed this allotopic ATP8 mouse with a mouse model that harbored a specific mutation in its ATP8 gene to see if their allotopic ATP8 could restore normal energy production and metabolism in the face of a mutation in the inherited mitochondrial gene. Careful breeding and genotyping confirmed that the allotopic ATP8 is robustly expressed and is passed down through at least four generations in the progeny. And on the critical question, the allotopic ATP8 gene works: the mice’s cells express the allotopic protein, its mitochondria take the protein up, and it effectively assembles into the correct Complex of the mitochondria’s energy-producing machinery without any adverse effects. Studies are ongoing to quantify how much the engineered ATP8 displaces the mutated mitochondrial version of the gene and the team hopes to publish these results soon. 

Thanks to everyone at LEAF and all the crowdfund donors who helped make this amazing advance possible! We are several large steps closer to human mitochondrial gene therapies thanks to you. 

We are excited to announce that our successful work of backing up two mitochondrial genes into the nuclear genome has been accepted for publication in the journal Nucleic Acids Research! Please see the announcent from our recent Rejuvenation Biotechnology Conference here, starting at 2h15m6s:

Hi Everyone, it’s been an amazing few months. In short, we have been tremendously successful in our efforts to rescue a mutation in the mitochondrial genome!

Essentially we’ve shown that we can relocate both ATP6 and ATP8 to the nucleus and target the proteins to the mitochondria. We can show that the proteins incorporate into the correct protein complex (the ATPase) and that they improve function resulting in more ATP production. Finally, we show that the rescued cells can survive and grow under conditions which require mitochondrial energy production while the mutant cells all die.

We have finished writing up our results and submitted them for review and publication. It may take a while for our results to be published (the peer review process can be lengthy) but as soon as it is I’ll post an update here so you can see the full paper.

We have also started the project that you helped us get to our stretch goal on. We have made all the combinations of MTS with ATP6 that we proposed and are now working on testing them. I’ll let you know when we know more.

Thank you so much for your support!

Oki

Hi everyone, thanks so much for your support in reaching our initial goal! I’m proud to announce that we have just received a donation from a local company in the form of a large quantity of free DNA primers. We used the donation to design a huge set of primers that we can use to make dozens more mitochondrial targeting sequences (MTSes) to test for their ability to target proteins to the mitochondria. So instead of the 3 that we’ve tested so far we could test many different ones that we suspect might be good candidates as stretch goals for this campaign.

If we reach a total of $45,000 we can test all of these MTSes on ATP6 and see if we can bring it up to full activity.

If we reach a total of $60,000 we can also test all of these targeting signals on a 3rd gene, Cytochrome B, which has long been a challenging gene for us and others in the field to make functional. If we can get this gene working, we should be able to make any gene in the system work.

In addition, we are excited to announce matching funds! Several of you have asked for this. For every dollar that you donate to the Mitochondrial Repair Project another dollar will go directly into the SENS Research Foundation general fund to support all the great research we do at SRF. Thanks to Reason at fightaging.org for helping to organize this fund to match your donations!