Fight Aging!

The SENS Research Foundation science team is taking the next step in their work on moving mitochondrial genes into the cell nucleus, a process called allotopic expression. Having proven that they can carry out this task with the ATP8 gene in cells, they are now aiming at proof of principle in mice. This will require the production of transgenic mice, using a novel technology funded by the SENS Research Foundation called the maximally modifiable mouse. This mitochondrial project is being crowdfunded at Lifespan.io: you, I, and everyone else can contribute to advancing the state of the art one step further towards eliminating mitochondrial DNA damage as a cause of aging.

Mitochondria are the power plants of the cell, a herd of organelles descended from ancient symbiotic bacteria. They reproduce by replication and are recycled when damaged by cellular maintenance processes. Mitochondria carry the remnant of the original bacterial DNA, encoding thirteen genes vital to the process by which mitochondria package chemical energy store molecules. Unfortunately mitochondria generate reactive molecules as a byproduct of their operation, and this DNA is less well protected than the DNA of the cell nucleus. Some forms of damage to this DNA can break mitochondrial function in ways that allow the broken mitochondria to outcompete their functional peers, leading to dysfunctional cells that export massive quantities of damaging, oxidative molecules into the surrounding tissue. This contributes to conditions such as atherosclerosis, via the production of significant amounts of oxidized cholesterol in the body.

Allotopic expression of mitochondrial genes will work around this issue by providing a backup source of the proteins necessary to mitochondrial function. It has been demonstrated to work for ND4, and that project has been running for some years at Gensight Biologics to produce a therapy for inherited conditions that involve mutation of that gene. This work must expand, however, to encompass all thirteen genes of interest. So lend a hand, and help the SENS Research Foundation team take the next step forward in this process.

MitoMouse: SENS Transgenic Mouse Project

The SENS Research Foundation (SRF) has formulated seven practical repair strategies to the common drivers of aging. Whereas some of these strategies are now widely researched by the scientific establishment the MitoSENS strategy for dealing with mitochondrial damage is among the most novel. Our theory is, through allotopic expression, that is by placing functional copies of critical mitochondrial DNA (mtDNA) genes in the nucleus of the cell one could alleviate defects arising due to mutations in mtDNA.

When it was proposed, this unique and ambitious strategy was perhaps too daring for mainstream labs and funding agencies to contemplate. Consequently, the MitoSENS approach has been an in house project for SENS that would not have been possible without community support. So far, this community-funded approach has an excellent track record leading to groundbreaking discoveries. In 2013 SENS organized its first crowdfunding campaign specific to MitoSENS in partnership with LongeCity. The small initiative seeded significant research momentum and paved the way for a larger fundraiser in 2015 at Lifespan.io. Breakthrough discoveries followed and a proof-of-principle for the MitoSENS approach was established for the first time in human cells. Here, the MitoSENS team in collaboration with scientists from the Buck Institute showed that allotopic expression of two mtDNA genes could bring back several functions in a patient cell line with a severe mutation in one of the mtDNA genes, namely ATP8.

To move this strategic advancement toward the clinic, SRF then created the "maximally modifiable mouse model". This mouse has a unique modification in their nuclear genome to allow a targeted insertion of new genes at a specific location. Using this mouse, we are ready to take the next step and pursue mitochondrial gene therapy in an animal model.

Mice of the C57/BL6MT-FVB strain (let's call them "SickMice") have a mitochondrial gene defect, a mutation in the mitochondrial ATP8 gene, and exhibit several age-related symptoms including lower fertility, arthritis, type II diabetes, and neurological impairments. Since mitochondria are only inherited from the mother, cross-breeding female SickMice with male mice from other models will result in the same mitochondrial dysfunction.

We will use the maximally modifiable model to create a new transgenic mouse (the "allotopic ATP8 transgenic mouse - Mitomouse"). This mouse will have the ATP8 gene that is important for mitochondrial function hidden in the cell nucleus and thus capable of being passed on to offspring irrespective of gender. Our hypothesis is that both male and female offspring from SickMice x MitoMice will result in rescued mitochondrial function. This would prove the viability of the MitoSENS strategy by showing that functional backup copies of mitochondrial DNA genes in the nucleus can replace their mutated counterparts in live animals.