Fight Aging!

Here I'll point out one concrete example of the way in which the SENS Research Foundation puts our charitable donations to good use in rejuvenation research. You'll find many more in the yearly organizational reports. The in-house MitoSENS research team, focused on allotopic expression of mitochondrial genes to eliminate the contribution of mitochondrial damage to degenerative aging, has achieved considerable progress in the past two years. Allotopic expression is the process of placing copies of mitochondrial genes into the cell nucleus, altered in such as way as to allow the proteins produced from that genetic blueprint to find their way back to the mitochondria where they are needed. When mitochondrial genes become damaged, as happens over the course of aging, the backup source of proteins prevents this damage from starting a chain of events that causes lasting harm to tissues and organs.

Last year's MitoSENS crowdfunding initiative provided the funds needed for the SENS Research Foundation team to finish up the demonstration of allotopic expression of ATP6 and ATP8, the second and third mitochondrial genes for which this has been achieved. The SENS Research Foundation also used philanthropic donations to help fund the allotopic expression of the first such gene, ND4, some years ago. That research is now being carried forward to the clinic by Gensight Biologics, with sizable venture backing. To complete this defense against mitochondrial damage and aging, the same work must be completed for thirteen mitochondrial genes in total, and building upon recent success the SENS Research Foundation is expanding the MitoSENS team. If you happen to know a qualified researcher or biotechnologist, point them in this direction:

MitoSENS is Hiring

SENS Research Foundation (SRF) is hiring a Research Assistant for our research center located in Mountain View, CA. SRF is an exciting, cutting edge non-profit dedicated to transforming the way the world researches and treats age-related disease. We are seeking a research assistant in our MitoSENS group for a research project geared toward discovering a gene therapy approach to treating mitochondrial mutations; for more information see the project page. Qualified candidates will be local residents who have a BS or MS in the chemical/biological sciences and at least 2 years of work experience in either academia or industry. Duties will include mostly bench work in a small team-oriented environment. Candidates with experience in molecular cloning, tissue culture, protein analysis / biochemical assays are encouraged to apply. Experience working with mitochondria is a plus.

Engineering New Mitochondrial Genes to Restore Mitochondrial Function

Mitochondria provide energy for the cell by synthesizing energy in the form of high energy bonds. This energy synthesis occurs through a process called oxidative phosphorylation in which respiratory enzymes in mitochondria convert a molecule called adenosine diphosphate (ADP) into the energy currency of the cell, ATP. One interesting feature of mitochondria is that they contain their own DNA (mtDNA). As cells and mitochondria have co-evolved, most of this genetic information has been transferred to the nucleus, leaving only thirteen protein-encoding genes in the mtDNA. Housing these thirteen genes within the mitochondria themselves is precarious because the conditions required to synthesize ATP create reactive oxygen species. Over time, these toxic free-radical byproducts damage the mitochondrial genes in more and more cells, compromising respiratory chain function and hence energy production. The accumulation of mutations in mitochondrial DNA is implicated in the metabolic derangement of aging and in accelerating the course of the degenerative aging process as a whole. One need only examine clinical manifestations of mitochondrial genetic diseases to see the similarities they share with the maladies of aging. For example, mutations in the gene ND1 have been implicated in the development of Parkinson's disease, and Cytochrome B (CYB) mutations can cause muscle fatigue and exercise intolerance in young patients.

SENS Research Foundation's strategic approach to this problem is to engineer a way to let mitochondria keep producing energy normally, even after mitochondrial mutations have occurred. Although damage to mitochondrial DNA is inevitable so long as it is housed in the mitochondria, the harmful effects of mitochondrial mutations can be bypassed by engineering backup copies of the thirteen protein-encoding genes and housing the copies instead in the nucleus of the cell. These allotopic gene copies could continue to provide the necessary proteins even when mutations have compromised the mtDNA's ability to do so. Moreover, the nuclear gene copies would be better shielded from damaging toxins and better maintained by DNA repair machinery. Since the majority of mitochondrial proteins are naturally nuclear-encoded, the natural mechanism to deliver the allotopically-expressed genes to the mitochondria can be co-opted.

The SENS Research Foundation mitochondrial mutations team is moving forward on a method for targeting engineered nuclear-encoded genes (that could function as "backup copies" for cells with deletion mutations) to the mitochondria, and for furthermore optimizing the precision of this targeting. The "working copy" of the relocated mitochondrial gene in this method is equipped with two special sequences. One "untranslated" sequence is not turned into a protein itself, but helps protect the engineered protein during the import process. The other, called the mitochondrial targeting sequence, is a tag appended to the final protein following expression that allows it to be imported once expressed. Combining the two sequences allows the "backup copies" of genes to be turned into working copies in the cell nucleus; to have the "working copies" targeted to the surface of the mitochondria to be decoded and turned into protein. Even as it is still in the process of being decoded, the emerging protein is quickly directed to the surface of the mitochondria for import and incorporation into the electron transport chain (ETC), restoring mitochondrial function.

In 2013, the SENS Research Foundation mitochondrial mutations group created two new cell lines which are 100% null for two mitochondrially-encoded genes: ATP8 and CYB. Using these two new cell lines, this year the team was finally able to unleash their engineered ATP8 gene in cells whose mitochondria completely lack the ability to generate the corresponding proteins on their own, and announced the dramatic rescue of such "ATP8 null" cells using their protein targeting strategy. They anticipate that these results will deliver the proof-of-concept for the overall approach, which should then be applicable as a rescue platform for all thirteen mitochondrially-encoded proteins. Further work by the team aims to enable delivery of working instructions for building proteins that can keep the ETC intact and functioning in the event of age-related mutations of the original mitochondrial genes for these proteins. This method utilizes a "borrowed" structure already employed by mitochondria to take in RNA from the main body of the cell. The team has now achieved the critical first benchmark - i.e. delivering any RNA into the mitochondria - in this pioneering work using a convenient (but not naturally mitochondrially-expressed) RNA.