Aubrey de Grey Explains the Role of Mitochondrial Mutations in Aging, and What to Do About It
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The SENS Research Foundation (SRF), cofounded by biogerontologist and advocate Aubrey de Grey, funds work on the foundation science needed for tomorrow's rejuvenation therapies. We age and die because the operation of our metabolism generates various forms of cellular and molecular damage, some fraction of which goes unrepaired. Like rust, it accumulates and degrades the operation of organs and tissues to cause age-related disease and, ultimately, death. Work aimed at treating and repairing the root causes of aging is arguably the most important research presently taking place today: even if we combine every other cause of human suffering and death into one total, that toll is only half of the harm caused by aging.

In addition to funding research, the SENS Research Foundation staff and supporters also engage in advocacy relating to rejuvenation research: education, raising awareness, and fundraising. Too few scientists are engaged, there is far too little funding considering the gains that might be obtained comparatively soon with a suitable large-scale research program, and the public is largely ignorant and indifferent, even as they age to death, with more than hundred thousand lives lost to aging every day.

One aspect of the Foundation's outreach efforts is a growing YouTube video library of lectures and presentations by researchers in the field. A recent addition has Aubrey de Grey walking through the role of mitochondrial DNA damage, the present state of knowledge in the field, and what might be done to reverse this contribution to degenerative aging:

In this video, SRF Chief Science Officer Dr. Aubrey de Grey discusses mitochondrial mutations, their role in aging, and the SENS approach to combating their deleterious effects. Dr. de Grey opens his lecture by describing the structure of mitochondrial DNA (mtDNA) in humans. In particular, he explains that only thirteen protein-encoding mitochondrial genes actually reside in mitochondria. Throughout the course of human evolution, over a thousand other mitochondrial genes have migrated to the nuclear genome.

Next, he explains the major theories developed between the 1970 and the present that aimed to explain the role of mtDNA mutations in aging. During his discussion of the most recent theoretical ground, Dr. de Grey explains his own contribution to the field: an alternative hypothesis to explain how clonal expansion of mutant mitochondria might occur. He then turns to therapeutic strategies and discusses the three main mechanisms by which scientists might intervene in mitochondrial aging.

Dr. de Grey closes by describing the mechanism SRF finds most promising: inserting the thirteen protein-encoding mitochondrial genes into the nucleus modified in such a way that the corresponding RNA transcripts or protein-products can be imported into the mitochondria.

Comments

Aubrey states in this video that people doubted that mitochondrial mutations could be a cause of aging because, even in aged individuals only a small percentage of cells in the body have been taken over by mutant michondria (correct me if I am wrong about that).

He then says that he and others have proposed that this small number of cells somehow causes aging by affecting the surrounding tissue in some way (not unreasonable).

His proposed method for repairing this damage is to place genes for the 13 genes in the mitochondria into the cell nucleus via genetic engineering.

BUT... if only a small number of cells in the body are taken over by mutant mitochondria, but this small number is enough to wreck havoc, then it will be necessary to carry out genetic engineering on pretty much every cell in the body in every tissue in which mutant mitochondria cause aging.

Is there genetic engineering technology available now that can do this? And what are the actual prospects like for this technology coming about any time soon? It seems like a very tall order.

Posted by: Jim at December 25, 2013 6:57 PM

@Jim: Yes, both organism-wide and tissue-specific nuclear DNA genetic alteration for a very high proportion of cells is an existing technology, with numerous different technology platforms competing with one another.

The time-consuming part of the process is figuring out what to insert into the nuclear DNA such that the mitochondrial protein is shuttled back to the mitochondria where it is needed - producing it is easy, getting it to where it is needed is hard. That's only solved for a couple of the genes, demonstrated in the laboratory for one or two of them. But some researchers think that they have a general system for doing this that might work for all of the genes. We shall see.

Posted by: Reason at December 25, 2013 7:03 PM

Comprehensive gene therapy technology is already available? How come people are still dying from cystic fibrosis then?

Posted by: Jim at December 25, 2013 9:08 PM

@Jim: Because there is a very large span between what can be done with mice in the laboratory and what is available as a treatment for humans. Some of that is regulatory, some of it is proving that a particular methodology does in fact help for specific condition, and by the sound of it some is that some tissues are more challenging than others.

E.g. for cystic fibrosis:

http://www.ncbi.nlm.nih.gov/pubmed/22229571

CRISPR is an example of the sort of modern gene therapy approach I had in mind. Still in the lab at this stage:

https://en.wikipedia.org/wiki/CRISPR

Posted by: Reason at December 25, 2013 9:36 PM

Is there any gene therapy that improves your POLG mice? And if so, how far off do you think before trials begin in humans?

Posted by: Doug Lingard at January 1, 2014 11:53 PM
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