Rejuvenation Research, Volume 10 Number 2
The latest Rejuvenation Research is available online, and as I said in this week's Longevity Meme Newsletter:
While we're out there fighting the good fight, remember that some segments of the biomedical research community are very willing to sign their names to the defeat of aging - and are publishing in a well-regarded, influential journal.
I've pointed out a couple of the more interesting papers as they came up in PubMed over the past few weeks, but here is one of the others - an important paper with an overly intimidating title. If you're feeling weak of constitution you might want to skip to the explanation, but this is really just a case of some science having a language and style all of its own.
The possibility of synthesizing mitochondrial DNA (mtDNA)-coded proteins in the cytosolic compartment, called allotopic expression, provides an attractive option for genetic treatment of human diseases caused by mutations of the corresponding genes. However, it is now appreciated that the high hydrophobicity of proteins encoded by the mitochondrial genome represents a strong limitation on their mitochondrial import when translated in the cytosol. Recently, we optimized the allotopic expression of a recoded ATP6 gene in human cells, by forcing its mRNA to localize to the mitochondrial surface. In this study, we show that this approach leads to a long-lasting and complete rescue of mitochondrial dysfunction of fibroblasts harboring the neurogenic muscle weakness, ataxia and retinitis Pigmentosa T8993G ATP6 mutation or the Leber hereditary optic neuropathy G11778A ND4 mutation.
What is this all about, and why is it relevant and interesting? Let's start with the mechanics: mitochondria are the powerplants of your cells, evolved from bacteria that brought their own DNA to the party. Some of your DNA is in the cell nucleus, and some is in the mitochondria. These researchers are taking genes normally found in the mitochondrial DNA and putting them into the cellular nucleus, to do their jobs there. This engineering feat is called allotopic expression.
The job of a gene is, in essence, to act as the instruction set for the production of proteins, the components of cellular machinery. A core problem in moving the factory from the mitochondria to the nucleus is that these proteins would then have to struggle their way back to the mitochondria where they are needed; this has been a challenge for a variety of reasons.
These researchers have demonstrated a way to overcome that challenge for at least a subset of mitochondrial genes - via what might be viewed as a rather clever hack to the programming of the cell - and thus can repair dysfunctional mitochondria that results from damage to those genes and a local absence of vital proteins.
So what's the big deal about that for those of us interested in healthy life extension? Well, evidence presently supports ongoing, accumulated damage to mitochondrial DNA as one contribution to age-related degeneration. All aging is damage, and this form of damage appears important, the root cause of free-radical propagation throughout the body. The engineering approach to dealing with this damage - and thus repairing or halting its contribution to aging - seems to have at least two viable paths forward at the present time:
- Replace all damaged mitochondrial DNA with fresh, undamaged DNA, such as via protofection
- Copy all the important mitochondrial genes into the nucleus, thus making damage in the mitochondria irrelevant
The second path would make damage irrelevant because the necessary proteins will be generated in the well-protected nucleus even if the mitochondrial genes are no longer functional. This is the path favored by biomedical gerontologist Aubrey de Grey and proposed in the Strategies for Engineered Negligible Senescence. de Grey suggested a different clever hack to move the proteins produced by these genes to where they need to be, but the overall scheme is much the same at the high level.
That is why this paper is interesting and important: it provides more concrete validation for allotopic expression as a means for eliminating one important contribution to the aging process.
Technorati tags: biotechnology, life extension, SENS