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Recommended reading:
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A newly-published call-to-arms and technical exposition on the SENS approach to age-related disease
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An early study of one of the seven targets of SENS research
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What to do in the meantime:
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Full of diet and lifestyle tips based on current science, to preserve your health until better technology is developed
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LMRF Beneficiaries:
MitoSENS
MitoSENS is a SENS initiative to test medical interventions based on the mitochondrial free radical theory of aging.
Mitrochondria used to be bacteria, before plants and animals split off from each other over a billion years ago. They gave an evolutionary advantage to the single-celled organisms they infected by giving the host cell an additional source of energy.
Over time, most of their thousand genes have migrated into the more hospitable environment of the nucleus, where several DNA repair mechanisms are available (not just one) and the genes are safe from the damaging free radicals naturally produced by metabolic processes inside mitochondria.
In mammals, 13 genes haven't made the jump. Given aging mitochondria's complicity in the negative effects of aging, MitoSENS is working on gene therapy to place engineered versions of these 13 genes into the safer environment of the cell nucleus. The trick is to design genes with the same function, but whose proteins can make the full journey into mitochondria, as is already done by a thousand other proteins that mitochondria use.
Expression of these 13 proteins from the nucleus is called "allotopic expression" (allo- meaning "other"; -topic meaning "place"). You can read more about it below.
For more on MitoSENS's work, check out the following links:
Free radical creation is just a natural part of normal mitochondrial creation of ATP. Natural as it may be, enough of it can lead to DNA and cellular damage, and even death.
Superoxide (O2-) is a byproduct of ATP production in mitochondria. It is normally neutralized by reacting with an enzyme called superoxide dismutase. Nevertheless, superoxide still manages to react deleteriously with mitochondrial DNA (mtDNA) and to create other molecules that also cause such damage.
As with all other objects of SENS research, normally benign levels which don't elicit an evolutionary selection have some threshold which can lead to a cascade of damage.
Enough free radical damage to mtDNA shuts down the usual ATP-producing mechanism. Another ATP-producing mechanism takes over, which produces the electron transporter NADH, instead of recycling it as in healthy mitochondria. As "bad" mitochondria replicate more than the healthy ones, NADH builds up and needs somewhere to transport electrons. To protect itself, the cell exports the electrons.
As with many mechanisms under SENS scrutiny, a healthy natural protection eventually backfires. The electrons that the cell spews out combine with oxygen molecules throughout our bodies to become damaging free radicals. How they cause damage (including arteriosclerosis) and the steps leading to their creation is fleshed out more here.
Allotopic expression (AE), the expression of mitochondrial genes from the nucleus, is a proposed solution to mitochondrial mutations and the subsequent damage that results.
Mitochondrial DNA is circular, since mitochondria used to be bacteria. Therefore, its genes have to be reengineered before insertion into nuclear DNA.
Furthermore, the 13 proteins for which mitochondrial genes code aren't easily dissolved in water. Instead they prefer to stick together. This means that while in the cytosol (the watery region in which the nucleus and mitochondria float), they tend to clump together too much to pass into the mitochondrion.
There are organisms that can express analogues of these 13 genes from their cell nuclei, beating the hydrophobicity problem by tagging the proteins with extensions that improve dissolvability. By borrowing this idea, and perhaps modifications of these extensions, researchers plan to make significant progress in making AE a reality.
To date, at least three of the 13 mitochondrial genes have been successfully expressed in vitro from the nucleus, including transport of the corresponding proteins through the mitochondrial membrane.
AE is not the only proposed solution to mitochondrial mutations. Enhancing gene maintenance within the mitochondrion is also being pursued by some researchers outside of MitoSENS with some significant success.
Furthermore, AE would entail gene therapy. Any gene therapeutic approach requires a great deal of time to get through clinical trials, due to liability concerns and cautionary regulation. Meanwhile, a more short-term approach may be developed to kill off mutant mitochondrial cells instead of preventing them. Independent of MitoSENS, it has been shown that exogenous mtDNA can be directed into the mitochondria. This approach has already been demonstrated in vivo.
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