The Longevity Medical
Research Fund

"More Life, More Life Worth Living"
To donate through PayPal:
Recommended reading:
A newly-published call-to-arms and technical exposition on the SENS approach to age-related disease
An early study of one of the seven targets of SENS research
What to do in the meantime:
Full of diet and lifestyle tips based on current science, to preserve your health until better technology is developed

Only 7 Pathogenic Age-related Precursors: Mitochondrial Mutations


Two of the seven early precursors of age-related pathology are chromosomal and mitochondrial mutations.

The former leads to a single malignant cell. The latter leads to a few (1% of the body, in elderly subjects) cells that assault the body.

Free radical creation is just a natural part of normal mitochondrial creation of ATP. Natural as it may be, enough of it can be deadly. 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 the mitochondrial DNA (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.

So what's the solution? One proposal is to improve the mtDNA repair mechanisms. But another is to make versions of the 13 mtDNA genes for expression from the nucleus.

The nucleus has more DNA-repairing mechanisms and isn't full of free radicals. This way, OXPHOS can keep going in free-radical damaged mitochondria after the mtDNA has been damaged to the point of having to switch over to non-OXPHOS ATP production. Damage to the mitochondrial membrane would still signal lysosomes when it's time for the mitochondrion to be degraded and recycled. So OXPHOS-negative mitochondria would not get a leg up on OXPHOS-positive mitochondria by evading lysosomal destruction. All damaged mitochondria would be exposed to natural selection. Preferential selection against damaged OXPHOSE-positive mitochondria would stop. The replicating mitochondrial population would then stay OXPHOS-dominated and NADH wouldn't build up to pathogenic levels.

Currently MitoSENS, one of LRMF's beneficiaries, is working on expressing these 13 mitochondrial genes from the nucleus, what they call "allotopic expression" (allo=other, topic=place).

Allotopic expression would entail gene therapy. Any gene therapeutic approach requires a great deal of time to get through clinical trials, due to safety concerns. 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.

(You may wonder what DNA is doing in mitochondria in the first place. The reason is that mitochondria used to be bacteria, billions of years ago. Before plants and animals split off, these prokaryotes infected eukaryotes (organisms whose cells have nuclei). These mitochondrial ancestors brought with them ATP-production. With this additional source of energy, the "infected" host eukaryotes now had an evolutionary advantage over the "uninfected", an advantage which has been passed down to all plants and animals. Because of the number of chromosomal genes that mitochondria use, we know that mitochondria used to have a thousand genes, but slowly these genes were expressed in the safety of the nucleus, setting up a symbiotic relationship between mitochondrion and host. Most of the mitochondral genome disappeared. Why 13 genes remain is of some debate but hopefully won't be a serious obstacle for MitoSENS. There are arguments that the obstacles are not of the type that can't be engineered around, such as dissolvability (and therefore transportability) in the cytosol separating the mitochondrion from the nucleus where the genes would be maintained.)