Reversing Mitochondrial Aging

Credit: NICHD/U. Manor

Increasing mitochondrial turnover and breakdown is able to drastically reduce mutation load in fruit flies, reversing age accumulated damage

Accumulation of deleterious mutations in mitochondrial DNA is believed to be a significant influence on the aging process, and ensuring healthy mitochondrial function is critical for good cellular function. If we want to live longer, healthier lives aging mitochondria are undoubtedly one of the primary rejuvenation targets in research today. 

"We know that increased rates of mtDNA mutation cause premature aging. This, coupled with the fact that mutant mtDNA accumulates in key tissues such as neurons and muscle that lose function as we age, suggests that if we could reduce the amount of mutant mtDNA, we could slow or reverse important aspects of aging"

An increasing burden

While the exact mechanisms are still being deciphered, it's clear that mutations in mitochondrial DNA (mtDNA) rise with age and lead to a rising burden of mutant mitochondria. Each cell has a large number of mitochondria at any one time. containing mtDNA. Most mitochondrial genes actually reside in the nucleus with the bulk of your DNA, but a few still remain at mtDNA inside mitochondria; encoding important proteins that are difficult to transport from the outside in.

Nuclear DNA does experience mutations, which of course can lead to cancer, but it's fairly well protected for the most part and undergoes relatively few mutations during age. mtDNA in contrast is at the heart of the engine of the cell, surrounded and bombarded with energetic molecules all the time. The cell has existing mechanisms to repair and prevent problems occurring because of this but they are insufficient to prevent a gradual rise in mutation during age. mtDNA is not repaired like nuclear DNA, but is instead discarded along with its host. This recycling system is used to bin dysfunctional mitochondria - maintaining a fresh population. It's thought that increasing levels of mtDNA mutations begin to impact on healthy function and drive part of the aging process. Mutated or damaged mitochondria are also linked to a range of neurodegenerative conditions including Parkinson's and Alzheimer's. 

Can we repair aging mitochondria? 

In an exciting study on the model organism drosophila, researchers at Caltech and UCLA have demonstrated a new technique to rejuvenate ailing mitochondria and significantly decrease the number containing mutations.  They began by engineering fruit flies to undergo early and increased levels of mutation in mitochondrial DNA exclusively within their wing muscles, which led to about 75% of the mtDNA became mutated in early adulthood. In order to tackle this level of mutation the researchers turned to stimulation of mitophagy, the turnover and breakdown of mitochondria.

A previous study has already shown that increasing expression of a gene called Parkin can extend drosophila lifespan by up to 25% and maintains them in better health for longer by increasing mitophagy. Too much Parkin was damaging because it removed healthy mitochondria too, but just the right increase proved highly beneficial. In this new study researchers used a number of strategies to increase autophagy and activated the PINK1/parkin pathway this did indeed decreases levels of mutated mtDNA. When they decreased levels of mitofusin (a protein present on the outer membrane involved with mitochondrial division) and increased levels of a gene called ATPIF1, they further lowered levels of corrupt mtDNA. 

 

The effect was so striking that overexpression of Parkin reduced the fraction of mutant mtDNA from 76 percent to 5 percent, while overexpression of Atg1 reduced the fraction to 4 percent

 

 

"Such a decrease would completely eliminate any metabolic defects in these cells, essentially restoring them to a more youthful, energy-producing state. The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes. Now that we know mtDNA quality control exists and can be enhanced, our goal is to work with Dr. Guo's lab to search for drugs that can achieve the same effects. Our goal is to create a future in which we can periodically undergo a cellular housecleaning to remove damaged mtDNA from the brain, muscle, and other tissues. This will help us maintain our intellectual abilities, mobility, and support healthy aging more generally"

A promising approach

The research is admittedly on fruit flies, but fundamental aging mechanisms remain strikingly consistent in many different organisms. If this process can be adapted and extrapolated to human trials in the future it could prove to be a great way of rejuvenating mitochondria throughout the body. The SENS Foundation is also working on a way to transfer remaining mtDNA into the nucleus where it will be much safer, so we can look forward to more exciting news in the future. 

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