Longevity Briefs: Replacing Aged Mitochondria With The Help Of Magnets

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The mitochondria are the power plants of the cell, responsible for producing the cell’s universal ‘fuel’ known as adenosine triphosphate (ATP). Deep in our evolutionary past, mitochondria were separate organisms and still retain some of their own DNA, kept separate from the DNA in the nucleus at the centre of the cell. This unfortunately makes mitochondrial DNA particularly prone to damage, and with age an increasing proportion of mitochondria within the cell become dysfunctional. This is thought to contribute to many age related diseases.

There are several approaches we could take to tackle mitochondrial dysfunction. Some involve reversing dysfunction or preventing it in the first place, but another option is simply to provide cells with new, healthy mitochondria grown in a bioreactor. This is possible because human cells will readily accept foreign mitochondria without immune rejection. Over time, these cells may clear the dysfunctional mitochondria – effectively replacing them with the healthy ones. The difficulty is getting those mitochondria into the target cells in the first place, as mitochondria don’t survive well in the blood, nor will they necessarily be taken up by the cells that need them. In this study, researchers develop and test a system for delivering mitochondria to target cells within the body – in this case bone marrow mesenchymal stem cells (BMSCs). These cells play a vital role in bone healing, but suffer from mitochondrial dysfunction in old age. This impairs their ability to divide and contributes to slow bone healing in the elderly.

The discovery:

The researchers’ delivery system used gelatin hydrogel microspheres. These are essentially microscopic capsules made of artificial cell membranes and a protein core, approximately 6.5 micrometres in diameter – about the size of a red blood cell and several times smaller than an average BMSC. Mitochondria from foetal mouse BMSCs were then loaded into these microspheres in order to protect them from damage in the blood. However, that wasn’t all – researchers also incorporated magnetic materials into the mirospheres so that they could be concentrated at the desired location using magnets placed outside the body. The microspheres were also designed to be stable at low storage temperatures but to begin to dissolve at body temperature.

After confirming that the microspheres showed the desired properties, researchers injected them into three groups of 5 18‑month-old mice with fractured tibias, using magnets to concentrate the microspheres at the injury site. They found that, compared to control mice or mice given foetal mitochondria alone, mice that were treated with the microspheres had reduced inflammation and markers of senescent cells (cells that are incapable of dividing) and, most importantly, significantly accelerated fracture healing without any evidence of toxicity. Fracture lines disappeared nearly completely in microsphere-treated mice after 3 weeks, whereas residual fracture lines were still visible in other groups. There were also statistically significant improvements in metrics of bone healing (like the ratio of bone mass to tissue mass) in microsphere treated mice compared to the other two groups.

The implications:

This study shows how advances in bioengineering are bringing promising but previously impractical solutions to age-related disability closer to clinical use. Being able to provide healthy mitochondria in a targeted way could be beneficial in many age related diseases, perhaps most enticingly in cognitive decline and neurodegenerative disease, since mitochondrial dysfunction seems to play an important role in both. Mice are, of course, much smaller than humans, and the magnetic targeting approach may not work as well in larger animals. There is also the issue of obtaining the large numbers of mitochondria that would be necessary to make such therapies practical. Techniques for growing mitochondria in bioreactors are making progress, but for the moment, a therapy like the one described here would most likely be impossible to implement today, even if it were proven to be effective.