I came across a fun article recently published in Nature Communications titled "Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster." Here the authors were utilizing a model organism of fruit flies (Drosophila melanogaster) inorder to study an aspect of the aging process that many of us might not even know about, the functionality of our mitochondria. I think this is a pretty interesting paper and it will allow us to have a nice discussion about aging (perhaps even from a unique perspective for you). So lets dive in!

** Disclaimer: THERE IS A TON OF DATA IN THIS PUBLICATION, we will only discuss a subset of that data here. Please refer to the above linked article for more if you are interested in a deeper dive **

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This article is centered around this group of researchers interest in the relationship between aging and mitochondria that are not functioning properly. This is a concept that has been studied in some detail in the past, where researchers have identified that these dysfunctional mitochondria are linked to a variety of diseases that are associated with getting old (examples being: diabetes, heart disease, and metabolic syndrome). [2], [3], [4].

In fact there are a whole host of other diseases that also have links to less than functional mitochondria, which perhaps shouldn't be all that surprising considering this cellular organelle is the source of its energy (ATP) processing machinery.

A second concept they were exploring was the involvement of autophagy, the process that cells use to take out cellular garbage (break down broken components), in removing mitochondria that are not working properly.

They were interested in this as the rate of mitophagy (autophagy of mitochondria!) has been reported to decrease as we age. [6].

So, we know that mitochondria are linked to age related diseases, and the recycling process used to get rid of malfunctioning mitochondria slows as we age. These are two compelling reasons to think that aging and mitochondria might have a relationship.

Perhaps even one where the aging process can be slowed down by stimulating those very mitochondria?

Dynamin-related protein 1

The process of breaking down the old mitochondria is related to the inverse, mitochondrial growth processes as well. Mitochondria can replicate through a process called fission in which a single mitochondria splits into two (it requires replication of the mitochondrial genome... yes they have their own genomes).

This fission process requires a protein called Dynamin-related protein 1 or DRP1. Interestingly DRP1 is also required for the breakdown mitophagy process. [7]

The authors postulate that these findings are indicative that the splitting of mitochondria in the fission process, may be required to sequester away dysfunctional mitochondria, and allow for their destruction in the cellular garbage disposal...eer mitophagy process.

Enough Background Get To The Data

Okay.

Here the authors were studying mitochondrial fission in some flies. They wanted to see whether or not stimulating this fission process could lead to an extended fly lifespan. So they turned to the DRP1 protein, which is essential to the mitochondrial fission process and they cranked up the expression levels of this protein in the flies.

What they found is fascinating!

Figure 1 subsections d and e

In the figure above section (d), the authors increased the DRP1 expression in some young flies at times between 0 and 30 days in age (after 30 days they stopped the excess expression), when they did this (black dotted circles) there was no observable difference in how long the flies lived. HOWEVER, when the DRP1 expression in middle aged flies (so it was turned on after 30 days and left on) was increased (e) they found that the flies with the extra DRP1 lived quite a bit longer! You can see this as the black circles (where the protein was expressed) show a longer survival time then the open circles (where it was not expressed). They then confirmed that it was expression in the midlife period specifically that caused this effect.

So here we can see that the flies had the protein expression increased only from days 30 - 37 (mid life), however as a result of this the flies that had the protein expressed (circles with a black dot in them) lived longer then did the flies who never had the DRP1 overexpressed (circles with no black dot in the center).

This means that there is a time dependent component on when mitochondrial recycling is most important, and can extend lifespan. It also means that its a SPECIFIC time, as the protein expression doesn't need to remain on, the effect happens and remains even after the protein expression levels are back to normal.

What Else Was Going On With These Flies? Did Anything Else Change Which Aided Them In Developing This Increased Lifespan?

The authors explored some other aspects about the flies, for instance how often/how much they fed. Looking at the image to the right (a) you can see that the flies that had the DRP1 expressed more highly (red) did not eat more then the flies that did not have it expressed (blue), however in (b) you can see that the DRP expressed flies (again, red) were much more active.

The authors tested when this activity occurred and found that it was only during the day. So the flies were more active when they were awake but not restless at night.

More DRP1 Keeps Mitochondria Looking Young

So here what we are looking at are some red stained muscle cells and some green stained mitochondria. What you can see is that as time goes on the mitochondria in regular flies get much more elongated and stretched out, but in the right most box after 37 days and with extra expression of DRP1 the mitochondria look like those from much younger flies. Compare the size of the green mitochondria to the 37 day untreated sample directly to its left. Strikingly different!

The authors also discussed that expression of more DRP1 not only corrected the structure of the mitochondria but also restored them to more youthful function levels

Other Reported Findings

Increased expression of DRP1 was observed to:

• increase mitochondrial enzymatic levels
• reduce radical oxygen species levels. (Low levels are necessary, but levels too high are known to cause cellular damage)
• reduce levels of protein aggregation (clumping together into non functional blobs) in the mitochondria
• lower the amounts of mitochondrial DNA present in muscle tissue (hypothesized due to increased destruction of non functional mitochondria)
• Found that the autophagy process (how the broken mitochondria are degraded) is necessary for the added longevity that extra DRP1 caused

A ton of interesting information in this paper!

Brief Conclusions

In this article the authors explored a protein called Dynamin-related protein 1 (DRP1) which is necessary for both mitochondrial replication/splitting (fission) as well as the recycling process where broken old mitochondria get destroyed (mitophagy). They report that increasing the expression of this protein in flies that are middle aged, is able to pretty drastically extend the lifespan of those flies. Indicating that ability of mitochondria to be recycled is essential to longevity.

The results are so fascinating that I hope to read more papers looking into whether this phenomenon is possible in other model organisms as well. Can we extend the lifespan of a mouse through increasing the expression of the mouse variant of this enzyme when they are middle aged? If so, is this a potential avenue for improving the quality of our own lives? Quite fastinating stuff.

What do you think about all of this? Would you want to live a longer life if it required stimulating the expression of this mitochondrial growth/recycling protein? I think I would.

Sources

Text Sources

1. https://www.nature.com/articles/s41467-017-00525-4
2. https://www.ncbi.nlm.nih.gov/pubmed/23746838
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566449/
4. https://www.ncbi.nlm.nih.gov/pubmed/17243117
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990190/
6. https://www.ncbi.nlm.nih.gov/pubmed/26549682
7. http://cshperspectives.cshlp.org/content/5/6/a011072.full

Image Sources

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2. Image 1-2
3. Image 1-3
4. Image 1-4

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