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Youthful mitochondria

Optimizing Energy Production by Mitochondria. Podcast with Bruce Hay

Have you ever marveled at the energy of a young child? I have. Therefore, I wasn’t surprised this morning when I saw this article headline, Children are as fit as endurance athletes. Kids are fit in part because they have irrepressible energy to play. Yet some older adults seem to lack energy for anything. Why is there such a big change in energy in humans over the lifespan? That is the crux of this post.

Now, you’ll know that geroscience (the science of aging) is a subject of interest to us at humanOS. One reason is that scientists are beginning to crack the code on how to delay aging. A critical piece of this puzzle is maintenance of cellular energy. I’d wager that regardless of how old you are, you can look back in time and identify some amount of decline in your energy over your life. I can remember as a teenager constantly bouncing one leg whenever I would sit. I needed to move, I had too much energy not to.

A main interest of mine in geroscience is preservation of function. In large part, how you feel predicts how you live. I value taking care of my body (self-care is essentially the keystone principle of this entire humanOS.me endeavor), and it’s easier to look after yourself when your energy is good – it’s easier to go for a hike when you have the energy to do so.

Now, there are several promising anti-aging strategies, including calorie restriction, exercise, and certain drugs and nutrients. Interestingly, these strategies in part act through shared mechanisms. Several mechanisms involve effects on mitochondria – organelles in our cells that not only process nutrients into chemical energy (ATP) stores, but also influence cellular growth and death.

 

Mitochondria: a main source of energy

On hearing the word “genome”, many of us immediately think of the genome that contains the coding sequence that make proteins that comprise our body. This genome resides in the nuclei of our cells (it is nuclear DNA). You inherited your nuclear genome from your parents – half from Mom, half from Dad. But you also have many mitochondrial genomes, and you got these from your mom (and her mom, and her mom’s mom) only.

There are hundreds to thousands of mitochondria in each of our cells, and mitochondria produce most of our bodies’ ATP. Interestingly, the landscape of mitochondria within you is forever changing. They are always being created and destroyed, and they are also always fusing together (mitochondrial fusion) and breaking apart (mitochondrial fission). The reason they fuse is to combine their contents to maximize ATP production.

As we age, more of our mitochondrial genomes develop mutations. These mutant mitochondria are problematic because they accumulate over time and produce less energy than non-mutated mitochondria. Thus, mutations in mitochondria are a core reason for the perils of aging, which makes perfect sense: there is less energy to fuel activity and take care of body maintenance. As a result, function starts to deteriorate when the proportion of damaged mitochondrial DNA exceeds a certain threshold – perhaps about 70% of mitochondrial DNA – and the effects of aging become increasingly apparent. Unsurprisingly, there is a lot of interest in how to preserve mitochondrial function across the lifespan.

So, why do the mutant mitochondrial genomes tend to predominate with advancing age?

If mitochondria deteriorate with age and are passed on from mothers to their kids, why doesn’t mitochondrial function deteriorate with each subsequent generation?

And are there ways to enhance mitochondrial quality-control as the years pass by?

Such questions bring us to the subject of our latest podcast.

New strategy to keep cellular energy high across the lifespan Click To Tweet

Guest

In this episode of humanOS Radio I speak with Bruce Hay, Professor of Biology at Caltech. Much of Professor Hay’s work focuses on the genetic and molecular mechanisms that regulate cell death, cancer, and neurodegenerative diseases like Alzheimer’s. In brief, Professor Hay’s research has shown that “we want to slow or stop… accumulation of the mutant genomes that inexorably occurs as we age”.

Professor Hay and his team have done work (1) showing that when they stimulate mitophagy – a process in which mutant mitochondria are selected, tagged, and then shipped to organelles that break them down – healthy mitochondria substitute in place of dysfunctional mitochondria, rejuvenating cellular function. This finding that could have profound implications for those of us seeking to ward off aging.

Tune in below to find out more!

 

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References

  1. Kandul NP, Zhang T, Hay BA, Guo M. Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila. Nat Commun. 2016;7:13100. doi: 10.1038/ncomms13100.

 

CONTRIBUTIONS

Dan prepared for and conducted the interview, Greg wrote the first draft of this blog post, Dan edited the draft, and Dr. Hay continues to do the hard work!

 

Transcript

Bruce Hay: What we’ve been interested in, is the question of, whether mitochondrial DNA quality control exists and if it does exist, whether it can be stimulated.
Kendall Kendrick: humanOS. Learn. Master. Achieve.
Dan Pardi: Professor Bruce Hay, [00:00:30] welcome to humanOS Radio.
Bruce Hay: Thanks, glad to be here.
Dan Pardi: Today, we’re gonna be speaking about your fascinating work looking at mitochondria and the effects on aging. Let’s do a primer on what mitochondria are, first.
Bruce Hay: Mitochondria, first and foremost, are these double membrane bound organelles that are in, essentially, all cells in your body. What makes them particularly interesting is that there are hundreds to thousands of them in each cell. The mitochondria produce the bulk of the ATP that you [00:01:00] use every day, ATP is the energy currency of the cell. You need mitochondria to get things done, and in fact, the amount of ATP that you utilize, convert to ADP, and then back to ATP, is roughly your body weight in ATP, per day.
It’s a huge, ongoing process that takes in fuel from the environment, and converts it into energy of various sorts. Mitochondria work a bit like a dam [00:01:30] does, where water flows into the area that’s dammed, and then the energy stored in that water, taking advantage of gravity, gets utilized to turn turbines and that creates energy.
The mitochondria do pretty much the same thing and that they push protons out. That creates a large pool of these protons that are sitting out there that, because it’s charge imbalanced, they want to get in, and the way they get in, is they work through the ATP synthase, and as [00:02:00] they penetrate through the ATP synthase, they cause a rotor to turn, that ends up taking ADP and turning it into ATP. That’s the equivalent of the turbine for a power plant.
The other critical thing about mitochondria, is they have their own genome. The key thing about all of the cells in your body is that you don’t just have one genome floating around in each of your cells, you actually have thousands of genomes. You have your nuclear genome, where you got one copy from your mother, [00:02:30] one from your father, but with respect to mitochondrial genomes, you have hundreds to thousands of them. Those are distributed among these organelles floating in the cytoplasm. We’ll just abbreviate it as mtDNA. So, you need this, in order to create energy, you need this DNA.
A final feature of mitochondria that turns out to be very important, they’re not just static structures that sit in the cytoplasm like parked cars. They actually fuse with each other and then [00:03:00] share contents and then they can also break apart, undergo fission. They should, in many ways, be thought of as, kind of a dynamic network in which, they’re coming together, going apart, sharing, being isolated for a while, coming back together, and that sharing is very important because, it’s a bit like a team.
If you’re working as a team, you can share components. The sharing of components allows cells to, often times, maximize [00:03:30] the amount of ATP that they want to produce. This turns out to have important consequences because it also does something else that’s not so good, that defeats the ability to identify mitochondria containing mitochondrial DNA that is in some way mutant.
The way to think about this is the idea of quality control. The question is, mitochondria are always being generated, they have to work very hard, they create a lot of free radicals, [00:04:00] a lot of damaging small molecules, and eventually they get turned over. So, even in non-dividing cells like muscle and neurons in your brain, the mitochondria are always being generated and then always being destroyed.
That’s important, because if you didn’t get rid of these damaged mitochondria they would accumulate, and your cells wouldn’t survive that, because they would lose the ability to generate energy. If a team is always together, it’s hard to identify [00:04:30] those who aren’t pulling their own weight, because everybody is sharing. What a quality control system needs, in some way, when you’re talking about team members, is it needs for those team members to be isolated at some point, where you can actually observe how they do on their own. Do they each have a basic ability to accomplish the tasks that are needed?
An important idea in the field now is that, fission provides one way of doing that, because by having mitochondria [00:05:00] isolated from each other, you’re providing an opportunity for them to be tested for their ability to make this charge gradient that allows them to make ATP. If they can’t, then perhaps, that acts as a signal that tells the cell to remove those mitochondria, and thus, potentially, to remove the damaged mtDNA.
The thing that comes up with aging is, often times, it seems like bodies are designed to maximize short- [00:05:30] term gains. What I mean by that is, to maximize your fitness, up through, let’s say you’re 40s, because in preindustrial life, that was the average lifespan. If you survived to birth, your expected lifespan was 40s, not 80s, 90s, and 100s, which is what we’re trying to achieve now, with an average life expectancy in the 70s and 80s, depending on the culture.
The key issue with respect to quality control and mtDNA, and the fact [00:06:00] that there are many mitochondria, or many mitochondrial genomes per cell, is that quality control may take a backseat, often times, to meeting more immediate cellular needs, like maximizing ATP production, allowing you to do the things you need to do, when you’re young, to survive, to thrive, and to maximize your output in various ways.
With quality control happening, when you have time for it as a backseat activity, the way I think about [00:06:30] it is, if you were to see my office, you would see a big mess. That’s because, at least with me, housecleaning always takes a backseat to some other more immediate emergency.
Thus, we think, in some sense, that cells may often times, do a similar sort of thing. They have short term, very immediate, important goals and quality control may often times take a backseat to that. Which is fine when you’re young, but as you get older, and as that damage starts to accumulate, [00:07:00] then you would really like it if quality control could kick in and do a bit of housecleaning.
Dan Pardi: In every cell we have hundreds to thousands of these organelles. They’re always being generated, and they have their own genomes. It’s not just one genome for all mitochondria, but thousands. They generate energy from broken down food products and it produces energy like a turbine. They fuse together to work as a team, to more efficiently produce ATP, but this creates room for [00:07:30] mutant DNA to be produced, and the body’s always trying to maximize for short-term gains, therefore, quality control happens when there are less emergencies happening.
Bruce Hay: That’s right. Another important concept that’s worth thinking about, and sort of keeping in mind when we think about mitochondria is that, they originally arose as the result of an endosymbiotic interaction between some cell, long ago in the past and another cell, which engulfed that cell. The one that was engulfed, ultimately became [00:08:00] the mitochondria. Endosymbiosis meaning, taking up some other organism and keeping it within you.
Over many, many millions of years, that set of interactions between the host cell and the bacteria that became the mitochondria, has created this thing we call the eukaryotic cell. The magic of the eukaryotic cell, is that because it has these thousands of mitochondria, it effectively, internally, has a really high surface area [00:08:30] that allows you to collect these proton charges. The magic of eukaryotic cells is, they’re able to create, store and utilize much more energy than prokaryotic cells, because they have all of these mitochondrial membranes that are working hard to store this energy.
But, the flip side of this is that, we should also think of mitochondrial DNA in a way, perhaps, still having their own selfish interests. [00:09:00] Is the mitochondrial DNA that survived from being in you when you were a baby, and because there is constant turnover, the mitochondria in you today aren’t necessarily the ones that make you the most fit, you, the individual. They’re the ones that survive this intracellular competition with other mitochondria and other mitochondrial genomes. It’s perhaps, not surprising that the ones you see [00:09:30] as you age are the ones that manage to avoid being degraded.
What you see, are the survivors, you see the ones that have found a way to increase in frequency. The reason this relates to aging is that it turns out, as we age, we accumulate mutant mitochondrial DNA, such that, at some point, cells have so much mutant mtDNA that they, either, die or become otherwise dysfunctional. That [00:10:00] leads to loss of function in critical tissues like, heart, muscle and the nervous system.
A very interesting question that we don’t know the answer to is, to figure out how it is that mutant genomes, in particular, deleterious genomes, seem to preferentially get amplified. There seems to be something a little bit haywire in cells, often, such that, the quality control machinery, while it may exist, it doesn’t get rid of [00:10:30] the bad mitochondria with their mutant genomes. Those genomes have instead, found some way to increase in frequency and that then leads to a problem with aging.
Dan Pardi: Are there signals in the environment that are somehow shaping the situation about how many mitochondria are present, and what type they are? I’m getting at the question of, the chicken or the egg, with aging. Is something hurting the energy system, allowing for this accumulation of damage to happen?
Bruce Hay: I guess the way I think about aging is, that it involves a lot of different [00:11:00] things. We don’t want to imply that mitochondria are the only thing that goes wrong, but it often times works in cycles. There are things from the environment that influence the mitochondria, the amount of energy they’re able to generate, stresses that are placed on them from the environment. They respond, and as a part of that response, as a part of making ATP, they create their own damage within the mitochondria, that ultimately has to be, either, repaired or the mitochondria have to be removed.
Damage accumulates [00:11:30] from both directions, both from inside the mitochondria, the mtDNA itself, because it’s next to these oxidate phosphorylation electron transport chains, and those end up producing a high frequency of oxygen free radicals and those can damage DNA. So, damage is definitely created within the mitochondria and it can come from outside, as well.
Dan Pardi: Bruce, is there a way to influence this process in a manner that’s beneficial to us?
Bruce Hay: Great question. [00:12:00] A couple of answers. The nuclear DNA is well positioned for repair, because we have two copies of all of our chromosomes. What that means is, that if the copy you inherited from your father is damaged in some way, the copy you have from your mother can actually act as a template for repair. In that way, through homology based repair, you can oftentimes reconstruct the information that was lost in the damaged strand.
Mitochondria do [00:12:30] have repair pathways, because they do get damaged all the time, but in the animals, little evidence for frequent recombination of the sort that happens in the nucleus. And because mitochondria are only inherited through your mother, what tends to end up in cells and in mitochondria are just one kind of mitochondrial genome. The independent genomes tend not to interact with each other. That lack of interaction, then means, that they often [00:13:00] times don’t have some other partner to exchange information with, if there’s damage to one of the molecules. Then, this is how the damage occurs.
An interesting question is, of course, how I’ve told you that damage accumulates throughout your life, but how is it that women, every generation, give rise mostly to offspring who are healthy, even though on average, every woman who gives birth, let’s say, is 30 years old? Your great, great grandmother [00:13:30] gave her mitochondria to your great grandmother, who gave them to your grandmother, who gave them to your mother, who gave them to you, those mitochondria are now 100 years old. How is it that those genomes aren’t complete garbage?
The answer is, that in the female germline there are mechanisms of quality control that tend to weed out, either, defective mitochondria with defective mitochondrial DNA, or … These aren’t necessarily mutually exclusive, [00:14:00] they’re removing cells in the early germline of females that happen to have a preponderance of mutant genomes. Selection can happen either at the level individual mitochondria, or it can happen at the level of cell death.
Now, that’s fine for thinking about the germline, but cell death is not the way we want to think about the somatic cells in our body, the body we care about on a daily basis, muscles, neurons and brains. There, what we want [00:14:30] to do is we want to slow or stop and hopefully even reverse, this accumulation of the mutant genomes that inexorably occurs as we age, because we can’t really stop the damage. Damage is a function of ATP production. That damage is more or less inevitable. Things like taking antioxidants and so on don’t seem to actually help with that, oftentimes, they actually make the situation worse.
What we’ve been interested in, is the question [00:15:00] of whether mitochondrial DNA quality control exists, and whether if it does exist, it can be stimulated? The focus of our recent paper is addressing this question. The way we do this, is by creating animals that artificially have a lot of damage to their mitochondrial genome. We actually express a restriction enzyme in drosophila, in muscle tissue, postmitotic tissue that cleaves the mitochondrial genome twice [00:15:30] and then snips out a piece and then like it took back together again.
It creates a circle but a circle is a smaller circle and its missing genes required for electron transport proton pumping, so that then generates a situation in which we now have young animal that have an old flies mitochondrial DNA, and then what we ask is what happens to that mitochondrial DNA when we tweak various cellular pathways [00:16:00] with the golden of asking. We know this happens in all animals, we know it happens in humans.
You can watch it happen in muscle by taking biopsies of people over time, they accumulate these mutations that ultimately cause the death of muscle fibers, this strength as we age. So we can model this in Drosophila in flight muscle which turns out to be one of the most energy intensive muscles in the world, because it has to be hundreds of times per second [00:16:30] and keep the fly able to fly over really long distances.
The long and the short of it is, then when we build these flies we get a very high frequency of mutant empty DNA about 75%. When we then look at quality control what we find is that in fact it is possible to selectively eliminate the mutant mitochondrial genomes.
Dan Pardi: How do you go about that?
Bruce Hay: If the mitochondria loses its membrane [00:17:00] potential because it’s lost the ability to do electron transport then that causes the mitochondrial membrane to depolarized that the polarization stabilizes the PINK protein on the mitochondria, PINK recruits Parkin ubiquitinates modifies a number of other proteins and that then ultimately results in the damaged mitochondria being taken up by autophagy, taken up by membrane structures that target it off to the [00:17:30] lysosome sort of garbage disposal of the cell.
The question then became that pathway has been known now for a few years, but what’s never been clear is does that pathway act at the level of just the mitochondria or can it selectively promote the removal of just those mitochondria that carry mutant mtDNA damage genomes. What we found which is really exciting is that if we simply stimulate the autophagy process [00:18:00] which is normally occurring at a basal level in the cells, or if we increase the activity of PINK and Parkin, either one of those modest increases in activity can drive down the level of mutant genomes from about 75% to about 4% or 5%.
That’s really a remarkable decrease because we know that you only show the consequences of having mutant mtDNA if you have a high frequency, something like [00:18:30] 75%, 60% or not. The goal really that’s implied by our work is that it may actually be possible to take one aspect of aging, this accumulation of damaged genomes that always occurs. We may actually be able to reverse it to actually get rid of the mutant genomes and then allow cells to repopulate themselves with the remaining genomes which by definition are functional.
Dan Pardi: You created this model [00:19:00] in fruit flies that was aiming to reproduce older phenotype within a younger animal. Mutant DNA, it’s about 70% in the cell which is the level at which it becomes really problematic.
Bruce Hay: That’s correct.
Dan Pardi: By reducing it down to 4%, is 4% closer to the level that most of us start with?
Bruce Hay: Oh yeah, it turns out that almost all of us carry some level of mutant mtDNA when we’re bored, because not all of it gets cleared out through [00:19:30] this maternal quality control mechanism. Again, as soon as you’re born you’re 68 pounds you have a huge number of cells, those cells have already started to accumulate some of this damage. Then again, through this mysterious mechanism that we don’t understand some of the mutations that you inherited from your mother are going to comely expand their increasing frequency.
I should mention that mothers are perfect in [00:20:00] getting rid of these mutant genomes and that’s why there’s a whole family of maternally inherited diseases of the mitochondria that are quite devastating, because the individuals who inherit a significant fraction of the mutant genomes then those genomes expand and they end up affecting our muscles, eyes, other tissues. So oftentimes people with these mitochondrial diseases will show an age dependent but oftentimes early age dependent [00:20:30] decline and all of the things that we care about.
Dan Pardi: Were you able to study the function of the muscles in the fruit fly wings after stimulating [mit of 00:20:41] aging.
Bruce Hay: We were but the results were not bad, the bottom line is in the flight assays that we used it’s a very short distance flight assay. At the altar structural level the muscles look fine, at the flight level flying after you release them into a container that also [00:21:00] seems to be fine, that reflects the fact that this essay is really just a do the muscles function at all assay. To really test mitochondrial DNA, you oftentimes need something a little more extreme like anaerobic exercise or a long flight if you’re a fly.
Our allies even though they have 70% mutant genomes, at a gross level they’re pretty normal. They can fly for short distances in a bottle which is as far as they can go because [00:21:30] the bottle is pretty small. So they look normal. This actually is the same thing that happens in humans, you really only start to see problems at the cellular level and the organismal level when the frequency of the mutant genomes reaches 70%, 80%, 90%.
The reason is again it comes back to this idea of sharing even though you have a high frequency of these mutant genomes, so long as the mitochondria that host them are fusing with [00:22:00] each other creating this interlock network, the good mitochondrial genomes can buffer the dysfunction that’s caused by having a high frequency of mutant genomes and so ATP production actually doesn’t, at the cellular level decrease oftentimes until you get a very high frequency of mutation.
Dan Pardi: Is there any plans for this work to move up into a different animal model?
Bruce Hay: Two ideas. One is to create a mouse that say creates deletions and young animals and tissues [00:22:30] we care about particularly the brain and the muscle and then use that as a system in which to identify genes and drugs that promote the selective removal of the mutant mtDNA.
At the same time, we would also create mammalian cell based screening systems, so of course what we’d like to do is to go screen for molecules that specifically target mutant mtDNA removed without having other effects on the cell.
[00:23:00] The way you do that is you start off for example with a cell based system and you find drugs that do what you want them to do and cell culture, and then you take those drugs and you go introduce them into animal models. The idea behind for example making a mouse or making other organisms that carry this construct of ours that induces mitochondrial deletions. With the animals you can then take the focus [00:23:30] out of drugs that you identified that had an effect in cell culture and you can go test those drugs now in animal models that are either distant way related to humans or fairly closely related like the mouse.
In that way, because mouse muscle ages in a very similar way to humans both in muscle and the brain. We can test the drugs for efficacy and also look for off target effects.
Dan Pardi: Are there any bio engineering techniques that are being looked at [00:24:00] to also affect [mit of 00:24:01] aging.
Bruce Hay: Because we’re talking mostly as we age with about postmitotic cells like muscles or neurons, we don’t have easy ways of getting large molecules like proteins into those cells because we would have to do them all throughout the body and in particular getting things into the brain can be quite difficult.
What we’re focused on then, is taking advantage of the fact that we know from our work where we get rid of the quality [00:24:30] control system completely, we see then an increase in the frequency of deletions that tells us that quality control does exist. The converse experiment increasing the levels of the quality control machinery and seeing we get a big decrease in the levels of the mutant genomes tells us that we can stimulated.
What we’re focused on is not so much genetic engineering in the classic sense of put a new genes into people but rather gently tweaking using small molecules, [00:25:00] components that normally would carry out the quality control but don’t because they’re usually tied up doing other things.
A good example of this is the whole cycle of mitochondrial fusion, fusion promotes ATP production, it is a great thing to do if you’re in a fight or flight situation or you’re using your brain a lot, using your eyes. You don’t have time for quality control. You have things to do, but if you want to have those cells be functional for a very long time, [00:25:30] you need a time for quality control.
We think the way to do that is to use small molecules that can and otherwise healthy people transiently up regulate these processes, so that they work a little harder for a while. Just like cleaning your office once a year, you spend one day, you do a little house cleaning and the hope is that you can eliminate some of this damage in a way that doesn’t have other effects on cells in your body, [00:26:00] but it’s an empirical question. We’ll have to try a bunch of those drugs.
Dan Pardi: There are thousands of mitochondrion cells that are digesting essentially, food substances, good extended periods of fasting. Give them some relief for quality control.
Bruce Hay: That’s a great question, it’s a very important question because we know that intermittent fasting caloric restriction does extend lifespan, that’s very clear. Now, why does it do that? One of the things that happens when you starve is you stimulate autophagy, [00:26:30] actually stimulate within yourself. This process of self-feeding, the cells are actually using that as a way to turn over resources that they already have within the cell if resources aren’t coming in from the outside.
A very interesting question would be either through intermittent fasting and/or through various kinds of exercise perhaps coupled with that can you create situations that are more conducive to quality [00:27:00] control such that then drugs that you take would have a better chance of stimulating this process.
An example of this that we found in our work is that if we simply decrease the rate of mitochondrial fusion, so we forced mitochondria to remain isolated from each other, longer than they normally would before they fuse with each other we could again dramatically stimulate the removal of the mutant genomes. Without suggest is that [00:27:30] it’s not only about stimulating autophagy and stimulating the PINK Parkin pathway that tags the mitochondria, but it’s also about decreasing the levels of these antagonistic processes mitochondrial fusion.
Because simply by allowing mitochondria to display their true colors, by keeping them in an isolated state you’re keeping them apart from the team and in doing that you’re requiring that they be able to generate their own ATP, or be [00:28:00] able to generate their own electron transport chain proton gradient. If they can’t do that, then the idea is that they’re recognized and removed.
The idea would be testing in various ways things like coordinately increasing autophagy and perhaps at the same time decreasing the amount of mitochondrial fusion, so that you try and create a synergy between the processes that are going on in the cell. You want to keep more mitochondria isolated, so they can be tested and degraded [00:28:30] if they’re found wanting.
But you also need to stimulate the basal process autophagy that picks them up and takes them away to the garbage disposal, because if either one of those things is not optimized for quality control, if it’s optimized for short term gains, then the system is just not tuned well and it won’t work well.
The idea is that, that’s why we age with respect to mitochondrial DNA, with respect to this accumulation of mutations that causes us to [00:29:00] lose strength, to lose cognitive function, and ultimately to have self-doubt is that fusion and fusion, autophagy, the PINK Parkin pathway. These are tuned to mostly take care of daily business. What we need to do is to tweak the system so that these processes are for some period of time more focused on our future self.
Dan Pardi: We’re very glad you’re working on this, it’s so important. Science takes time but it’s [00:29:30] also a thrill I think with a lot of the genome research that taking place right now in the various areas that relate to aging that there could be some really legitimate therapies for us within our lifetime.
Bruce Hay: There are a lot of things that go wrong with aging just to give us specific example that highlights the difference between the nuclear genome and the mitochondrial genome is the following. The nuclear genome does accumulate mutations and we have two copies of it, and that protects us to some extent but we only have two copies. [00:30:00] While those copies can be repaired, over time they accumulate mutations.
Importantly there’s no way of wholesale replacement of those genomes, so that kind of accumulation of damage is more or less inevitable and it’s not clear how we could reverse it other than through things like stem cell therapies, from cells from your own body. But again those also have to be from a younger you, not an older you otherwise you’re just putting an older genome back into you again.
Whereas with the mitochondrion genome [00:30:30] because they can undergo a process of quality control of selection based on their ability to maintain its proton gradient. With those genomes and because we have thousands of them per cell, we can’t afford to lose some of them because they can always be replaced, because every mitochondria divides a bit like a bacteria, it just divides mitochondrial DNA replicates. As long as there is a selection procedure [00:31:00] that works to eliminate the ones that can’t carry out the basic functions then we actually have hope for reversing this cause of aging.
Again, the key observations that make us think that mitochondria are important in aging is one that mitochondrial function very clearly does decline and a lot of tissues with aging, mutations do accumulate as you age in particular, and cells that lose function that we care about muscles and [00:31:30] neurons. Also from the mouse, there are very interesting studies where people have made versions of the DNA polymerase that replicates the mitochondrial genome that are mutation problem thus those mice accumulate a high frequency of mutations early in life.
In consequence, they actually show premature aging phenotypes, a lot of them altogether those kinds of observation is really suggests pretty strongly that mutant mtDNA [00:32:00] accumulation is likely to be an important cause of aging.
Again, not the only cause but what makes us excited is we think it really clearly is different and that it’s reversible. We really can house clean away these mutant genomes leaving behind the functional ones because you can carry out a selection, that’s just something you can’t do with a nuclear genome.
Kendall Kendrick: Thanks for listening and come visit us soon at humanOS. [00:32:30] me.