Mitochondria and Aging

Sep 17, 2008

This is a compilation of recent articles and blog posts by Reason about mitochondria and aging.

***The latest news regarding autophagy, aging, and mito function - updated December 15th***

Originally appearing at Fight Aging! and The Longevity Meme

Many thanks to Reason (former director) on all his advocacy efforts throughout the years. We are a lot farther ahead in the game because of the Longevity Meme.

Further discussion found here and here (with comments from Aubrey De Grey).


Functional bridges preceded the tools and understanding of modern architecture, just as beneficial medical techniques preceded the biotechnology revolution. More knowledge and science brings better bridges and more effective medicine - but you can still do good and save lives at earlier stages in the progression of knowledge.

"Is [a full understanding of our metabolic biochemistry] important and useful? Yes, of course, very much so. Is this knowledge necessary for us to proceed to reverse and repair aging? No. We already know what the damage of aging is, at the cellular and molecular level. Knowing more about the way in which that damage twists our metabolism and controlling biochemistry will help, in the same way that modern techniques of architecture improve bridge building, but the absence of that knowledge does not hold back significant advances in the engineering of healthy longevity.

"The only present barriers hindering rapid and aggressive progress towards rejuvenation of the aged are those of will and funding. That is why we can all help to make a difference to the future of aging science - you don't have to be a scientist to help make will and funding a reality."


What are people willing to pay for a medical therapy that is expected to add healthy years to life? Following that trail will give you a good idea as to how the development and commercialization of longevity therapies will proceed over the next few decades. As it happens, good research on the value placed on life already exists:

"Studies of real-world situations produce relatively consistent results, suggesting that average Americans value a year of life at $100,000 to $300,000 ... So let's take the hypothetical of a longevity therapy that the consensus believes will add ten healthy years to the average life. Replacing age-damaged mitochondrial DNA might do that in humans, for example. This suggests that to bring a first widespread commercial version to the high-end medical practices of the world, the price tag on the therapy has to be brought down below $1-3 million, or the value of a decade of healthy life."

That's the story for first few years of availability, of course, in which investors are recouping their initial investments, and before competition and refinement of the technology has started in earnest. The price will fall rapidly and quality increase as many more groups enter the market: competition is what drives the path to faster, better, cheaper.

"The stable state for a medical treatment is that in which many specialist staff are available, and a competitive marketplace exists to train those staff and supply needed raw materials. At that point, the cost is much the same for medical procedures across the tiers of specialist labor and complexity - it's largely down to the wages of those folk performing the work.

"Replacing mitochondrial DNA should be a hands-off outpatient procedure, once the technology is mature. Have a sample taken, send it off to the lab to work up a repaired genome and the viral vector, get injected with the vector that will replace your mitochondrial DNA with repaired versions, and then come back for regular testing for a couple of months. That is nowhere near as labor intensive as, say, heart surgery today. So one could look at comparable procedures that require supporting individual lab work on the back end, such as limited genetic testing, and take a stab at the price tag in the $10-30,000 range."

"That's a hundred times smaller than $1-3 million, which seems fair for the progression from early version to mature technology, especially in this age of rapidly advancing biotechnology. It's also a hundred-for-one bargain on the consensus expectation of value of life gained, which is a pretty good deal - good enough to tempt a very broad customer base, and enough profit for a large and competitive industry to form."

By way of a reminder, safe whole-body replacement of mitochondrial DNA was first demonstrated in laboratory animals three years ago:

Mitochondrial DNA damage is presently believed to be one of the more important root contributions to aging:

Funding and regulation are the highest barriers to developing a working mitochondrial replacement technology, gaining a consensus as to how much it will likely add to human lifespan, and bringing it to human trials over the next five to ten years.

Hopefully you know the story behind mitochondrial DNA, free radicals and the accumulating damage to our biological machinery that we call "aging." If not, a summary of the modern mitochondrial free radical theory of aging can be found back in the Fight Aging! archives, and a more detailed version in the book "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime".
The very short summary: mitochondria inside your cells produce fuel to power cellular machinery, but side-effects of that process tend to damage the DNA the mitochondria carry within them - quite separate from the DNA in the cell nucleus, and much more fragile. An accumulation of damaged mitochondria over the years leads to more free radicals in the body, which in turn cause all sorts of varied destruction to molecular machinery and important molecules. That contributes to, and some would say is the dominant cause of, aging and age-related disease.
The best way to deal with all this? Either replace all the mitochondrial DNA with fresh undamaged versions every few decades, a feat demonstrated in mice a few years ago via protofection, or make the damage to mitochondrial DNA irrelevant by blocking its ability to generate more free radicals. This latter approach is used by Methuselah Foundation funded researchers, amongst others, and is a part of the Strategies for Engineered Negligible Senescence.
So, with the background out of the way, I can now point out some interesting research via FuturePundit. It seems that not all human mitochondrial DNA (mtDNA for short) is created equal: some leads to a more rapid accumulation of age-related damage than others. Perhaps not in all tissue in the body, and perhaps not of great enough relative significance to spend a lot of resources investigating, but take a look and see what you think based on this evidence:
Genetic variation in the DNA of mitochondria - the "power plants" of cells - contributes to a person’s risk of developing age-related macular degeneration (AMD)
Variation in the mitochondrial genome reflects human migrations and different environmental exposures. Changes in the mitochondrial DNA can alter the efficiency of energy generation and lead to over-production of "reactive oxygen species" - free radicals that can damage the cell.
"By identifying genetic changes associated with the mitochondria, our results lend additional confirmatory evidence for the role of oxidative stress in AMD. This supports study of interventions that attempt to bolster our antioxidant defenses."
The interesting question: if you're going to use protofection to replace your mitochondrial DNA every few decades, is it worthwhile to replace it with the best of breed, most efficient human mitochondrial DNA? Since you're wiping the slate clean every time regardless, and the normal course of human life suggests that 30 years is a fine length of time to be carrying a set of mitochondrial DNA without replacement, the answer might be "no," unless the additional cost is very small.
Looking at research priorities, identifying best of breed mitochondrial DNA, or manipulating our mitochondrial DNA to look more like it via some form of gene therapy, is clearly nowhere near as important or impactful as wholesale replacement and repair of all our mitochondrial DNA.



Mitochondria are the power plants of your cells, busy machines working to repackage the energy in food molecules into other forms. All machinery wears down with use, however. As time advances, damaged mitochondrial DNA becomes dominant in a small but important fraction of your cells, causing the mitochondria to switch to a less efficient mode of generating energy. This in turn causes these cells to export large numbers of reactive, damaging molecules throughout the body, contributing to many of the diseases and degenerations of aging. This is the mitochondrial free radical theory of aging in a nutshell:

As it turns out, damaged mitochondrial DNA may be at the root of other changes in aging as well. For example, evidence suggests that mitochondrial DNA damage is associated with the age-related slowdown in processes that repair nuclear DNA damage:

Also, consider the evidence for advancing mitochondrial DNA damage to accelerate the well-known shortening of telomeres with age, driving more cells into a senescent state that can damage surrounding tissue:

Now to add to all that, we have a recently discovered association between mitochondrial DNA damage and metastasis in cancer:

"Cancer often strikes its final, fatal blow when a tumor spreads to other organs. A new study sheds light on this poorly understood process, called metastasis. The researchers report that mutations in mitochondrial DNA can spur metastasis."

There's more to aging than just faulty mitochondria, but we should all be happy to see so much piled atop just one cause. The discovery of more benefits that could result from repair of mitochondria means a greater likelihood of significant funding for medical technologies capable of achieving that end. Any connection to cancer research, given the size of that field, raises the chances considerably.

When it comes to wholesale replacement of damaged mitochondria or mitochondrial DNA, progress has been very promising in recent years - with the important exception of the money side of the research equation. It has been several years since protofection of new mitochondrial DNA was demonstrated to work in mice, for example, and other groups have shown similar results via mechanisms discovered in tropical parasites. The state of funding in no way matches the potential for this sort of research, however.

Consider that it takes 30 years or more of life and wear for your mitochondria to become damaging to long-term health. With a single application of a working method of protofection in humans, replacing all mitochondrial DNA with an undamaged version, it is plausible to think that we could entirely remove this significant contribution to age-related degeneration for an additional 30 years. I think that merits a great deal of attention.



Damage to mitochondrial DNA (mtDNA), the blueprint for your cell's power
plants, is an important component of aging. When one or more of a few
important genes in a mitochondrion are damaged or deleted, that
mitochondrion begins to malfunction. This leads to a growing chain of
molecular and cellular damage, expanding to disease and degeneration of
health. Now researchers are peering into individual cells to catalogue the
damage they see:

"By employing quantitative single cell techniques, we were recently able to
show significantly high levels of mtDNA deletions in dopaminergic
substantia nigra (SN) neurons from [Parkinson's disease] patients and
age-matched controls. In the present study we used the same approach to
quantify the levels of mtDNA deletions in single cells from three different
brain regions (putamen, frontal cortex, [substantia nigra]) of patients
with [Alzheimer's disease] as compared to age-matched controls."

The short of it: we all have a lot of deletions when we get old, as
expected in the mitochondrial free radical theory of aging. Some regions of
the brain get hit worse than others, such as the population of neurons
whose loss causes Parkinson's disease, but it's a universal problem - and
not just in the brain.

As I point out in the post linked above, there are a good half-dozen
methods presently in early conceptual or laboratory demonstration stages
for replacing entire mitochondria, replacing damaged mitochondrial DNA, or
restoring function without repairing damage. These are important
technologies for the future of our health, as we all suffer from the
results of degraded mitochondrial DNA. This research should be receiving
much more attention and funding than it is at present - and that is
something we can all help with. Start by showing your support for the
MitoSENS project of the Methuselah Foundation:

MitoSENS website



A nice demonstration in mice shows that at least one genetic change exists
that significantly slows the pace of age-related mitochondrial dysfunction
and consequent degeneration of the brain. For the specific details, have a
look at this Fight Aging! post:

"Mitochondrial transcription factor A (TFAM) is now known to have roles not
only in the replication of mtDNA but also its maintenance. TFAM transgenic
(TG) mice exhibited a prominent amelioration of an age-dependent
accumulation of lipid peroxidation products and a decline in the activities
of complexes I and IV in the brain.

"In the aged TG mice, deficits of the motor learning memory, the working
memory, and the hippocampal long-term potentiation (LTP) were also
significantly improved. The expression level of interleukin-1beta
(IL-1beta) and mtDNA damages, which were predominantly found in microglia,

significantly decreased in the aged TG mice."

Doing something about the decay of mitochondrial function has a number of
evident benefits, as demonstrated above. But slowing things down is a
second rate strategy at best - especially if it involves genetic
engineering, a technology unlikely to be in widespread use for humans for
another ten to twenty years. A slowing of damage does little for those who
are already damaged and aged. What we really want to be capable of
achieving is reversal of existing damage - to be able to restore old and
damaged mitochondria to a pristine state. This goal is unlikely to be any
more expensive or time-consuming than engineering a slowing of
mitochondrial decay, so it should be the first priority.

Further discussion found here and here.