Mitochondria in Aging, I Mechanisms and Background

A popular theory a generation back sought to trace aging to oxidative damage originating in the mitochondria.  Every cell in the body has hundreds or thousands of mitochondria, the sites of the high-energy chemistry that produces ROS as toxic waste. The hope was that by quenching the ROS, aging might be turned off. The “Mitochondrial Free Radical Theory” is built on a flawed theoretical foundation, and anti-oxidants don’t extend lifespan. Nevertheless, the mitochondria play a role in aging.  Historically, mitochondria were mediators of the first organized mechanisms of programmed death over a billion years ago, and they retain a role in processing signals that regulate lifespan.  Curiously, though a quadrillion mitochondria are dispersed through the body, they act in some ways like a single organ, sending coordinated signals that regulate metabolism and affect aging.

Mitochondria are in the cells of all plants and animalshundreds or thousands of mini power plants in each cell.  They burn sugar to make electrochemical energy in a form the cell can use.  They are loyal and essential servants.  But it wasn’t always so.  More than a billion years ago, mitochondria came into the cell as invading bacteria.  Though they’ve long ago been domesticaed, they retain a bit of their autonomy as a relic of the past.  Mitochondria have their own DNA.  Like bacteria, mitochondrial DNA is in the form of loop, a plasmid rather than a chromosome.  Each mitochondrion keeps several copies of the plasmid.  

Mitochondria retain from their distant pathological past the capacity to kill the cell.  This is an orderly process known as apoptosis=programmed cell death.  Mitochondria are not the jurors that sentence the cell to death, but only the executioners acting on external signals.

Aging of the body as a whole is centrally coordinated, though the nature and location of the clock(s) remain a major unsolved problem.  Communication about the age state of the body is carried through signal molecules in the blood, and tissues respond accordingly.  Mitochondria not only pick up on these signals, they also contribute circulating signals of their own.  Apoptosis is dialed up in old age.  Along with inflammation, it is a primary, local mode of the self-destructive process that is aging.  We lose too many cells to apoptosis, cells that are still healthy and useful, and mitochondria are the proximate cause of this loss.

Portrait by scanning electron microscope, artistically colorized


Signaling, up, down and sideways

The big picture is that mitochondria take their orders from the cell nucleus, where the vast majority of the DNA is housed.  The transcription factors that determine what mitochondrial genes are expressed are housed in the nucleus.  In addition, there is feedback, retrograde signaling, by which mitochondria communicate to the nucleus the state of their own health and of the cell’s energy mtabolism in general.  The nucleus responds with changes in transcription based on communication from the mitochondria.

A great part of the diverse benefits of caloric restriction, and perhaps of exercise, too, are thought to originate in signaling from the mitochondria.  

In addition to sending and receiving signals from the cell nucleus, mitochondria talk to each other.  They coordinate extensively within a cell, and they also generate hormones that are transmitted through the bloodstream, talking to distant cells and foreign mitochondria.


Mitochondria and Cancer

Cancer cells have impaired mitochondrial metabolism.  They don’t burn sugar through the usual, high-efficiency mode that combines with the maximal amount of oxygen; rather they use fermentation—anaerobic breakdown of sugar.  Cancer cells do this even when oxygen is plentiful, despite the fact that it generates much less energy per sugar molecule.  Cancer cells are starved for energy, and they gobble up sugar at a high rate.  (PET scans are able to visualize tumors on the basis of their sugar consumption.)  Eating a very-low-carb diet is a cancer therapy.  

90 years ago, a Nobelist and Big Thinker in biomedicine named Otto Warburg gave us the hypothsis that mitochondria with impaired glucose metabolism are the root cause of cancer.  We usually think of cancer as starting with mutations that lead to uncontrolled growth and proliferation, but in the Metabolic Theory of Cancer, mutations and proliferation are secondary to this change in mitochondrial chemistry.  Today, proponents of the Warburg Hypothesis are a small but enthusiastic minority, armed with facts and arguments that I have not yet found time to assess.  But I am struck by the fact that when the nucleus of a cancer cell is transplanted into a healthy cell, the healthy cell remains healthy; and when the nucleus of a healthy cell is transplanted into a cancer cell, the cell remains cancerous [ref, ref].  This seems to be prima facie evidence that the essence of cancer is not to be found in chromosomes of the nucleus.


Fewer, less efficient, and more toxic waste with age

We have fewer mitochondria as we age, and this is plausibly connected to lower muscle strength and endurance as well as energy in the organ that uses energy most intensively=the brain [ref].  The relationship is subtle enough that it is not completely nailed down, despite decades of work from true believers.  Since mitochondria mediate apoptosis, it is also plausible that loss of muscle cells and nerve cells with age (at least partially through apoptosis) is also mediated by mitochondria.

Cells that need a lot of energy have a lot of mitochondria. Heart muscle cells are packed with them.

Compounding the problem, the mitochondria that we do have become less efficient with age.  They are giving us less energy, and they are generating more reactive oxygen species (ROS).  Simultaneously, the cell is generating less of the native anti-oxidants that protect from ROS.  Glutathione, ubiquinone, and superoxide dismutase all decline with age.  This is one of the ways the body destroys itself.  Oxidative damage accumulates in old but not young people.  Oxidative damage may also contribute to telomere shortening.

Somehow, ROS generated by impaired mitochondria produce damage that accumulates, but ROS generated by exercise signal the body to ramp up the repair processes, and produce a net gain in health.  It is not clear how the two processes are distinguished.  The reason that anti-oxidants don’t work to extend lifespan is probably that they interfere with the signaling functions of ROS.

The best-documented way in which mitochondria deteriorate is that their DNA develops mutations.  I find this something of a conundrum—not that mitochondria should accumulate mutations over the course of a lifetime but that they don’t accumulate mutations from one generation to the next (in the germline).  Mitochondria proliferate clonally, without sex.  Sex shuffles genes in many combinations, so that the good genes can be separated from the mutated ones, and the latter eliminated before they get fixed into the genome.  Without sex, how do mitochondria avoid accumulating mutations over the aeons?  And since they largely do manage to avoid accumulating mutations over millions of years, why can’t they avoid accumulating mutations over the course of a few decades within a human body?


Are mutations in mitochondrial DNA a cause of aging?

Mitochondrial mutations accumulate with age.  Genetically modified mice with a defective gene for replication of mitochondrial (but not nuclear) DNA age faster and die earlier.  This has generally been taken as proof that mitochondrial mutations are a factor in aging, but it need not be so.  In fact, mitochondria function well with a high tolerance for genetic errors, and it is not clear whether levels of mitochondrial mutations in aging humans cause significant problems, or even whether mutations are related to the general decline in mitochondrial function with age.  An alternative explanation for the mito-mutator mice is that they have developmental problems already in utero, and these may lead to premature aging even without accumulation of mito mutations.

Mitochondrial mutator mice

Stem cells keep dividing and producing new functional (differentiated) cells through the life of the animal.  They seem smart enough to minimize the damage from mitochondrial mutations.  Stem cells have been observed to hold on to the best mitochondria, and pass the damaged ones off to the cells that have a limited lifetime. This helps keep the errors from proliferating, and is in the best interest of the organism as a whole.  It’s interesting that mother budding yeast cells do the opposite—they hold on to their damaged mitochondria and pass the cleanest and purest on to their daughter cells [ref].  Mammalian mothers also seem able to choose the best mitochondria to pass to their daughters, purifying the germline [ref].  In other words, though their behavior is the opposite of stem cells, both behaviors are adaptive for the long-term interest of the organism (and its progeny).

In summary, the age-related increases in oxidative damage and ROS production are relatively small and may not explain the rather severe physiological alterations occurring during aging. Consistent with this hypothesis, the absence of a clear correlation between oxidative stress and longevity [across species] also suggests that oxidative damage does not play an important role in age-related diseases (e.g., cardiovascular diseases, neurodegenerative diseases, diabetes mellitus) and aging. Experimental results from mtDNA mutator mice suggest that mtDNA mutations in somatic stem cells may drive progeroid phenotypes without increasing oxidative stress, thus indicating that mtDNA mutations that lead to a bioenergetic deficiency may drive the aging process [but this is not assured, since these mice seem to suffer substantial damage already in utero]. There is as yet no firm evidence that the overall low levels of mtDNA mutations found in mammals drive the normal aging process. One way to address this experimentally would be to generate anti-mutator animal models to determine whether decreased mtDNA mutation rates prolong their life span. [Bratic & Larsson review]


Mitochondrial evolutionary conundrum

Mitochondria reproduce clonally, like bacteria.  In fact, all the mitochondria in your body were inherited from one of your mother’s egg cells, and she got her mitochondria from your maternal grandmother, and so forth back in time—matrilineal all the way.  How is it that defects don’t accumulate in the mitochondrial genome?

As far as I know, the way in which the integrity of the mitochondrial genome is maintained remains an unsolved problem.  We do know that mutations in mitochondrial DNA increase with age in some tissues but not others [ref].  The reason you have to speak up when you talk to your grandmother is probably related to mitochondrial defects in neurons [ref].

Over the course of millions of years, mitochondria do not lose their genetic integrity, though the mitochondrial genome evolves more rapidly than the nuclear genome, and different species tend to have distinctive mitochondrial genomes.  The mystery is why detrimental mutations should accumulate over decades, but not over aeons.

To me, this is powerful evidence that there is a mechanism for managing the evolution of the mitochondrial genome.  It probably involves selection by the cell so that mitochondria that are functioning efficiently are encouraged to reproduce.  The cell acts like a human lab that is breeding tomatoes or Labrador retrievers for specific characteristics that the breeder or the cell finds most useful.  Probably there is also gene exchange among the different copies of the plasmid within a mitochondrion, and between mitochondria as they sometimes merge during the lifetime of a cell (my speculation).


What’s going on?

A theme in this blog (and in my thinking) has been that aging is not a dispersed process of locally-occurring damage, but is centrally orchestrated.  Well, mitochondria are about as far from “central” as you can get.  We have about a quadrillion of them, dispersed through every cell in the body (except red blood cells).

Mitochondria talk to each other within a single cell.  They merge and they reproduce, coordinating with one another and with the cell nucleus.  Now it appears they also send signals through the bloodstream (more next week).  Could they be acting like a single organ, dispersed through the body? Maybe.  Sensing the body’s state of energy usage and fuel sufficiency, they send signals that contribute to calculations about lifespan.

My guess is that aging is coordinated by a few biological clocks (centralized like the suprachiasmatic nucleus and the thymus or dispersed like telomeres and methylation patterns), and that mitochondria are not counted among the clocks.  But mitochondria are important intermediates.  The old story is that they generate energy and generate tissue-damaging ROS.  The new story is that they are also centers of signal transduction, probably based on their first-hand knowledge of the energy status of the body.

End of Part I.
Next week, I will discuss some supplements
and health strategies based on mitochondria.

34 thoughts on “Mitochondria in Aging, I Mechanisms and Background

  1. Interesting article about something that affects me directly. I do have a mitochondrial mutation (single large scale deletion). My primary symptoms are ptosis (droopy eyelids) and diplopia (double vision, corrected by surgery). Other than that, I am doing fine.

    For what it’s worth, I am 46 years old, but people often tell me that I look 5-6 years younger. I eat well, do some exercise and sleep religiously 7-8 hours per day.

    Can’t wait for part 2. In case you haven’t looked at it, melatonin is probably one of the best supplements for mitochondrial health. I take 1mg (rest days) or 3 mg(workout days) before bed and, in my case, my recovery ability is greatly enhanced.

  2. Great work Josh. I can’t wait to see part 2 and hope you plan to include Vitamin NR (Nicotinamide Riboside, brand name Niagen) and Benagene (thermally stabilized oxaloacetic acid), both described as beneficial mitochondria function and health.


    • I find these compounds useless for mitochondrial health, at least in my specific case. I tried both because they were all over the internet, but then, there is very little scientific evidence, if any.

      If you want to take this route (NADH/NAD+ pool ratio manipulation), I find plain old NADH (I use Enada brand) much more effective. It will give you instant energy for 8-10 hours. I take it maybe once a month, when my “myopathic” fatigue kicks-in. Not sure if this is good for my health though.

  3. Say Josh, if you don’t mind my commenting, I’d rather say that the nucleus and mitochondria interact with each other – and furthermore the mitochondrial responses are communicated to distant parts of the body where they influence mitochondria there. So I do not believe that aging is a cell-autonomous process – it is systemically controlled. For example in the lowly worm C. elegans, the gene impairment that doubles the lifespan of the worm need only be expressed in certain neurons, (which don’t age) but appears to have its effects in the intestine, where the mutant gene is never expressed.
    Mainly though I wanted to correct you about the Warburg effect: it is not due to a mitochondrial deficiency – it is an alternate form of energy utilization by embryonic and motile cells. During development, the mitochondrion is not completely functional at first and a different sort of metabolism apart from catabolic processes in the mitochondrion are needed – because cells are cycling, there must be allowance for the formation of nucleotides, NAD+ and all other cellular components, as cells must reproduce all their contents in order to divide. It also seems migrating cells, like neural crest cells, use the same sort of metabolism (and they too are free of anchorage dependence as metastasizing cancer cells). This seems more to show that these cells may be playing out an ancient ‘program’ from their past – an early, though discombobulated development.

    • Josh Essay July 14, 2017 : Mitochondria in Aging, I Mechanisms and Background

      Avi Conversation & Question: Very interesting & valuable thoughts about Mitochondria and Aging. I am thinking about “translational medicine” to reduce impact of aging. So, we know that as humans age, there are less mitochondria cells, say in a critical brain location as is the Microgalia geography of the brain.
      What pharmaceutical or physical process can be introduced to increase mitochondria cells in this region which we know is critical area both for Alzheimer & stroke ? Would blood flow increase can trigger mitochondria cell numbers ? Stem Cell delivery via a key enzyme perhaps ?

    • All antioxidants prolong the average life span, but not the maximum life expectancy. This is because the formation of mitochondria inhibits the substance called lipofuscin, which arises during life.

        • I have the proof. In Poland “is the area” where the inhabitants suffer from civilization diseases, there is a higher incidence of infertility, abortions, and cancer. The average life expectancy is 9 years shorter. Residents have increased lipofuscin content in cells.

          • Interesting. Have you any reference to studies/statistics, showing that the antioxidant intake among Polish people is lower than in its in for example the US or the rest of Europe?

          • Antioxidant intake has not been observed in the article. I wrote that in Poland “in the area” (the size of the state of Israel) people suffer from diseases, die 9 years earlier and have increased lipofuscin content in cells. Let google out what is lipofuscin. The area in Poland was not specified in the article. All I know is that there was an oversized, high mineral content of monteponite and hawleyite in the soil.

  4. I am learning all I can about low carbohydrate – high fat diets; this diet can go so far as to cause the body to use ketones instead of glucose for fuel – body and brain; some consider this will be more beneficial to the mitochondria; if you have any thoughts on this please share!

  5. Although a deeper calculation would be required, seems enough explanation to me that the ovule just sits there the entire lifespan until it’s called for reproduction.
    Compare that, say 20years per generation, to how many times intestine stem cells differentiate (or perhaps the most mtDNA damaged organs?) during a lifetime.. doesn’t it seem on par to the mutation rate required to see the variation among species?

  6. Vigorous exercise (or potentially some supplements) can adjust the NAD+/NADH ratio up enough to cause mitochondrial fission to take precedence over mitochondrial fusion. This means MtDNA damage is more visible to the cell based on low intermembrane potential (fused mitochondria can share DNA so make up for any damage that does not affect all component mitochondria) and these defective mitochondria can be tagged for destruction. The result is a smaller but healthier pool of mitochondria.

    This is probably why those who exercise religiously hold onto muscle mass, and can hold off dementia for longer.

    And although there does seem to be some evidence that mitochondria regulate maximum lifespan, I am inclined to agree with you Josh that they are intermediaries, and ‘decide’ when to trigger widespread apoptosis. The body is more than capable of maintaining healthy mitochondria – ROS doesn’t increase much with age, it is more likely repair mechanisms controlled from the nucleus are down-regulated through such epigenetic mechanisms as shortening telomeres.

    The work of Sinclair et al. seems to support the idea that NAD+ goes down with age, and this down-regulates repair mechanisms.

  7. I just discovered your blog and find it very interesting reading. For some time I have been interested in the idea of centrally controlled, programmed process of aging and death. I think this hypothesis explains some things better than the idea that aging is just an uncontrolled deterioration of the body. But there are a couple difficulties I haven’t been able to find an explanation for, and would like to know your thoughts.

    First, if aging is a built in process, ought there not to have been an occasional mutant with very long life? We see plenty of examples of people who have defects of built in regulatory systems, and display symptoms accordingly: people with hormonal defects who experience uncontrolled physical growth, accelerated aging, etc. Shouldn’t we expect to see an occasional person with a defective aging regulator who ages much slower than normal? Is the explanation just that the process has multiple redundancies that make it impossible to disable?

    Second, if this regulated aging is an evolutionary development which is found throughout the animal kingdom: Given that evolutionary competition explores a myriad of different solutions in different species, each of which works to varying effectiveness in different scenarios and environments (just about any survival strategy one can possibly imagine can be observed in at least one species), I would think that there would be at least one species for which, for whatever reason, it is advantageous to have unlimited life span. For example, perhaps a species is heavily predated upon, and longevity would be more beneficial to the species than dying to make way for the next generation. It strikes me as improbable that there are NO species for which “immortality” is not a reproductive advantage.

    Forgive me if you’ve addressed these issues previously. As I’ve only just discovered your blog, there’s a lot of content that I’ve missed.

    • I think aging is a consequence or continuation of the developmental process (gastrulation, organogenesis). Its like you have nothing but a brake pedal. Some animals push it harder so develop and age faster, other animals develop and age slower.
      You cant mutate it away because it would be embryonic lethal.
      Also aging probably has evolutionary advantages as aging controls the learning rate of the evolutionary algorithm that species process.
      Now that we learn via neural networks instead of genetic mutations this age old process of aging should be discarded.

      Also there are immortal animals. E.g. hydra that does not gastrulate – has a relatively simple development program.

      • I personally don’t think aging is a program, but it is advantageous (to a species rather than an individual). This is why we do see some negligibly senescent species, such as tortoises, turtles and crocodiles, but not many compared to the number of aging species.

        A heavily predated upon species would likely grow up and breed faster, so would also age faster – see rats vs squirrels; the latter live 10x longer because they live up trees.

        If you want to grow fast and age slow, now that is tricky, and would require such adaptions as v. efficient mitochondria (see birds).

  8. It is a good job SENS has managed to migrate 4 mito genes now to the nucleus as part of MitoSENS. This once perfected should make us and our mito passengers greatly more resistant to aging.

    • In my opinion, migrating genes to the nucleus is unlikely to work. First, the genes have to be regulated to be useful. They have to turn on at the right time and the products have to be labeled and transported to the mitochondria. We don’t know how this will work. Second and more fundamentally, there is no good evidence that mito mutations are a significant factor in human aging. My guess is that they are not.

      • Agreed, allotopomania already looks foolish, it should be obvious mitochondria aren’t built like that. Mitoribosomes are optimatized to cotranslationally insert extremely hydrophobic subunit directly into matrix side of the inner membrane in tandem with the cytosolic ribo efforts

      • In fact there is a whole discussion of precisely that in the comments here:

        In particular the exit tunnel region of the mitoribosome, as well as the minimalist codon set and usage spectrum, which the ribosome employs in what is basically a virtualization of the cofactor binding site with tRNAs outnumbering proteins 2 to 1, and a vieritable zoo of ecclectric assembly factors and modifiers (pseudouridinylation,methylation, etc,to pull of respiratory subunitconstruction.
        Addtionally, these guys just elegantly explained exactly why mitoribosomes can include so many accessory protein subunits (80), at such amino acid lengths, and critically, at such a high ration of protein to rRNA in the mitoribosome relative to bacterial and Eukaryotic ribosomes;
        their optimization for autocatyltic production, with cytosomes building mitoribosomes, is mainly driven by the requirement to minimize construction time for ribosomes, which in turn is essentially limited by the time needed to translate protein subunits of the ribosome, which in turn explains why all the proteins are so short, and why RNA is prefered in bacteria with brief cell cycling times relative mitochondria.

      • While I don’t recall the exact paper. I think I once read that ramping up cellular mechanisms that maintain mitochondrial quality, is able to significantly reduce from the mitochondrial population the prevalence of some harmful mutations that were detectable in the mitochondrial population

        The article “Mitoptosis, a Novel Mitochondrial Death Mechanism Leading Predominantly to Activation of Autophagy” suggest that there are mechanisms targeting defective mitochondria selectively. The accumulation of dysfunctional mitochondria may be due to ramping down on mitochondrial quality control by the body. Though the following article “Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila” differs in its conclusion, it appears to show that mutations can be removed if quality control is ramped up.

        Michael Fossel, iirc, has suggested that part of aging is the result of the body ramping down things like the turn over of certain proteins, allowing for damaged proteins to accumulate. A similar mechanism at the level of mitochondria, wouldn’t be out of the question

        • The mechanism is transcellular distribution and selection of mitochondria through the body wide network of the nervous system

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