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 animals—hundreds 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.
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.
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.
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.
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.