Mitochondria in Aging, II: Remedies

The once-popular mitochondrial free radical theory of aging proved to be too glib. Aging isn’t fundamentally about dispersed damage; rather, dispersed damage is a result when the body’s defenses stand down in old age.  Nevertheless, the mitochondria do play a role in aging, largely through signaling and apoptosis.  Antioxidants targeted to mitochondria may be an exception to the rule that antioxidants don’t prolong lifespan.  And other supplements and strategies that either promote production of new mitochondria or enhance their efficiency of operation show promise for modest lifespan extension.

Growing new mitochondria

A ketogenic diet leads to generation of new mitochondria, as do caloric restriction and exercise.  Exercise when the body is starved for sugar (low glycogen) is the most potent stimulator of new mitochondrial growth.  Exercise while fasting, or continue to exercise after you “hit your wall”.

Hormones that promote mitochondrial proliferation include thyroxin, estrogens, and glucocorticoids.  Promoting new mitochondria has a tendency simultaneously to suppress apoptosis, programmed cell death [ref].  At later ages, apoptosis of cells that are still functional tends to be a larger problem than the failure of cancerous cells to eliminate themselves by apoptosis.  In other words, suppressing apoptosis is (on balance) a good thing for anti-aging, but the downside is it can also increase risk of cancer.



Coenzyme Q-10 (aka ubiquinone) is an essential part of mitochondrial chemistry, shuttling electrons along their way to the ATP molecules that mitochondria generate as their primary energy export to the cell.  It’s often called an antioxidant, but that’s not the primary role of CoQ10.

As a supplement, it is well-established with a good reputation.  There is lots of evidence for benefits to health markers, especially athletic endurance, several aspects of heart health, and erectile dysfunction.  If you have fibromyalgia or if you are taking statins, CoQ10 is strongly indicated.  For chronic fatigue syndrome, it’s definitely worth trying.  

But there’s no reason to expect it will increase your life expectancy.  Supplementing with ubiquinone increases the lifespan of worms but not mice or rats [ref, ref].

Worms that cannot make unbiquinone live 10 times as long.  Just saying…

A few years ago, ubiquinol was introduced as a more bioavailable form of ubiquinone.  It’s more expensive, but there is not clear evidence that it is more bioavailable.



Pyrroloquinoline quinone is helpful but not necessary part of mitochondrial chemistry.  Bacteria make a lot of it; plants less; mammals only tiny quantities.  Mice completely deprived of PQQ show growth deficiency, but the amount that they need is tiny compared to the quantities in PQQ supplements.

PQQ is a growth factor for bacteria, and the principal health claim for PQQ is that it can stimulate growth of new mitochondria.  The evidence is based on biochemistry and cell cultures.  In live mice, it has been shown that PQQ deficiency results in a mitochondria deficiency, but not that large quantities of PQQ lead to more mitochondria.

Bill Faloon (LEF) and Joseph Cohen (selfhacked) are big fans of PQQ, and you can read a list of benefits here.  Cohen claims PQQ helps with sleep quality and nerve growth, leading to better cognitive function.  

Small quantities of PQQ can be absorbed from many plant foods, but not animal foods.  Much larger quantities come in supplement form. 100 g of tofu has just 2µg (micrograms).  Supplements are usually 5-20 mg, hundreds of times as much as you’re likely to get from a vegetarian diet.  Here is a table of PQQ concentrations in foods:


SkQ and MitoQ

These are two closely related molecules, originally synthesized in Russia in the 1970s, but it wasn’t until the 1990s that their therapeutic value was documented by two New Zealand scientists.  One end of the molecule is CoQ10 (or a version found in plants, claimed to be even more powerful as an antioxidant).  The other end of the molecule is an electric tugboat that pulls the molecule into mitochondria.  

I’ve written a  detailed report three years ago.  At the time, I noted that the Russians claimed to extend lifespan of mice modestly with SkQ, and SkQ was found (also in Russian labs) to be a powerful rejuvenant for aging eyes.  The Russians sell SkQ as eye drops.  The Kiwis sell MitoQ as skin cream and also as pills.

Earlier this year, the Russian labs announced that SkQ had substantially extended lifespan of a mouse strain that was short-lived because of a mitochondrial defect.  None of the Russian claims have been reproduced in Western labs.  Three years ago, I was inclined to give the Russians the benefit of the doubt, but now I’m starting to wonder, since the New Zealand company has a laboratory arm, and they haven’t announced anything nearly so impressive.


Humanin and her sisters

Mitochondria have ringlets of their own DNA, encoding just 37 genes.  (That doesn’t mean that the mitochondria only need 37 proteins; the great majority of proteins needed by mitochondria are coded in chromosomes of the cell nucleus, and transported to the mitochondria as needed.)  Just 16 years ago, the first mitochondrial-coded protein to be discovered was named Humanin, because it was found to improve cognitive function to dementia patients, restoring some of their “humanity”.  In addition to being neuroprotective, humanin promotes insulin sensitivity.  Humannin’s action is not confined to the mitochondrion in which it was produced, but in fact it  circulates in the blood as a signal molecule.  Blood levels of humanin decline with age.


In experiments with mice, humanin injections have been shown to protect against disease.  Lifespan assays with humanin are not yet available.

To date, HN and its analogs have been demonstrated to play a role in multiple diseases including type 2 diabetes (25, 43), cardiovascular disease (CVD) (2, 3, 47), memory loss (48), amyotrophic lateral sclerosis (ALS) (49), stroke (50), and inflammation (22, 51). The mechanisms that are common to many of these age-related diseases are oxidative stress (52) and mitochondrial dysfunction (53). Mitochondria are major source of ROS, excess of which can cause oxidative damage of cellular lipids, proteins, and DNA. The accumulation of oxidative damage will result in decline of mitochondrial function, which in turn leads to enhanced ROS production (53). This vicious cycle can play a role in cellular damage, apoptosis, and cellular senescence – contributing to aging and age-related diseases. Indeed, oxidative stress is tightly linked to multiple human diseases such as Parkinson’s disease (PD) (54), AD (55), atherosclerosis (56), heart failure (57), myocardial infarction (58), chronic inflammation (59), kidney disease (60), stroke (61), cancers (62, 63), and many types of metabolic disorders (64, 65). We and others have shown that HN plays critical roles in reducing oxidative stress (6668). [2014 review]

Pinchas Cohen, MD (Dean, School of Gerontology, University of Southern California Davis, Los Angeles, California) is an expert in humanin, a protein (peptide) produced in mitochondria. Mitochondria are energy-generating organelles in cells, which have their own DNA separate from the DNA in the nucleus. The amount of DNA found in the mitochondria is much less than that found in the nucleus. As such, mitochondrial DNA contains codes for only a few proteins, humanin being one of them. Humanin was discovered by a search for factors helping to keep neurons alive in undiseased portions of the brains of Alzheimer’s disease patients. Humanin protects neurons against cell death in Alzheimer’s disease, as well as protecting against toxic chemicals and prions (toxic proteins)[ref].  Dr. Cohen’s team has shown that humanin also protects cells lining blood vessel walls, preventing atherosclerosis. In particular, they have shown that low levels of humanin in the bloodstream are associated with endothelial dysfunction of the coronary arteries (arteries of the heart).[ref] Humanin has also been shown to promote insulin sensitivity, the responsiveness of tissues to insulin. Because humanin levels decline with age, it is believed that reduced humanin contributes to the development of aging-associated diseases, including Alzheimer’s disease and type II diabetes. [Ben Best]

Personal notes: This lab near where I am visiting in Beijing is taking leadership in characterizing a group of short peptides similar in origin to humanin, and this company across the street from us is selling mitochondrial peptides.

If humanin were a patentable drug, there would be much excitement and multiple clinical trials for AD, probably leading to expansion into general anti-aging effects.



This is another short peptide of mitochondrial origin, only recently discovered and characterized.  I was alerted to its existence by a study from a USC lab that was written up here in ScienceBlog just this month (reprinted from a USC press release).  Results are new but impressive.  Mice injected with MOTS-c had more muscle mass, less fat, more strength and endurance.  MOTS-c protected their insulin sensitivity when mice were fed a high fat diet [ref].  Lifespan studies haven’t been done yet.

Like humanin, MOTS-c is manufactured inside mitochondria from a template in mitochondrial DNA, but it is exported from the cell and appears in the bloodstream as a signal molecule.  Blood levels of MOTS-c decline with age.  It is a mini protein molecule with 16 amino acids, too big to survive digestion so it can’t be taken orally.  

MOTS-c holds much potential as a target to treat metabolic syndromes by regulating muscle and fat physiology, and perhaps even extend our healthy lifespan.”[ref]

Let’s keep your eyes on this one over the next year or two.


Gutathione / NAC

I’ve never heard anyone say a bad word about glutathione.  It’s the antioxidant with no downside.  Genetic modifications that upregulate glutathione have increased lifespan in worms, flies and mice.  

For a long while, it has been assumed that you can’t eat glutathione, because it doesn’t survive digestion.  Some researchers at Penn State disagree, finding impressive increases in tissue and blood levels when people were supplemented with up to 1 g per day raw glutathione.  Liposomal glutathione is an oral delivery form that gets around the digestion problem, especially when taken with methyl donors like SAMe.

The herb Sylimarin=milk thistle may increase glutathione.  For now, the precursor molecule N-Acetyl Cysteine (NAC) is the best-established supplement we have to promote glutathione.  In the one available study, supplementing with NAC greatly increased lifespan in male but not female mice.  NAC also increases lifespan in worms and flies.

N-Acetyl Cysteine



For the future, we might hope to do better.  Less than 20% of the cell’s glutathione actually makes its way to the mitochondria, where it is most needed.  There are esters of glutathione that, in theory, ought to be attracted into the mitochondria.  They have been tested in cell culture only, but are more than ripe for animal testing [ref].


Nicotinamide Riboside (NR) and other NAD+ enhancers

The chemicals NAD+ and NADH are alternative, cycled forms of an intermediate in the process by which mitochondria make energy.  Levels of NAD+/NADH decline with age.  NR is a precursor to NAD+, and it has been demonstrated (preliminary results in humans) that NR supplementation increases blood levels of NAD+.

It may be awhile before we know for sure whether this leads to better health or longer lifespan.  Niagen and Basis are heavily promoted with credible scientifists behind their products, and many early adopters offer subjective reports of short-term benefits.  There is one mouse study claiming to pull a 3% extension of lifespan out of the noise, and perhaps I am less open to the finding because the article, published prominently in Science, seems so breathless in describing benefits.



The primary role of melatonin is to regulate the body’s sleep/wake cycle.  Melatonin declines with age and the timing of our daily melatonin surge gets fuzzier and less reliable with age.sleep quality deteriorates.  Sleep quality suffers.

Melatonin is well-established in mice as a modest longevity aid, although results have been inconsistent.  12 out of 20 studies showed a lifespan increase, and the remaining 8 showed no increase or decrease.  Whether nightly supplementation affects mortality rates in humans has never been determined.

Melatonin is concentrated in mitochondria as much as 100-fold, and it may even be created there [ref], independent of the circulating melatonin that is secreted from the pineal gland at night.  One of its actions is as a mitochondrial antioxidant and scavenger of ROS.

Twenty years ago, Walter Pierpaoli promoted melatonin as a sleep aid, cancer fighting hormone that would enhance your mood and your sex life while keeping you young.  Russian labs have also been optimistic.  My take is that melatonin is a legitimate anti-aging hormone, and is especially useful for those of us whose sleep is disrupted with age.  It is widely available, cheap and safe.  Unless you’re fighting jet lag, 1 to 2 mg at night is all you need.

Also worth mentioning

Magnesium is required for manufacture of glutathione.  Selenium works along with glutathione.  Omega-3 fatty acids can promote synthesis of glutathione.  Acetyl L-carnitine transports fat fuels through the mitochondrial membrane.  Alpha-lipoic acid is part of the mitochondrial energy metabolism.

The Bottom Line

Commercial interests can make some messages louder than others, and the health news we hear is affected by what is profitable as much as by what is healthy.  Exercise is primary, but has no sales value.  Of the supplements reviewed here, NAC is the best-established for mitochondrial health and a possible effect on lifespan.  It is cheap and available.  Liposomal glutathione is certainly more expensive and possibly more effective.  Melatonin is even cheaper, and has been found to increase lifespan in multiple rodent studies, with broad benefits apart from modification of mitochondrial function.  Humanin and MOTS-c, not yet close to commercial availability, seem to be promising substances to explore for health, though not for profits.

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.