Telomere biology has the potential to extend human life span, to dramatically lower rates of the great remaining killer diseases: heart disease, stroke, and Alzheimer’s.  All three diseases increase exponentially with age, and their toll will be slashed as we we learn how to address the body’s aging clocks.

You would think that the 2009 Nobel Prize might have done more to raise the profile of research in telomere biology, but the field remains a specialized backwater of medical research, and few biologists (fewer doctors) take it seriously as a panacea for the diseases of old age.  If the National Institute of Health has money to put into heart disease and cancer and Alzheimer’s and Parkinson’s diseases, there is no better place to invest than in telomere biology.  Research on these diseases commands multi-billion dollar budgets, because they are considered “medicine”, funded by NIH, while telomere biology is considered “science” and is funded by NSF.  The total NSF budget for all cell biology is only $123 million, and the portion devoted to telomere biology is a few million. The private sector is doing a little better – there are several companies selling herbs that stimulate our own bodies to liberate telomerase.  But this is short-sighted venture capital, and what we need is focused research with a ten-year vision.

There is good reason to think that telomere length is a primary aging clock in the human body.  The body knows perfectly well how to lengthen telomeres, but chooses not to.  All we have to do is to signal the body to activate the telomerase genes that are already present in every cell.   Of course, there is no guarantee that this will work, but compared to the sluggish rate of progress on individual diseases, it’s a pretty good bet, and the target is rather simple.  IMHO, it’s worth a crash research effort.

Three objections raised against telomerase research

1.  “Aging is inevitable because Physics tell us that nothing can last forever.”  This statement refers to the Second Law of Thermodynamics, which says that closed systems, evolving in isolation, must become more disordered over time.  But living systems are open, taking in free energy in the form of food or sunlight, dumping their entropy out into the environment.  There is no reason that such systems cannot maintain themselves indefinitely.  Indeed, growth and maturation would not be possible if this law of physics applied to open thermodynamic systems. Since the 19th Century when the laws of thermodynamics were formulated, it has been understood that aging cannot be explained from physics, and therefore commands an explanation from evolution.

2. “Evolution has been working to maximize animal life spans in order to increase fitness.  It is unlikely that any simple adjustment to physiology that humans can discover will do better than evolution has done over millions of years.”  In fact, evolution has not worked to maximize life span, but only to make it sufficient to assure time for reproduction.  Aging is a form of programmed death, on a flexible but finite schedule.  It is fixed in our genes.  There are mechanisms of aging that have been programmed into living things since the first eukaryotic cells.  Telomere attrition has been used to time the life cycle and form a basis for programmed death for at least a billion years.  Many species of protozoans do not express telomerase during mitosis (but only during conjugation), so their telomeres shorten with each reproduction, leading to a limit of a few hundred reproductions per cell line.  This mechanism is the precursor to telomeric aging that exists to the present day in humans and many other higher animals.

3.  “Expressing telomerase will increase the risk of cancer.” There is a great deal of theoretical concern in this direction, which I think is entirely misguided.  It is true that cancer cells express telomerase.  It is not true that expressing telomerase causes a cell to become cancerous.  This relationship is clearly explained by two seasoned experts (Shay and Wright 2011)

In early studies, the only way of increasing telomerase activity in lab animals was to add extra genes for telomerase.  Technology in the early 2000s did not permit a gene to be added at a targeted location, but only inserted randomly into a chromosome.  Tampering with the structure of DNA in this way is known to increase cancer risk no matter what gene is added or subtracted.  In three of these early studies, cancer rates in mice were increased [1, 2, 3].

There are no lab studies to my knowledge in which activating the native telomerase has increased the risk of cancer.  The modern view is that “while telomerase does not drive the oncogenic process, it is permissive and required for the sustain growth of most advanced cancers.”  Recent perspectives from both Harvard lab of de Pinho and the Spanish lab of Blasco focus on the potential for telomerase to decrease cancer risk, and these were the very people who produced the three studies suggesting caution a decade earlier.

And there are many studies showing that (a) telomerase expression does not increase cancer risk in lab animals, and (b) short telomeres are a very strong cancer risk.  I believe that telomerase activators will greatly reduce the cancer rate, first by eliminating cells that are pro-inflammatory and potentially carcinogenic because their telomeres have become short, and second by rejuvenating the immune system, which is our primary defense against cancer.  I published an article on this subject last year.

Why we might expect big life expectancy gains from extending telomeres

This is the affirmative question, then: what makes me think that telomere extension will have such a powerful effect on diverse aspects of aging biology?

A)    Telomere attrition is an ancient mechanism of aging.

Protists were the first eukaryotic cells, and they appeared on earth a billion years ago (they were a leap up in complexity from bacteria, which had been around 3 billion years before).  In protists, DNA is linear and hence there are telomeres and a need for telomerase.  Since protists reproduce by simple cell division, you would not expect that the cells would “age” or even that the concept of aging could have any meaning for their life cycle.  But a protist cell lineage can age, and indeed some do.  This is the oldest known mechanism of aging, and it is implemented through withholding telomerase.

Paramecia are an example.  When paramecia reproduce, their cells simply fission, the DNA replicates, and no telomerase is expressed.  Hence, telomeres get shorter with each cell division. Paramecia can conjugate, which is a primitive form of sexual gene exchange.  Two paramecium cells merge, mingle their DNA, and then separate.  It is only in the conjugation process that telomerase is expressed.  Therefore, any cell lineage that does not conjugate will die out after a few hundred generations.  This prevents cell colonies from becoming too homogeneous.  Thus aging is a billion years old, and some of the genetic mechanisms of aging have been conserved and passed on through all the transformations of multicellular life (William R Clark has written two accessible books [1, 2] on this topic.)

B)    Telomeres shorten with age in humans.

This has been known for twenty years.

C)    People with shorter telomeres have a much higher risk of mortality.

This was established by Richard Cawthon (2003) in a paper which took the field by surprise.  Researchers before then had assumed on erroneous theoretical grounds that telomere attrition, which was known to occur, could not have anything to do with human aging.  After all, if aging were as simple as telomere attrition, then the body could solve the problem merely by expressing telomerase.  This would enhance individual fitness.  Why would not evolution have found such a simple expedient?  (The answer, of course, is that natural selection favors aging, for the sake of the demographic stability – an evolutionary force not recognized by most evolutionary biologists.)  In Cawthon’s study, the top ¼ of 60-year-olds in terms of telomere length had half the overall mortality risk as the bottom ¼.  Cawthon had access to a unique database of 20-year-old blood samples, and to my knowledge his study has not been replicated or refuted these 11 years.

 

D)     People with short telomeres have a higher risk of diseases, especially CVD, after adjusting for age.  The association with cardiovascular disease has been consistent, not just in Cawthon’s original study, but also several other studies [Ref Ref Ref].  There are also associations with dementia [Ref, Ref] and with diabetes [Ref, Ref].

E)    Animals with short telomeres also have a higher risk of mortality, after adjusting for age.

This has been established in several bird species [Ref Ref Ref], and in baboons.  In 2003, it was already known that long-lived species tend to lose telomere length more slowly, and short-lived species lose telomeres more rapidly.

F)    In limited studies with mice, telomerase enhancers have led to rejuvenation.  (Mice are expected to be a much less effective target for this strategy than humans, because to all appearances, aging in humans relies on telomere attrition much more so than in mice.)

The first experiment of this type was done in 2008.  In the Spanish lab of Maria Blasco, Tomas-Loba engineered mice that were both cancer-resistant and contained an extra telomerase gene, expressed in some tissues where, even in mice, it would not normally be found.  Cancer-free mice with the extra telomerase lived 18% longer than cancer-free mice with only the normal gene for telomerase.

But soon it was discovered that all the experimental precautions around cancer may not have been necessary.  The same lab Bernardes de Jesus (2011) reported that they could increase health span in mice with the commercial product called TA-65 (widely rumored to be cycloastragenol) with no increase in the incidence of cancer.  Cycloastragenol is a weak telomerase activator compared to man-made chemicals discovered at Sierra Sciences, and even compared to some other herbal extracts.  Nevertheless, the Blasco lab was able to show that the shortest telomeres in the mice were elongated, and that markers of health including insulin sensitivity were improved by short-term treatment with TA-65.

Blasco’s lab then worked with a more potent (though more dangerous) method of telomerase induction: infection with a retrovirus engineered to introduce telomerase into the nuclear DNA of the infected cell.  “Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging.” (Bernardes  de Jesus, Vera et al. 2012)  The mice lived 13% longer when AAV treatment began at age 2 years, and 24% longer when treatment began at 1 year.  There was no increase in cancer incidence.

The most dramatic example of rejuvenation is from the Harvard laboratory of Robert de Pinho.  Normally, mice (unlike people) express telomerase freely through their lifetimes.  These scientists engineered a mouse without the normal (always on) gene for telomerase, but instead had a telomerase gene that could be turned on and off at will by use of a chemical signal that the experimenters could feed to the mice.  As these mice grew older, they developed multiple, severe symptoms of degeneration in the testes, spleen, intestine, nervous system and elsewhere.  All these symptoms were not just halted but reversed when telomerase was turned on late in the animals’ lives. The effect on the nervous system is particularly interesting because nerve cells last a lifetime and do not depend on continual regeneration from stem cells, the way blood and intestinal and skin cells do.  Nevertheless, these mice with telomerase turned off suffered sensory deficiencies and impaired learning that was reversed when the experimenters administered the chemical signal to turn telomerase back on.

A Stanford/Geron research group worked with “skin” grown from human cells in a lab setting.  They found they were able to restore youthful elasticity, softness and texture to the cultured “skin” by infecting the cells with an engineered retrovirus that inserted the gene for telomerase.

G)     In addition to its function in lengthening telomeres, telomerase also acts as a kind of growth hormone.

This fact was suspected as early as the 1990s, and confirmed definitively in a Stanford experiment [Ref, Ref, Ref, Ref].  In this experiment, mice were engineered with “denatured” telomerase that lacked the RNA template for creating telomeres.  Still, the telomerase was shown to induce hair growth.  Telomerase has been shown to activate affect a hormonal signaling pathway called Wnt. Other functions for telomerase are reviewed by Cong and Shay (2008).

H)        In one human case, huge doses of herbal telomerase activators has led to rejuvenation.

I am recently in touch with a physicist from Kansas who has been taking super-high doses of telomerase-activating herbs and supplements for six years and claims to look and feel younger, with improved athletic performance.  He may be an interesting case study.  Jim Green has commented on this blog site.

 The Bottom Line

In my opinion, telomerase activation is a field that offers the most potential for human life extension in the next few years.  This research is languishing for lack of funds, and for lack of attention.

CoQ10 plays a crucial role both in energy production and in detox.  Our bodies make less of it as we age, and we function less well for that. For more than 30 years, supplementation with CoQ10 has been identified as a promising anti-aging strategy and preventive for diseases of the heart and the brain.  But in extensive animal studies and dozens of clinical trials, CoQ10 has shown modest benefit, or none at all.  Part of the problem is that, when CoQ10 is taken into the digestive system, very little of it gets to the site where it can work.  Where CoQ10 belongs is in the cellular energy factories, the organelles called mitochondria.  Very recently, a mitochondria-targeted form of CoQ10 has become commercially available.  Preliminary experiments with MitoQ in animals and humans are very promising.

 

How much is enough?

At the Second SENS conference in 2004, I sidled up to an expert whom I respected and asked, “What’s the optimal dose of CoQ10?”  He laughed and asked, in reply, “How much can you afford?”*

Mitochondria are “organelles”, hundreds of them in every cell, that provide the energy that is used for everything from thinking to fleeing Sabre-tooth tigers.  We have less mitochondria as we age, and the mitochondria we do have function less efficiently.  This fact contribuetes to diverse aspects of aging.  The high-energy redox chemistry of the mitohondria is also the primary source of free radicals that cause oxidative damage associated with age.

Another role played by mitochondria is that they are the designated hit-men when a cell outlives its usefulness, or becomes cancerous or diseased, or needs to be eliminated for any reason.  Apoptosis is the process by which an individual cell is programmed to commit suicide for the sake of the larger organism, and the mitochondria orchestrate the killing, emitting the chemicals that do the dirty work.  In older animals (and people), apoptosis becomes over-active, and we lose perfectly good nerve and muscle cells to cell suicide.

Coenzyme Q, a.k.a. ubiquinone, is a small molecule, a key chemical component in the working of the mitochondria and also the first-line anti-oxidant that prevents the generation of free radicals in the course of energy generation.  As we age, each mitochondrion has less ubiquinone than it needs to function well.  Long-lived species have more CoQ, pound for pound, than short-lived species. Hence CoQ has been recognized as an anti-aging compound for twenty years.  Today it is routinely prescribed by many cardiologists, because statin therapy depletes CoQ.

But eating ubiquinone doesn’t work very well.  It is poorly absorbed in the digestive tract (the molecular variant called ubiquinol is supposed to mitigate this problem), little of it makes it into the blood stream, less into the cells, and a pittance to the mitochondria where it is needed.

This may be one reason CoQ supplementation has failed to live up to its potential.  A Spanish Study (2004) found that CoQ could increase the mean and maximum life spans** of rats on a diet rich in polyunsaturates.  (Polyunsaturated fats are prone to oxidation.)  Doses were modest, equivalent to daily 50mg capsules for humans.  But this result was exceptional.  More typical are these studies (Ref Ref Ref Ref), which begin with great enthusiasm, but report no benefit for life span or mortality in mice and rats.

 

Provenance of Mito-targeted CoQ

In the 1990s, Michael Murphy and Robin Smith, two New Zealand biochemists, had an idea to get ubiquinone more efficiently into the cells’ mitochondria – the only place where it is useful.  It happens that part of the mitochondria’s electrochemical activity is to continuously pump protons out through their membranes.  Hence they maintain a negative electric potential relative to the rest of the cell.  Anything with a positive charge is drawn into the mitochondria, and if it’s not a proton, it won’t be pumped right back out again.  Murphy and Smith were inspired to create a molecule that combined ubiquinone at one end with a chemical tugboat at the other, a positive ion that is “chelated”, meaning that the positive charge is spread over a large number of atoms so that there is less tendency for it to simply pair up with a negative ion and be permanently neutralized.  The chemical “tugboat”, called TPP for tri-phenyl phosphonium, had been developed 25 years earlier in the Moscow State University lab of Vladimir Skulachev (Grinius et al, 1970).  Connecting the tugboat to the ubiquinone is a simple carbon chain that prevents interference between the chemical properties of the two ends (Smith and Murhpy, 1999)  

The next step was to synthesize this molecule in the lab – a task requiring a lot of ingenuity and lab experience, but Smith was up to it.  Then came years of testing the substance, first in cell cultures, then in animals, with various applications.  Targeting worked amazingly well, with virtually all of the Mito-Q molecules finding their way to the mitochondria. This means that very low doses can result in very high effectiveness.

Skulachev, who had pioneered the early work on the right-hand part of the molecule, picked up this thread early on, and has sponsored much of the research that has demonstrated the rejuvenating potential of the molecule.  The molecular tugboat is known as a “Skulachev ion”, and a similar molecule*** to MitoQ has been dubbed “SkQ” and explored in Russian experiments.

Last year, a New Zealand company completed licensing requirements and created a manufacturing facility, and MitoQ is now available by order on the Internet for delivery worldwide.  The product was first announced at the A4M annual showcase meeting in November.  A year earlier, Skulachev’s company had begun to sell SkQ as eyedrops, available thus far only in Russia.  Skulachev’s group has long-term plans to develop the product for other uses as well, and to obtain licensing in Europe and America.

Some of the reason for enthusiasm about MitoQ is theoretical, and hence tentative.  We know that apoptosis is on a hair trigger as we get older, and not just diseased cells but many useful, healthy cells are eliminating themselves.  Apoptosis has been linked to muscle wasting (sarcopenia) [Ref] and loss of neurons associated dementia [Ref].  It is found in cell cultures that MitoQ strongly inhibits apoptosis, not surprising since peroxides in the mitochondria are a signal that brings on apoptosis, and MitoQ eats peroxide for breakfast.  There are also theoretical reasons to believe MitoQ might be effective in curbing loss of insulin sensitivity [Ref].

 

Evidence for effectiveness of MitoQ

But the most convincing evidence comes from studies in animals and humans.  Rats were demonstrated to be resistant to a variety of insults, from ischemia (oxygen deprivation) to toxins to carcinogens to high blood pressure, after administering MitoQ to rats in their drinking water.  In a novel experment in mice, MitoQ was shown to protect against insulin resistance.  All these studies were reviewed in a 2011 paper by Smith and Murphy.  Historically, there is a strong correlation of life extension drugs and the ability to enhance stress resistance.  “Together these findings show that MitoQ is protective against pathological changes in a number of animal models of mitochondrial oxidative damage that are relevant to human diseases.”

A lot more animal research was performed in Russia***.  In a rat model of Alzheimer’s disease, SkQ reversed neuronal damage in a few weeks. SkQ fed to rodents led to more rapid healing of skin wounds, especially in old age.  The same paper reports that, applied topically, SkQ was able to reverse scarring.  Most interesting, the Russian team reports small increases in the mean life span of a variety of animals, including mice and fruitflies.  The authors claim without supporting data that there were dramatic life span increases of mice outside of standard (sterile) lab conditions, in which they were exposed to disease and infection.  In another paper by Skulachev (2007) a large number of animal studies are summarized, with impressive benefits for a broad range of aging diseases, including kidney damage and macular degeneration.  Many of the original papers behind this work are available in English through Springer from the journal Biochemistry Moscow.

There is very limited data thus far in humans.  Safety and toxicity tests were concluded with a year-long trial at 80mg/day.  In one study, MitoQ failed to improve the condition of advanced Parkinson’s patients, and in a second study MitoQ showed significant benefit for protecting against liver damage from Hepatitis C.  Dr Skulachev reports that he personally has improved his vision using Sk-Q eye drops.

 

Caveat

All this study was carried out under direction of people who have an interest in the success of the compound.  You don’t have to think that scientists are congenitally dishonest to believe it is a good idea to protect them from incentives that might subtly bias their thinking or reporting.  Science Magazine a few weeks ago reported on the failure of mouse studies to translate into human benefit.  Studies conducted by drug companies are notorious.

 

A Subjective Bottom Line

I’ve known Dr Skulachev as a friend and colleague for more than a decade.  I trust that his work is solid and honest.  I had known that he was planning a campaign to commercialize SkQ, beginning with eye drops that began selling last year in Western Russia.  I was surprised and delighted to see that MitoQ is available as a commercial product, 10 years before I had expected.  It’s my belief that MitoQ is a promising new anti-aging strategy, and I’m signed on to be an early adopter.

 

——————-

* Long-term supplementation with high-dose CoQ10 is being studied as a treatment for and Parkinson’s disease and other neurological diseases of aging.  “High” is up to 3,600 mg/day, though one study found no further increase in bioavailable CoQ above 2,400 mg.  The best price I was able to find for CoQ on line worked out to about $4/g, so 2,400 mg per day would cost over $3,500 /yr.

** For those who follow details of rodent studies, the survival curve of this one stands out.  Most interventions that extend life span work mostly to prevent early deaths (“squaring the curve”).  Often the mean life span is increased, but the max life span in the group benefits much less, or not at all.  In this study, there is no benefit at all until nearly half the rats have already died of old age.  Then the death rate for the remaining rats is much lower.  Max life span is extended 24%, even as average life span is extended only 11%.

*** In the Russian work, Skulachev is using a variant of the Mito-Q molecule based on plastoquinone rather than ubiquinone.  Plastoquinone is the equivalent of ubiquinone in green plants, and Skulachev reports that there is a wider range of effective dosage for plastoquinone compared to ubiquinone.  Scientists at MitoQ disagree that plastoquinone is better.

In preparing a major update of my Aging Advice web page this week, I’ve been revisiting my supplement shelf, asking why I’m taking each of these pills and whether there is new evidence, either from animals or humans.

I would be grateful to you my readers for comments on this work which is still in flux. The latest version of the Pills page will be found here, and themain page of the new Aging Advice site will be here.

Highlights of what I learned in preparing this page: There’s a New Zealand company selling the “Skulachev ion“, which I thought was years away from commercialization. I developed a new respect for Carnosine as a major boon in several ways. I am gradually coming to think that resveratrol has been over-hyped. I learned that horny goat weed has been used for hundreds of years in the Orient as an aphrodisiac.

I’m interested in what I missed and what I got wrong.  Also your personal experiences with any of these supplements and comments on the format and presentation.  You can comment below, or email me.

Thanks for your help!