What is the most promising medical technology on the horizon today?

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.

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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 [123].

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 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 [12] 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 [RefRef] and with diabetes [RefRef].

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.

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 [RefRefRefRef].  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 activateaffect 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.

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 The most promising medical technology on the horizon today

This post originally appeared on Josh’s blog here: http://joshmitteldorf.scienceblog.com/2014/01/25/the-most-promising-medical-technology-on-the-horizon-today/

2 Comments

  1. Aubrey de Grey’s idea is to turn off telomerase entirely and provide telomer lengthening therapy every few decades.

    It’s part of SENS, mate.

    Why would you conclude telomerase research isn’t getting enough attention?

    In my opinion, it makes a lot more sense to state that anti aging in general isn’t getting enough attention.

    And that’s only because it could never possibly get attention enough!

    I’m not worried about it though. Google’s on it.

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