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co m/2014/01/25/the-mo st-pro mising-medical-techno lo gy-o n-the-ho rizo n-to day/

The most promising medical technology on the horizon today

January 25, 2014

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

You would think that the 2009 Nobel Prize might have done more to raise the prof ile of research in telomere biology, but the f ield remains a specialized backwater of medical research, and f ew biologists (f ewer doctors) take it seriously as a panacea f or the diseases of old age. If the National Institute of Health has money to put into heart disease and cancer and Alzheimers and Parkinsons 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, f unded by NIH, while telomere biology is considered science and is f unded by NSF. T he total NSF budget f or all cell biology is only $123 million, and the portion devoted to telomere biology is a f ew million. T he 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 f ocused research with a ten-year vision. T here is good reason to think that telomere length is a primary aging clock in the human body. T he body knows perf ectly 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, its a pretty good bet, and the target is rather simple. IMHO, its worth a crash research ef f ort. T hree objections raised against telomerase research

1. Aging is inevitable because Physics tell us that nothing can last forever. T his statement ref ers to the Second Law of T hermodynamics, which says that closed systems, evolving in isolation, must become more disordered over time. But living systems are open, taking in f ree energy in the f orm of f ood or sunlight, dumping their entropy out into the environment. T here is no reason that such systems cannot maintain themselves indef initely. 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 f ormulated, it has been understood that aging cannot be explained f rom physics, and theref ore commands an explanation f rom 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 f act, evolution has not worked to maximize lif e span, but only to make it suf f icient to assure time f or reproduction. Aging is a f orm of programmed death, on a f lexible but f inite schedule. It is f ixed in our genes. T here are mechanisms of aging that have been programmed into living things since the f irst eukaryotic cells. Telomere attrition has been used to time the lif e cycle and f orm a basis f or programmed death f or 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 f ew hundred reproductions per cell line. T his 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. T here 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. T his 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 f or 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]. T here are no lab studies to my knowledge in which activating the native telomerase has increased the risk of cancer. T he modern view is that while telomerase does not drive the oncogenic process, it is permissive and required f or the sustain growth of most advanced cancers. Recent perspectives f rom both Harvard lab of de Pinho and the Spanish lab of Blasco f ocus on the potential f or 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, f irst by eliminating cells that are pro-inf lammatory and potentially carcinogenic because their telomeres have become short, and second by rejuvenating the immune system, which is our primary def ense against cancer. I published an article on this subject last year. Why we might expect big life expectancy gains from extending telomeres T his is the af f irmative question, then: what makes me think that telomere extension will have such a powerf ul ef f ect on diverse aspects of aging biology? A) Telomere attrition is an ancient mechanism of aging.

Protists were the f irst eukaryotic cells, and they appeared on earth a billion years ago (they were a leap up in complexity f rom bacteria, which had been around 3 billion years bef ore). In protists, DNA is linear and hence there are telomeres and a need f or 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 f or their lif e cycle. But a protist cell lineage can age, and indeed some do. T his is the oldest known mechanism of aging, and it is implemented through withholding telomerase. Paramecia are an example. When paramecia reproduce, their cells simply f ission, the DNA replicates, and telomerase is expressed. Hence, telomeres get shorter with each cell division. Paramecia can conjugate, which is a primitive f orm 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. T heref ore, any cell lineage that does not conjugate will die out af ter a f ew hundred generations. T his prevents cell colonies f rom becoming too homogeneous. T hus aging is a billion years old, and some of the genetic mechanisms of aging have been conserved and passed on through all the transf ormations of multicellular lif e (William R Clark has written two accessible books [1, 2] on this topic.) B) Telomeres shorten with age in humans.

T his has been known f or twenty years. C) People with shorter telomeres have a much higher risk of mortality.

T his was established by Richard Cawthon (2003) in a paper which took the f ield by surprise. Researchers bef ore then had assumed on erroneous theoretical grounds that telomere attrition, which was known to occur, could not have anything to do with human aging. Af ter all, if aging were as simple as telomere attrition, then the body could solve the problem merely by expressing telomerase. T his would enhance individual f itness. Why would not evolution have f ound such a simple expedient? (T he answer, of course, is that natural selection f avors aging, f or the sake of the demographic stability an evolutionary f orce not recognized by most evolutionary biologists.) In Cawthons study, the top of 60-year-olds in terms of telomere length had half the overall mortality risk as the bottom . Cawthon had access to a unique database of 20-year-old blood samples, and to my knowledge his study has not been replicated or ref uted these 11 years.

D) People with short telomeres have a higher risk of diseases, especially CVD, after adjusting for age. T he association with cardiovascular disease has been consistent, not just in Cawthons original study, but also several other studies [Ref Ref Ref ]. T here 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.

T his 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 ef f ective target f or this strategy than humans, because to all appearances, aging in humans relies on telomere attrition much more so than in mice.) T he f irst 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 f ound. Cancer-f ree mice with the extra telomerase lived 18% longer than cancer-f ree mice with only the normal gene f or telomerase.

But soon it was discovered that all the experimental precautions around cancer may not have been necessary. T he 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. Blascos lab then worked with a more potent (though more dangerous) method of telomerase induction: inf ection with a retrovirus engineered to introduce telomerase into the nuclear DNA of the inf ected cell. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse T ERT had remarkable benef icial ef f ects on health and f itness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. (Bernardes de Jesus, Vera et al. 2012) T he mice lived 13% longer when AAV treatment began at age 2 years, and 24% longer when treatment began at 1 year. T here was no increase in cancer incidence. T he most dramatic example of rejuvenation is f rom the Harvard laboratory of Robert de Pinho. Normally, mice (unlike people) express telomerase f reely through their lif etimes. T hese scientists engineered a mouse without the normal (always on) gene f or telomerase, but instead had a telomerase gene that could be turned on and of f at will by use of a chemical signal that the experimenters could f eed 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. T he ef f ect on the nervous system is particularly interesting because nerve cells last a lif etime and do not depend on continual regeneration f rom stem cells, the way blood and intestinal and skin cells do. Nevertheless, these mice with telomerase turned of f suf f ered sensory def iciencies and impaired learning that was reversed when the experimenters administered the chemical signal to turn telomerase back on. A Stanf ord/Geron research group worked with skin grown f rom human cells in a lab setting. T hey f ound they were able to restore youthf ul elasticity, sof tness and texture to the cultured skin by inf ecting the cells with an engineered retrovirus that inserted the gene f or telomerase. G) In addition to its function in lengthening telomeres, telomerase also acts as a kind of growth hormone. T his f act was suspected as early as the 1990s, and conf irmed def initively in a Stanf ord experiment [Ref , Ref , Ref , Ref ]. In this experiment, mice were engineered with denatured telomerase that lacked the RNA template f or creating telomeres. Still, the telomerase was shown to induce hair growth. Telomerase has been shown to activate af f ect a hormonal signaling pathway called Wnt. Other f unctions f or 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 f rom Kansas who has been taking super-high doses of telomeraseactivating herbs and supplements f or six years and claims to look and f eel younger, with improved athletic perf ormance. He may be an interesting case study. Jim Green has commented on this blog site. T he Bottom Line In my opinion, telomerase activation is a f ield that of f ers the most potential f or human lif e extension in the next f ew years. T his research is languishing f or lack of f unds, and f or lack of attention.