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January 25, 2014

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 remainingkiller diseases: heart disease, stroke, and Alzheimer’s. All three diseases increase exponentially with age, andtheir 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 prof ile of research in telomerebiology, 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 putinto heart disease and cancer and Alzheimer’s and Parkinson’s diseases, there is no better place to invest thanin telomere biology. Research on these diseases commands multi-billion dollar budgets, because they areconsidered “medicine”, f unded by NIH, while telomere biology is considered “science” and is f unded by NSF. The total NSF budget f or all cell biology is only $123 million, and the portion devoted to telomere biology is af ew million. The private sector is doing a litt le better – there are several companies selling herbs that stimulateour own bodies to liberate telomerase. But this is short-sighted venture capital, and what we need is f ocusedresearch with a ten-year vision.

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

Three objections raised against telomerase research

1. “Aging is inevitable because Physics tell us that nothing can last forever.” This statement ref ers tothe Second Law of Thermodynamics, which says that closed systems, evolving in isolation, must become moredisordered over t ime. 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. There is no reason that such systems cannot maintainthemselves indef initely. Indeed, growth and maturation would not be possible if this law of physics applied toopen thermodynamic systems. Since the 19th Century when the laws of thermodynamics were f ormulated, ithas been understood that aging cannot be explained f rom physics, and theref ore commands an explanationf rom evolution.

2. “Evolution has been working to maximize animal life spans in order to increase f itness. It isunlikely that any simple adjustment to physiology that humans can discover will do better thanevolution has done over millions of years.” In f act, evolution has not worked to maximize lif e span, butonly to make it suf f icient to assure time f or reproduction. Aging is a f orm of programmed death, on a f lexiblebut f inite schedule. It is f ixed in our genes. There are mechanisms of aging that have been programmed intoliving things since the f irst eukaryotic cells. Telomere attrit ion has been used to t ime the lif e cycle and f orm abasis f or programmed death f or at least a billion years. Many species of protozoans do not expresstelomerase 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. This mechanism is the precursor to telomericaging 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 inthis direction, which I think is entirely misguided. It is true that cancer cells express telomerase. It is not truethat expressing telomerase causes a cell to become cancerous. This relationship is clearly explained by twoseasoned experts (Shay and Wright 2011)

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

There are no lab studies to my knowledge in which activating the native telomerase has increased the risk ofcancer. The modern view is that “while telomerase does not drive the oncogenic process, it is permissive andrequired f or the sustain growth of most advanced cancers.” Recent perspectives f rom both Harvard lab of dePinho and the Spanish lab of Blasco f ocus on the potential f or telomerase to decrease cancer risk, and thesewere 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 labanimals, and (b) short telomeres are a very strong cancer risk. I believe that telomerase activators will greatlyreduce the cancer rate, f irst by eliminating cells that are pro- inf lammatory and potentially carcinogenic becausetheir telomeres have become short, and second by rejuvenating the immune system, which is our primarydef ense 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 af f irmative question, then: what makes me think that telomere extension will have such a powerf ulef f ect on diverse aspects of aging biology?

A) Telomere attrit ion 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 incomplexity f rom bacteria, which had been around 3 billion years bef ore). In protists, DNA is linear and hencethere are telomeres and a need f or telomerase. Since protists reproduce by simple cell division, you would notexpect 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. This is the oldest known mechanism of aging, and it isimplemented through withholding telomerase.

Paramecia are an example. When paramecia reproduce, their cells simply f ission, the DNA replicates, andtelomerase is expressed. Hence, telomeres get shorter with each cell division. Paramecia can conjugate, whichis a primitive f orm of sexual gene exchange. Two paramecium cells merge, mingle their DNA, and thenseparate. It is only in the conjugation process that telomerase is expressed. Theref ore, any cell lineage thatdoes not conjugate will die out af ter a f ew hundred generations. This prevents cell colonies f rom becomingtoo homogeneous. Thus aging is a billion years old, and some of the genetic mechanisms of aging have beenconserved and passed on through all the transf ormations of multicellular lif e (William R Clark has written twoaccessible books [1, 2] on this topic.)

B) Telomeres shorten with age in humans.

This has been known f or 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 f ield by surprise. Researchersbef ore then had assumed on erroneous theoretical grounds that telomere attrit ion, which was known to occur,could not have anything to do with human aging. Af ter all, if aging were as simple as telomere attrit ion, thenthe body could solve the problem merely by expressing telomerase. This would enhance individual f itness. Why would not evolution have f ound such a simple expedient? (The answer, of course, is that naturalselection f avors aging, f or the sake of the demographic stability – an evolutionary f orce not recognized bymost evolutionary biologists.) In Cawthon’s study, the top ¼ of 60-year-olds in terms of telomere length hadhalf the overall mortality risk as the bottom ¼. Cawthon had access to a unique database of 20-year-oldblood 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 forage. 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 withdiabetes [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 knownthat long- lived species tend to lose telomere length more slowly, and short- lived species lose telomeres morerapidly.

F) In limited studies with mice, telomerase enhancers have led to rejuvenation. (Mice are expected tobe a much less ef f ective target f or this strategy than humans, because to all appearances, aging in humansrelies on telomere attrit ion much more so than in mice.)

The f irst experiment of this type was done in 2008. In the Spanish lab of Maria Blasco, Tomas-Lobaengineered mice that were both cancer-resistant and contained an extra telomerase gene, expressed in sometissues where, even in mice, it would not normally be f ound. Cancer-f ree mice with the extra telomerase lived18% 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. The same lab Bernardes de Jesus (2011) reported that they could increase health span in mice with thecommercial product called TA-65 (widely rumored to be cycloastragenol) with no increase in the incidence ofcancer. Cycloastragenol is a weak telomerase activator compared to man-made chemicals discovered at SierraSciences, and even compared to some other herbal extracts. Nevertheless, the Blasco lab was able to showthat the shortest telomeres in the mice were elongated, and that markers of health including insulin sensit ivitywere improved by short- term treatment with TA-65.

Blasco’s 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 mouseTERT had remarkable benef icial ef f ects on health and f itness, including insulin sensit ivity, 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 treatmentbegan at 1 year. There was no increase in cancer incidence.

The 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. These scientists engineered a mousewithout the normal (always on) gene f or telomerase, but instead had a telomerase gene that could be turnedon and of f at will by use of a chemical signal that the experimenters could f eed to the mice. As these micegrew older, they developed multiple, severe symptoms of degeneration in the testes, spleen, intestine, nervoussystem and elsewhere. All these symptoms were not just halted but reversed when telomerase was turned onlate in the animals’ lives. The ef f ect on the nervous system is particularly interesting because nerve cells last alif etime and do not depend on continual regeneration f rom stem cells, the way blood and intestinal and skincells do. Nevertheless, these mice with telomerase turned of f suf f ered sensory def iciencies and impairedlearning that was reversed when the experimenters administered the chemical signal to turn telomerase backon.

A Stanf ord/Geron research group worked with “skin” grown f rom human cells in a lab setting. They f ound theywere able to restore youthf ul elasticity, sof tness and texture to the cultured “skin” by inf ecting the cells with anengineered retrovirus that inserted the gene f or telomerase.

G) In addit ion to its function in lengthening telomeres, telomerase also acts as a kind of growthhormone.

This f act was suspected as early as the 1990s, and conf irmed def init ively in a Stanf ord experiment [Ref , Ref ,Ref , Ref ]. In this experiment, mice were engineered with “denatured” telomerase that lacked the RNA templatef or creating telomeres. Still, the telomerase was shown to induce hair growth. Telomerase has been shown toactivate af f ect a hormonal signaling pathway called Wnt. Other f unctions f or telomerase are reviewed by Congand 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 telomerase-activating herbs and supplements f or six years and claims to look and f eel younger, with improved athleticperf ormance. 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 f ield that of f ers the most potential f or human lif e extension in thenext f ew years. This research is languishing f or lack of f unds, and f or lack of attention.