I strongly recommend everyone interested in Telomerase activators to read the review by Vince Giuliano
http://anti-agingfir...they-really-do/Bottom line: much publicity, not many scientific studies.
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Telomerase activators – what do they really do?
Astragalus-based dietary supplements that are known to activate the expression of telomerase have been on the market for several years now. However, there appears to be a significant difference between what these supplements are widely publicized to do and what published scientific research says they actually do. Specifically, the promotion and press coverage often implies that such supplements will extend the lengths of telomeres in people who take them and thus confer longevity benefits. However, there appears to be virtually no clinical research evidence to support such claims. On the other hand, research does suggest that at least one of the supplements can provide several important health benefits. In this blog post I seek to penetrate through the thick layers of commercial and PR fog about such supplements and get down to what is actually known about their actions.
History
During the 1990s and early 2000s, Geron, a small biotech company, was a leader in research relating to telomeres and telomerase. Few scientists and no other significant biotech or pharmaceutical company paid much attention to telomeres or telomerase back then. Based on its research, Geron applied for 279 patents related to telomeres or telomerase. One of the major areas of research concern to Geron then was telomere activation as an approach to disease prevention and longevity. The company discovered that certain extracts of the astragalus plant had a capability to activate the expression of telomerase in certain cell types, at least under test-tube conditions.
From the Geron web site: “Geron, in collaboration with the Biotechnology Research Institute (BRC), a company established by the Hong Kong University of Science and Technology (HKUST), began screening for telomerase activators in early 2000. The source of material for the screen was natural product extracts from traditional Chinese medicines. In the course of the screening, several extracts were discovered that reproducibly up-regulated the low, basal level of telomerase in human skin cells. With analysis of the extract and further testing, one compound in the extracts was identified as a key telomerase activator. It was capable of activating telomerase in other human cells types (e.g., lymphocyte immune cells) at very low concentrations. Another compound, a derivative of the first, was also present in the extract but at lower concentrations and was also found to possess similar telomerase activating properties. These molecules are currently under development for the treatment of degenerative diseases. Other small molecule activators discovered during the course of the research may also be developed for certain disease indications.”
The research resulted in Geron applying for a patent on telomerase activators which was finally issued just a few months ago. Filed 06/23/2004, the patent is called Compositions and Methods for Increasing Telomerase Activity. Since publication 05/15/2008, the patent application can be read by anyone and the descriptions found there still provide much of the scientific rationale for people taking astragalus-based telomerase-activator supplements. The patent application introduction states “The present invention relates to methods and compositions for increasing telomerase activity in cells. Such compositions include pharmaceutical, including topical, and nutraceutical formulations. The methods and compositions are useful for treating diseases subject to treatment by an increase in telomerase activity in cells or tissue of a patient, such as, for example, HIV infection, various degenerative diseases, and acute or chronic skin aliments. They are also useful for enhancing replicative capacity of cells in culture, as in ex vivo cell therapy and proliferation of stem cells.”
Geron subsequently shifted its focus to other areas of research including embryonic stem cell therapies and developing drugs that turn telomerase off in cancer cells. As far as I can tell, Geron is currently pursuing telomere activation mainly via a subsidiary and marketing licensing agreements. Geron is the majority owner of TA Therapeutics, a Hong Kong subsidiary which is focusing on telomerase activation for organ renewal and prolonging the lives of AIDS patients. A US company, TA Sciences, has licensed one telomerase-activator extract from Geron called TA-65 in 2002, a nutraceutical it has been marketing it to the public for over three years now.
Of the Geron-researched telomerase-activating products, two in particular have received the most attention: TA-65 being marketed to the public by TA Sciences and TAT2 under investigation as part of drug development by TA Therapeutics. Both formulations are carefully guarded proprietary secrets of the companies involved. I suspect the two substances are either highly related or identical. There has been much speculation as to what TA-65 consists of, particularly in online longevity-related forums(ref)(ref). Based on reading the Geron patent, it appears that a number of astragalus membranaceus extracts exhibit varying degrees of capability to promote the expression of telomerase(ref). One extract mentioned in the patent is astragaloside IV, and another extract with roughly ten times the activation potency is cycloastragenol, and there are others as well. Based on careful reading of the patent and the dosage originally suggested by TA sciences the best informed guess is that TA-65 and TAT2 are cycloastragenol, but this is only a guess.
TA Sciences is an active marketing company and any search on Google related to telomerase will often produce prominent advertising related to TA-65 and its health and longevity benefits. TA-65 does not come cheap. When the company first started marketing it, it was available only as part of a “Patton Protocol” package with cost of $25,000 for the first year. (Noel Patton is the founder of TA Sciences.) Now, the Patton Protocol is offered in either an a-la-cart mode or as a full package. The cost of six months of the protocol including the TA-65, some other supplements, a visit to a doctor and a number of diagnostic tests is $6,725. Cost of a six-month supply of TA-65 alone is $4,000. It is interesting that when it was originally marketed the daily dosage of TA-65 was 5 mg and the daily dosage has been increased now to 100mg, by a factor of 20. This has led to speculation that the substance may not be pure cycloastragenol which is very expensive to produce.
Besides TA-65 available from TA sciences, based on the information in the Geron patent other companies have started to market both astragaloside IV and cycloastragenol as telomerase activator supplements(ref)(rev). These supplements are being sold considerably cheaper than TA-65 with cost of a 30-day supply typically running up to $80. One such company, Revgenetics, decided to discontinue its cycloastragenol product line when the Geron patent was finally issued and sell of its existing stock at discount, charging $25 for a bottle which contains 30 5mg pills.
The concept of telomerase activation
A responsible formulation of the telomerase activation hypothesis is that through systemic intermittent activation of telomerase, specifically in stem and progenitor cells, it may be possible to delay shortening of telomeres and therefore delay the onset of multiple disease and degenerative processes associated with cell senescence. A very informative 2007 PowerPoint Presentation by Joseph M. Raffaele MD (an affiliate of TA Sciences) states the scientific rationale for telomerase activation and lays out results of a small clinical trial of TA-65. There is general consensus that too-short telomeres lead to cell senescence leading to the diseases and symptoms of aging. However, it must be pointed out that many factors affect telomere length, that many complex factors both known and yet-unknown promote or delay the onset of cell senescence, and that telomerase activation does more than affect the lengths of telomeres. For example, the protein TAp63 strongly affects senescence of stem cells(ref). I return to this important point later.
Research on telomerase activators
So, what research exists on the effects of telomerase activators beyond that which went into the patent? I will review research here that involves any of the four activator substances mentioned (TA-65, TAT2, Astragaloside IV, Cycloastragenol) recognizing that what is true for one activator may not be valid for another. With one exception, I will confine myself to publications in established journals or reputable online research publishers and will avoid ungrounded assertions in press releases or opinions stated in blogs.
· A small human trial was conducted in 2005 of TA-41, a precursor of TA-65, I believe sponsored by TA Sciences. This trial is described in a page on the TA Sciences web site and in the aforementioned PowerPoint Presentation. The trial was a 24-week double-blind, placebo-controlled study involving 36 male subjects between 60 and 85 years of age, a relatively short trial with scale far smaller than typical Phase III FDA-approved trials. TA-65 is the presumed major metabolite of TA-41. “ — subjects consumed 2 or 4 tablets daily of a placebo control substance (placebo groups) for 12 weeks or 2 or 4 tablets daily of a TA-65 precursor molecule (TA-41) for 12 weeks (product groups). The product tablets each contained 10 mg of TA-41 (an Astragalus extract) along with other botanical extracts and excipients. — The 12 week placebo or product use period was followed by a further 12 week follow-up period.” My impression is that the experimental design of the study and the treatment of statistical measures were handled quite responsibly. Nonetheless, because of the small sample size, statistical significance of the results is relatively crude. The study treated .2 as the p-value for statistical significance though in larger studies .05 or even .01 are typical values. The major benefits observed among those taking the products were “1. Apparent improvement in certain immune system measures, 2. Apparent improvement in eye sight, 3. Apparent improvement in certain sexual function measures, and 4. Apparent improvement in certain skin properties(ref).” No significant adverse events were identified. Detailed discussion and diagrams of results can be found on the TA Sciences web page for the study and in the PowerPoint presentation. To my knowledge the results of this 2005 study have never been published in an established scientific journal. Nonetheless the study seems to have been well done and I tend to take it seriously.
· Dr. Raffaele reports in his 2007 PowerPoint Presentation that “preliminary results of 16 patients o TA-65 for 3 months show an increase of mean lymphocyte telomere length.” I have seen no further or subsequent details.
· To my knowledge, there have been no further studies relating actual user experience of those taking TA-65 though by this time there should be considerable experience to report. Those taking TA-65 as part of the Patton Protocol have had extensive measurements of aging-related biomarkers and their telomere lengths. I would love to see the data derived from this user cohort laid out.
· The 2008 study report Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes looked at exposing lymphocyte cells from HIV-infected donors to TAT2. “ — , during aging and chronic HIV-1 infection, there are high proportions of dysfunctional CD8(+) CTL with short telomeres, suggesting that telomerase is limiting. The present study shows that exposure of CD8(+) T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity. The enhanced antiviral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation.” The study suggests a possible health benefit for HIV-infected individuals, individuals who experience an extraordinary high rate of telomere shortening in immune cells due to the disease. This benefit would have to be verified in clinical tests. This study says nothing about telomere lengthening. This study was co-authored by Rita Effros, a leading researcher in the role of telomeres in HIV infections. This study, by the way, referred to the experimental substance both as TAT2 and as cycloastragenol.
· A 2005 study Telomerase Therapeutics for Degenerative Diseases describes possible benefits of telomerase activation but provides no experimental results. There are numerous studies pointing to telomere shortening as an important process contributing to the advance of HIV and studies like this 2010 one looking at telomerase activity and replicative senescence in human CD8 T lymphocytes, but none of those studies are directly concerned with telomerase activation.
· The 2009 publication Cycloastragenol extends T cell proliferation by increasing telomerase activity covers another in-vitro study reporting “Naturally, there is a great deal of interest in finding inducers of telomerase that may help delay the onset of cellular aging. There are various nutraceuticals that claim to both increase the health of individuals and delay the onset of cellular aging. We tested the nutraceuticals resveratrol and cycloastragenol for their ability to enhance T cell functions in vitro. In this study we evaluated the effect of these compounds on cellular proliferative capacity, levels of telomerase activity, surface markers and cytokine secretion of human CD4 and CD8 T cells. Our results show that cycloastragenol moderately increase telomerase activity and proliferative capacity of both CD4 and CD8 T cells. These preliminary results suggest that nutraceuticals inhibit the onset of CD4 and CD8 cellular senescence.” Like in the previously-discussed study the effect was moderate, outside the body, and the study said nothing about extending telomeres.
Of the telomerase activators mentioned, perhaps the one best covered in the research literature is astragaloside IV. As I state in my treatise; “Astragaloside IV has been systematically studied for its medicinal properties only recently, mostly in Chinese and European research centers. It is an antiinflammatory, antifibrotic and antioxidant. It is known to have vasodilation and cardioprotective properties. It is neuroprotective and can protect the myocardium against ischemia/reperfusion injury. There are no reported negative side effects. Yet, my impression is that much is yet to be learned about this substance. Specifically, there appears to be little if any research available in the public domain relating astragaloside IV’s medicinal properties to its ability to induce telomerase expression.”
Research publications related to Astragaloside IV include the 2002 publication Effects of astragaloside IV on myocardial calcium transport and cardiac function in ischemic rats, the 2004 publication Astragaloside IV protects against ischemic brain injury in a murine model of transient focal ischemia, the 2009 publication Effects of Astragaloside IV on heart failure in rats, the 2009 publication Astragaloside IV attenuates cerebral ischemia–reperfusion-induced increase in permeability of the blood-brain barrier in rats, the 2008 report Astragaloside IV inhibits spontaneous synaptic transmission and synchronized Ca2+ oscillations on hippocampal neurons, the 2006 report Effects of astragaloside IV on pathogenesis of metabolic syndrome in vitro, and Effect of astragaloside IV on hepatic glucose-regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin, and the 2006 publication Astragaloside IV from Astragalus membranaceus Shows Cardioprotection during Myocardial Ischemia in vivo and in vitro. While these and many other research publications relate to potentially beneficial effects of Astragaloside IV, none relate to or even mentions the substance’s role as a telomerase activator. Of course, some or all of the reported benefits could ultimately be due to telomerase activation.
Other than the study cited above, the only discussions of cycloastragenol health activities seem to be in longevity blogs chewing over the same material covered here. It is a relatively unfamiliar substance. As for astragaloside IV, cycloastragenol suppliers appear to be in China. Purchasing either of these supplements from a US company, it is good to be on a lookout for independent laboratory verification of contents and purity.
Observation 1: When it comes to telomerase activation, the contrast between what is reported as “research” in the general and commercial literature and what is reported in the filtered scientific research literature is singularly stark. Pubmed.org is the definitive National Library of Medicine database of medical and related scientific research, containing millions of literature abstracts covering virtually every article in every research publications worldwide. The following lists the number of items retrieved using Google and using Pubmed in response to the given query.
Query Found in Google Found in Pubmed
TA-65 + telomerase 21,100 7 (all irrelevant)
TAT2 + telomerase 4,510 1 (cited here)
astragaloside + telomerase 7,200 0
cycloastragenol + telomerase 1,820 1 (cited here)
Observation 2: Published studies suggests that telomerase activation may have a positive effect on the immune function, though this conjecture based on lab cell-level studies must be confirmed via large-scale human studies. How much affect using what activator and under what conditions are as yet not established. There is also research strongly suggesting important potential health benefits from taking astragaloside IV in particular, and possibly also from taking TAT2 (likely to be the same thing). How telomerase activation relates to the beneficial effects of these substances, however, remains mostly unstudied.
Observation 3: The case for specifically taking TA-65 is mainly based on propriety information provided by TA sciences and doctors offering TA-65 as a treatment, and by the original research done by Geron. The most compelling positive information is that derived from the 2005 human trial sponsored by TA Sciences. While TA-65 has an immense standing in the popular literature I have had trouble finding any mention of it in the published scientific literature. In fact, if a query about TA-65 is made in PubMed, part of the reply is “The following term was not found in PubMed: TA-65.”
Observation 4: I remind readers that there are research studies establishing that there are other interventions that result in longer telomeres besides taking the telomerase activators discussed here. See the January 2010 blog entry Vitamins, supplements and telomerase – upregulation or downregulation? And also see my blog entries Exercise, telomerase and telomeres, Timely telomerase tidbits, Breakthrough telomere research finding, and Telomere and telomerase writings.
Observation 5: In the scientific literature I have found no published research whatsoever that establishes that any of the telomerase activators mentioned actually extends telomeres. The closest the literature comes are statements like “moderately increases telomerase activity, ” “modestly retards telomere shortening,” and “inhibit the onset of CD4 and CD8 cellular senescence.” And these statements are based on cell-level studies with results that may or may not be applicable in live humans. It is interesting that the TA Sciences web site does not now make the claim that TA-65 actually extends telomeres. Unfortunately, however, the claim keeps popping up in news stories and some blog postings about the activator substances.
Observation 6: What telomerase activators actually do in humans remains a mystery as far as the published scientific literature is concerned, and what the two proprietary activators consist of still remains a mystery as well. I keep awaiting more trustworthy published information.
Back to the science of telomeres and telomerase
For those familiar with the great complexities of telomere biology and pathways affecting telomere length management, it should not be surprising that is not so simple as “take a telomerase activator and get longer telomeres.” Whether telomeres get longer or shorter or stay the same is determined not only by the presence of telomerase but also by interactions involving many signaling paths and activation cofactors. “Telomere transcription is regulated by several mechanisms: developmental status, telomere length, cellular stress, tumour stage and chromatin structure(ref).” Presence of a telomerase activator is only one factor in driving telomere lengths. The literature related to telomerase and telomeres is extremely extensive and I have barely touched on it here. What is largely missing is literature specifically related to the astragalus-based telomerase activators.
Further, telomerase has other activities besides telomere length maintenance. Activating the TERT telomerase component may have other positive effects without making telomeres longer. These positive effects can include promoting cellular and organismal survival(ref) and increasing the rate of differentiation of quiescent adult stem cells(ref). So, in principle at least, a telomerase activator could convey health benefits independently of affecting telomere lengths. We just don’t know the extent to which this happens in humans in response to the astragalus-based supplements.
Personal experience
My personal experience with telomerase activators may be untypical. I started taking a large dose of astragalus extract in July 2007 with the intention of telomerase activation, switched to astragaloside IV 50mg a day in August 2008. As of mid-December 2009, I switched to taking a 5mg cycloastragenol capsule together with a simple astragalus-extract pill which may possibly increase bioavailability. On February 14 2010, I upped the daily cycloastragenol dose to 10mg. So I have been on some kind of telomerase activator or the other for close to three years now. What is the effect? I don’t know, especially because of all the other anti-aging supplements I have been taking and anti-aging lifestyle patterns I have been observing. If I use the criteria mentioned in the TA Sciences trial, I can personally comment that now at the age of 80:
1. Immune system measures: I seem to have as good or possibly better resistance to infections or viruses as ever.
2. Eye sight: Distance vision acuity in both eyes is excellent though I require corrective lenses for reading and close-up vision. My last eye exam showed no progression of druzen or signs of macular degeneration.
3. Sexual function measures: No decline in desire, perhaps even a bothersome increase. Performance and satisfaction enhanced by sildenafil seems OK.
4. Certain skin properties: Quality and texture of skin for my age are excellent.
5. Hair: And I add one other thing I have been monitoring, which is hair. About a year ago I wrote in my treatise “I have noticed a few small effects so far. The light patina of grey hairs on my mostly-bald scalp seems to me to be a bit thicker with a few black hairs as well. I have been nearly bald for over 30 years. It is known that in animal models at least, conditional telomerase induction causes proliferation of hair follicle stem cells (ref). It remains to be seen whether I will see more or darker hair as I continue with telomerase activation. Also there seems to be some increase in my sexual libido but this may be a subjective impression. I also do not know if my daily schedule of alternating taking the telomerase activator with the other supplements with a few hours of separation is effective or whether I would be better off alternating every other day or even every other week.” Since then there are many more grey hairs but not black ones. I am no longer absolutely bald. The grey hairs seem to keep coming back but very slowly.
I am planning to stay with the cycloastragenol supplements until my supply runs out in 3 months or so. I am not sure what I am going to do for telomerase activation after then. I keep waiting for the “shoe to drop” with more definitive research results becoming available as I have been waiting for three years now. I think it is ridiculous that we are still relying on 2005 test data from 36 people who were on an activator for only two weeks when now many people have been on such activators for three years or more and have been subjected to systematic age-biomarker and telomere length testing.
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