To questionable ends

Just published a new piece in Nature about ongoing research into the role of telomeres in human health, and you can read it here. As usual, I wrote much more than made it to the final version (what can I say, I’m a man of many words), and one of the casualties of the cut was an entire section on anti-aging therapeutics that supposedly work by ratcheting up telomerase activity.

Now, although the link between telomere shortening and age-related tissue degeneration appears to be relatively robust, it’s clearly a gross oversimplification to see telomere length as a sole driver of the overall aging process or as any kind of simple quantitative metric of ‘biological age’. But that hasn’t stopped several companies from attempting to capitalize on the general public’s limited understanding – and the extreme complexity – of telomere biology.

Boy, that stupid scientific community really burns my britches... what with all their "theories" and "experiments". Jerks.

(image from here)

Many of these products claim to harness “Nobel prize-winning technology”… such as Reneuve, which consists (for some reason) of pig thymus glands in grain alcohol with elderberry and currant juice. Yummers! Oh, wait… I meant to say, rejuvenating! Apparently, the idea is that you’re taking invigorating porcine telomerase with every delicious sip. But, you say, how on earth would eating glandular extracts manage to deliver telomerase enzyme intact into the nuclei of cells in every tissue of my body? Here’s the brain-melting explanation:

Throughout your first 25 years your blood passed through a particular gland in your body and carried the telomere lengthening enzymes from this organ to all your cells throughout your body. The enzymes in particular that are responsible for telomere lengthening are the size of a large molecule. These enzymes may pass through any barrier so long as that barrier has spacing to permit the passage. A chemical transport mechanism likely already exists.

That’s good enough for me! The rest of the Q&A is also a wonderful blend of malarkey and pseudoscience, and recommended reading for anybody who ever took a biology or physiology class at some point in life. Also a great way to depress any 26-year-olds you know.

There are a number of other companies with similar products. However, one of the most troubling offerings, in my opinion, is TA-65. This herbally-derived compound was initially discovered at California-based Geron (a respectable biotech company perhaps best known for their ongoing embryonic stem cell clinic trial) during a screen for telomerase activators, and subsequently licensed off to New York-based start-up ‘TA Sciences‘. In fact, TA repeatedly references Geron right on the front page of their website – even though Geron has severed all ties with TA-65 and no longer has anything whatsoever to do with this product. This product has already gotten considerable mileage in the mainstream media, and I’ve routinely seen it discussed on patients’ bulletin boards.

TA-65 is derived from Astragalus membranaceus, a species of plant commonly used in Chinese herbal medicine, and although the formulation itself is proprietary (ancient Chinese secret!), the key ingredient appears to be a molecule known as cycloastragenol (CAG), based on publicly available information and investigations by interested parties. TA claims that their formulation is far purer than the Astragalus-derived extracts one might buy at a health food store (“The product is then sent to a FDA certified, state-of-the-art, laboratory for final purification that ends up with 90+% pure TA-65.”), suggesting that CAG is indeed supposed to be the sole active component of TA-65.

To be fair – CAG does appear to have some degree of efficacy in stimulating telomerase activity in isolated or cultured cells – that’s how it was identified. And at least one study (published in the Journal of Immunology) showed that ISOLATED T cells from HIV-positive patients exhibited evidence of improved immune response following treatment with CAG. On the other hand, that’s a long way from working as a drug. Geron abandoned its own investigations of CAG relatively early on, based on this compound’s poor pharmacokinetic profile and limited bioavailability when taken orally. Indeed, a study by scientists from Geron and the Hong Kong University of Science and Technology concluded that “Extensive hepatic metabolism was observed for CAG after incubation with rat and human liver microsomes, indicating that only a small fraction of orally administered CAG may be able to reach the systemic circulation.”

Presumably TA Sciences has altered the formulation to improve the molecule’s pharmacological properties, but there’s no mention of such improvements on the site. I spoke to Maria Blasco, an independent researcher at the Spanish National Cancer Center who conducted some mouse studies with TA-65 that were actually published recently, and she told me that, “We only saw a significant increase in telomerase activity in the liver, probably because the compound is metabolized there… we saw a lower incidence of fatty liver disease in these mice, and betterment of some metabolic parameters, but we did not see an improvement in longevity, for instance.” Although the paper reports some other tentative benefits, it is also worth noting that they dosed these creatures with a whopping
25 mg/kg of TA-65 per day; by comparison, the recommended dose in humans (based on the website) tops out at 4 capsules daily, which is a CONSIDERABLY milder dose totaling 20 mg. On the other hand, those patients who do choose to shoot for the stars can expect to pay an average of $667/month (their estimate) with (of course) no support from insurance.

So what exactly do they claim TA-65 does? Well, at that highest dose:

Study subjects experienced lengthened telomeres, restoration of weak immune systems, bone density improvements and other important bio marker improvements which usually decline with age. Anecdotal reports include energy increase, endurance, cognitive improvements, improved vision, sexual enhancement, and an overall feeling of well being.

Ah, anecdote – the singular of data. The one published human study was not a randomized controlled trial, but rather an analysis of 114 TA Sciences customers taking TA-65 at different doses, with no placebo group for comparison. Most of the positive findings relate to an even smaller subset of cytomegalovirus-positive patients, in whom treatment is correlated with a statistically significant increase in killer T cells and a reduced overall percentage of short telomeres (although no change was reported in average telomere length). However, there is no comparison against untreated patients, and no attempt to demonstrate that the overall health of these patients is in any meaningful way improved. The authors state that randomized controlled trials are planned, but nothing has been announced to date. In addition, the website FAQ cites a ‘Pivotal 2005 Anti-Aging Clinical Trial’ “that statistically shows in black and white what real people experienced from TA-65” but provides no link to access that information, and this trial data was never published in a peer-reviewed journal.

This isn’t just to pick on TA Sciences – although I am bothered by the number of otherwise reputable biologists who have apparently been pulled into this particular company’s orbit. It’s about how companies latch onto an exciting field and exploit media-perpetuated ignorance. The vast majority of scientists I spoke to for this article were keen to avoid any simple equation of telomere length and “biological age”, especially given the tremendous gaps that still remain in terms of our biological understanding of how telomerase activity is regulated and how telomere function plugs into the larger whole of cellular physiology and survival.

UTSW’s Jerry Shay, a leading expert in the field, expressed outright disgust to me. “There’s absolutely no evidence to date of any medical intervention or nutraceutical or antioxidant or natural product that has any impact on telomere lengthening that I know of, much less to do with overall lifespan,” he said. “These companies have to do some controlled studies, and none of them so far is willing to spend the money to have people not taking their compound longitudinally along with the people taking their compound… until that happens, it’s just more snake oil salesmen as far as I’m concerned.”

On the other hand, snake oil could be better than the alternative of stumbling on something that actually works and having to deal with the unexpected consequences of unregulated, unsupervised consumption. Given that most ‘telomerase-activating compounds’ are treated as nutritional supplements, and therefore covered by the relatively lax standards of the US Dietary Supplement Health and Education Act, only limited safety assessments are required and no formal clinical trial data are necessary, as long as no concrete promises about disease treatment or health are being made.

However, if any of these drugs were to actually work as described, patients with stalled tumor precursors residing within their bodies might be in for a nasty surprise. Many cancer biologists – and telomere experts like Nobel laureate Carol Greider – see the cellular dormancy triggered by excessive telomere shortening as a crucial check on uncontrolled cell growth. “There may be precancerous cells residing in the body that are prevented from proliferating because their telomeres are too short, and if you start feeding individuals telomerase activators, maybe those cells would have a better chance,” Peter Lansdorp, an oncologist at the University of British Columbia, told me. “I have real concerns about that.”

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