Michael Fossel Michael is President of Telocyte

May 27, 2015

Four Ways to Lengthen Telomeres

Many of you have asked about Helen Blau’s work at Stanford, using telomerase mRNA [FASEB Journal]. Helen sent me a copy of her article when it came out and I’m a serious fan of her work. As some of you know from my upcoming book, The Telomerase Revolution, there are four approaches to resetting telomeres: 1) put in a new telomerase gene, 2) activate the telomerase gene that is already in cells, 3) put in the mRNA (as Helen’s group did) for telomerase, or 4) put in the telomerase protein itself.

 

The first problem with mRNA is that the molecule is incredibly fragile and has a short half-life at body temperature, making it hard to work with in the lab (in vitro) and even harder to work with in patients (in vivo). The second problem (with both mRNA and protein) is that you only get one copy of the final telomerase enzyme, whereas if you put in the gene or activate the gene, you get multiple copies of the enzyme and a lot more “bang for your buck”. In short, mRNA is great, but has a low ROI, clinically speaking. The third problem, a recurrent one in this field, is that if you read either Helen’s paper or the slew of media articles and interviews since publication, the emphasis is always on treating “genetic disease” (such as one of the muscular dystrophies) rather than “aging disease” (such as Alzheimer’s). There is an unspoken and almost universal assumption that genetic diseases like the various muscular dystrophies are “real”, but aging diseases like Alzheimer’s aren’t true “diseases” at all, but they “just happen because things wear out”. This common assumption leads most researchers to focus on inherited genetic conditions exclusively and completely ignore normal aging processes and their associated clinical pathology – such as Alzheimer’s. Even when researchers DO focus on Alzheimer’s they operate on the assumption that it must involve a “bad gene” (such as APOE4).

 

Both assumptions are false, but are shared by most of the academic and medical research community, even if neither assumption is ever clearly stated or acknowledged. Since researchers “know” that aging is not a classic genetic disease, they are equally complacent in thinking that aging diseases cannot be treated by a genetic approach. The result is that almost no one approaches aging diseases in a practical way, using fundamental interventions such as telomerase mRNA, telomerase activation, telomerase protein, or – as in our case at Telocyte – telomerase gene therapy.

May 12, 2015

The Telomerase Revolution

My new book, The Telomerase Revolution, is now finished and is being copy edited by the publisher. Oddly enough, it’s already selling well in preorders. Amazon.com says that it is now the “#1 release in medical research”, which is a delightful surprise, since it won’t actually be published and available to the public until October. For those of you who would like to order a copy, here is the link to Amazon.com:

  • http://www.amazon.com/Telomerase-Revolution-Enzyme-Aging%C2%85-Healthier/dp/194163169X/ref=sr_1_1?ie=UTF8&qid=1426777801&sr=8-1&keywords=telomerase+revolution

The book is a careful and clear discussion of how aging works in cells, how it causes the clinical diseases of aging, and what we can do to cure age-related disease. There is a good clear chapter on vascular aging and neurodegenerative disease — especially Alzheimer’s disease — that a lot of reviewers find especially intriguing. Len Hayflick, the researcher who first described cell aging more than fifty years ago, calls the chapter “superb”. Matt Ridley, author of several best sellers including The Rational Optimist, Genome, and The Red Queen, says that he read the chapter with “real fascination” and tells me “I badly want to read more of the book”.

If anyone would like to do a book review, please contact me, and I will arrange to send you a review copy.

May 6, 2015

Lymphocyte telomeres are not a good disease marker

A friend pointed out that a recent Danish study suggested that short telomere lengths in circulating peripheral lymphocytes account for about a quarter of the variance in mortality. Does this mean that lymphocyte telomere lengths (LTL’s) are really only a minor factor in age-related disease and mortality? Probably, but it’s not the important question. A better question is whether or not telomere shortening accounts for age-related disease and mortality, which it does.

In regard to the Danish study, I would expect that result. People seldom die directly as a result of immune senescence and to the extent that they DO die of immune senescence, the figure of 25% of the variance strikes me as about right. Most people die of vascular aging and there is no a priori reason) to believe (nor data to suggest) that the telomere lengths of the vascular endothelium have any direct relationship to the telomere lengths of circulating lymphocytes. People may have short endothelial telomeres in their coronary arteries and advanced vascular aging, without necessarily having short lymphocyte telomeres that show up when we look at the circulating blood cells. Endothelial cells (which cause vascular aging) are not the same as lymphocytes (which are involved in immune aging). Within any one patient, we would expect some correlation between the rate of telomere loss in one type of cell (endothelial cells) and the rate of telomere loss in a different type of cell (lymphocytes), but the correlation will not be high and will certainly not be causal. It’s disappointing to see large (and expensive) clinical studies that try to chase down lymphocyte telomere lengths and expect them to predict overall disease. Lymphocyte telomere lengths will be related to some diseases (cancer comes to mind, and the data supports this relationship) but not to other diseases. For those of you who would like to know more, read my biomarker paper for a partial discussion of this illogical thinking (Fossel, 2012). Whatever were they thinking (or NOT thinking)?

If we want to accurate predict (I’d rather cure) the risk of age-related diseases and death, we would need to acquire reliable measures of changing telomere lengths in, for example, the vascular endothelium and microglial    cells, as well as other cells and tissues. I’m sure that the circulating lymphocytes account for some of the variance in mortality, but not only can’t we restrict ourselves to lymphocytes, but there remain the (totally ignored) issue of circulating vs other, non-circulating lymphocyte reserves. Even if we can prove that lymphocyte telomere lengths (LTL’s) rise with a prolonged intervention (for example, using dietary change, telomerase activators, exercise, or other potential interventions), a peripheral increase in telomere lengths may still mask a decline in actual decline in overall telomere lengths as newer lymphocytes enter the circulation from the marrow and other repositories. The cells haven’t “become younger”, rather we are merely sampling a different set of cells.

My usual analogy applies here. If I were to sample the ages of the residents living in a single city block and find that over a twenty year period the mean age of the residents goes from 70 to 30 years old, that does NOT mean that we have made those residents any younger, only that the older residents have moved (or died) and that a totally different population of younger residents has replaced them. In fact the overall population of the city (or the country) may have undergone an increase in mean age, even if the particular city block that I measure shows a decrease in the mean age of its residents.

In a parallel fashion, when we measure circulating LTL’s, we are only measuring a single sample of circulating lymphocytes, not an entire population of the body’s lymphocytes. So even if I could prove a clinical intervention appeared to result in all of the circulating LTL’s getting longer, that doesn’t prove anything about the mean telomere lengths in the body as a whole. We certainly can’t claim that we have improved the immune function or “reversed aging” in lymphocytes. Such conclusions are not only invalid, they are naïve to the point of embarrassment.

If we really want to show that telomerase therapy can lower mortality or cure age-related disease, then we need to look at mortality and disease, not lymphocytes.

 

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