burger
October 19, 2018

I offer my apologies to all of our readers. Work has kept me from keeping up with the next blogs on the biology of aging, specifically those on human disease. My priority is to work to cure disease than update my blog on curing disease, so the blog has moved to the back burner as […]

An analogy: going back in time

I offer my apologies to all of our readers. Work has kept me from keeping up with the next blogs on the biology of aging, specifically those on human disease. My priority is to work to cure disease than update my blog on curing disease, so the blog has moved to the back burner as we move ahead toward FDA human trials.

However, a recent set of emails prompted me to explain the conceptual problem that faces us as we try to cure and prevent age-related disease. As has always been true historically, the major innovations are not technical or incremental, but conceptual and innovative. Major advances in medicine (and other disciplines) hinge upon our ability to open our minds and dispassionately reexamine our assumptions, which are often wrong. Assumptions are usually reasonable, but based on limited knowledge. Looking around us, the world might be flat. Watching the sun, stars, and planets, the universe might revolve around the earth. When we look a little further, however, the world becomes a sphere and the Earth is no longer the center of the universe. The same is true of aging: when we look a little further, we find surprises and a deeper understanding. Too often, we remain content with what might be true, to rarely do we look more deeply to find the truth.

A recent email suggested that even if telomerase gene therapy worked, wouldn’t we still need to consider using “concurrent stem cell therapy, endogenous stem cell boosting therapy, senolytic and NAD+ therapies, caloric restriction, low dose rapamycin, and acarbose “?

The problem is deeper than the question suggests, so I’ll try offering up an analogy.

A time-traveling 21st century physician goes back to 15th century Europe, approximately 6 months before a major smallpox epidemic is due to wipe out most of the population of the local towns. The physician knows that infection (and death) can be reliably prevented by vaccination with cowpox (literally, since the word derives from “vacca”, the Latin word for cow). Specifically, if the physician takes the fluid from the cowpox lesion of (for example) a milkmaid who has active cowpox and smears it on a dermal scratch of a potential smallpox victim, they can prevent smallpox. In short, it’s easy to prevent the epidemic, but only IF we understand understand the pathology.

However, the 21st century physician has become friends with the local 15th century healers, who have a deep knowledge of local herbal medicine. These local herbalists are remarkably observant, keenly intelligent, and have lifetime knowledge and experience with herbs, roots, flowers, bark, etc. They are profoundly competent within their framework, but have no understanding of microbes, vaccinations, or the immune response.

Now imagine an honest and well-intentioned conversation between the local professional herbalist and the 21st century physician and assume that they both respect each other’s knowledge (although the healer still can’t get over their limited assumptions about how to treat disease and cannot understand or believe in microbial disease). Even after the 21st century physician suggests that vaccination would effectively and easily prevent smallpox deaths, the 15th century herbalist persists in suggesting that “yes, that might work, but you still need to use herbs, prayer, incense, and specially made tisanes” to prevent smallpox.

Or to update our analogy, the modern age-researcher is profoundly competent within their framework, but have no understanding of how aging actually occurs at the cellular and epigenetic level. Even after 21st century data suggests that telomerase gene therapy would effectively and easily prevent age-related disease, the modern researcher persists in suggesting that “yes, telomerase therapy might work, but you still need to use concurrent stem cell therapy, endogenous stem cell boosting therapy, senolytic and NAD+ therapies, caloric restriction, low dose rapamycin, and acarbose “ to treat age-related disease.

For my part, I prefer the 21st century.

6 Comments

Back in the early 2000s everyone seemed to have their own theory of aging – and only their’s could be right. Now everyone agrees that everything is important, all is up and downstream of everything else – hence the need to address all possible avenues and create some huge great leviathan of biotech. Few are looking for a simple solution.

Telomeres are only one piece of the puzzle as is clear from Hallmarks of Aging. Epigenetic changes and Genomic instability will still remain a challenge regardless of restoring telomeres. I am optimistic that telomerase will be useful due to telomere loss being a hallmark but it is unlikely that is the only thing we need to fix. The data just does not support that.

To the contrary: not only are telomeres the major single key to the puzzle, but the data supports this both theoretically and as interventive data. The theoretical basis was covered in my Oxford University Press textbook (Cells, Aging, and Human Disease) as well as in articles in JAMA and elsewhere. In regard to the interventive data, no other intervention has achieved similar results, and the published results (e.g., those of DePinho and those of Blasco) are solidly supportive.
“Hallmarks of Aging” is an extraordinarily weak argument. The classic citation for the hallmark view is that of Lu et al (with Horvath as senior author) from Nature Communications in January of this year — which is an embarrassing example indeed. The paper is replete with technical jargon and obfuscation, perhaps because it was written by more than three dozen authors (39 actually) at 27 different institutions, making it difficult to construct a logical and coherent argument. Here are a few of the problems with the article:
1) They conflate simple correlations of leukocyte DNAm (DNA methylation age) with other cells and tissues without reference to cell or tissue specific pathology. This is like assuming that chronologic age correlates with pathology and is therefore a sufficient and accurate measure of age-related pathology.
2) They note that leukocyte (!) DNAm and LTL’s “appear to be independent predictors of mortality”, but a) leukocytes are poorly linked (i.e., are in a non-linear relationship) to major causes of age-related pathology and b) the correlation between DNAm and telomere length would be expected to be non-linear.
3) They assume that telomere length is the arguable link to gene expression change, then attempt to refute it, but they misrepresent the link. In effect, they create a straw man and (try to) knock it down but ignore the actual nature of the link. In reality, the link is a) related to the change in telomere length (rather than absolute length), b) non-linear in its relationship to epigenetic alteration.
4) They measure solely blood cells and fibroblasts (!), without sampling any of the cell types that are central to age-related disease.
5) Their in vitro fibroblasts results showed that non-TERT cells (at confluence) plateaued to a DNAm age of 13 years but continuing to proliferate until they senesced. TERT fibroblasts continued to show DNAm changes throughout their replicative lifespans (?). Note that these results derive from in vitro cells and that these cells were induced with TERT or empty vectors, but they used retroviruses (see below), which makes their data suspect in the first place.
6) They didn’t actually measure DNAm directly but estimated it (see Methods).
7) They didn’t measure shortest telomere lengths (the best method), but only mean telomere lengths, which are an invalid and unreliable marker for cell senescence. This method is cheap and technically easy, as well as all-too-common in such papers, but inappropriate if you wish to establish the degree of either cell or tissue senescence.
8) They used retroviruses (rather than, for example, AAV’s) which tend to insert into chromosomes, thereby skewing their results to create gene damage, mutations, and carcinogenic transformations. This is a VERY odd choice of intervention and would not be permitted in most human studies because of its known risks of carcinogenesis. Why would anyone accept data from an intervention that is known to create genetic damage?
9) They say that “TERT also possesses activities unrelated to telomere maintenance, such as in DNA repair, cell survival, protection from apoptosis or necrosis, stimulation of growth and cell proliferation”, but, these activities are directly related to telomere maintenance. They make their bald statement without considering the comprehensive and consistent data to the contrary. Telomere shortening directly results in slower DNA repair, decreased cell survival, increased risk of apoptosis or necrosis, and decreased cell growth and proliferation. The authors suggest that TERT affects these activities regardless of telomere maintenance, but the current data from other studies show the opposite. They have again created a straw man, knocked it down, and ignored the actual direction of the linkage.

I agree that Horvath’s papers have some pretty unsupportable conclusions. He seems to be flavour of the month though.
Steve, even though DNA damge is never reduced to zero, even with long telomeres, that is hardly a reason not to restore telomeres.

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