Michael Fossel, M.D., PhD, is the author of The Telomerase Revolution, The Immortality Edge, and Cells, Aging, and Human Disease. He is the president and co-founder of Telocyte, a company that aims to use telomerase therapy to cure Alzheimer’s.
Dr. Fossel believes that the shortening of telomeres, the caps on the ends of chromosomes, is the fundamental process behind aging, and his most recent book makes a convincing case for it. You can read an explanation of the telomere theory of aging here. In essence, as telomeres become too short after repeated cell divisions, the cell is unable to clear damaged molecules, and ultimately enters a state of senescence, and this is responsible for aging.
As I read the book, a number of questions came to mind, and Dr. Fossel agreed to answer them.
If the theory holds true and the technology is successful, we could be on the verge of a huge breakthrough in aging. Dr. Fossel asserts in his book that within a decade or two, we will be able to extend human life to up to several centuries in length.
Below are my questions with Dr Fossel’s answers. I thank Dr. Fossel for responding to my questions.
1. Some components of an aged cell appear to be very difficult or impossible to degrade, for example lipofuscin. How would the resetting of telomeres solve this problem?
A. Actually, lipofuscin, like almost all molecules, is NOT a molecule that passively and gradually accumulates, but rather represents a dynamic pool in which it is continually being produced (anabolism) and broken down (catabolism). The reason that it increases in some cells is that the overall rate of turnover (both anabolism and catabolism) decreases and permits the gradual increase in the percentage of denatured molecules. Parallels are found in all other molecular pools (such as beta amyloid), both intracellularly and extracellularly, as well as in cell populations themselves (such as occurs in the dynamic turnover of bony matrix via osteoblasts v osteoclasts). In short, we need to remember that lipofuscin is not simply “garbage” that accumulates passively, but is actually a reflection of slower cell product “recycling”. The rate of that recycling is directly correlated to telomere loss: the shorter the telomeres, the slower the rate of molecular and cellular turnover. Once we increase telomere length, we increase gene expression, increase molecular turnover, and bring lipofuscin levels back to those typical of “young” cell function.
2. You write in your book about how the shortening of telomeres changes gene expression so that molecular turnover becomes slower and damaged molecules accumulate. Yet the pattern of gene expression changes, not merely slows, with some gene products becoming more abundant with age, for example TNF alpha. Why does a change in the pattern and not merely the rate of gene expression contribute to the accumulation of damage?
A. It always depends on the gene in question. In the case of most inflammatory gene products, for example, the result in increasing (and increasingly inappropriate) gene responses. Overall, most enzymes, for example those involved in DNA repair, show a decrease and almost all protein and other molecular pools (lipids and glycoproteins, for example) show a slower rate of turnover. In the case of many markers, however, such as inflammation, ROS (production, leakage, and concentration), the levels rise, often due (as with ROS issues) to the slower turnover rates of the enzymes responsible for those levels. The key is that gene expression CHANGES and while almost all direct changes are to lower gene expression, indirect changes are legion. If I, for example, lower the gene expression of one gene, it may well induce a secondary increase in the expression of a second gene. That’s the beauty and the complexity of epigenetic (as opposed to genetic) relationships.
3. Perhaps the most accepted theory of aging at the moment concerns the pro-aging effects of insulin and IGF-1 signaling. Can that be reconciled with the telomere theory? What are its shortcomings, if any, in your opinion?
A. That’s not a theory, has no logical supportive data, and is naïve. They look at a small segment of biology and (unsuccessfully and with internal contradictions) try to paste together a theory. It’s no better than trying to explain aging by reference to hormones or ROS alone: it fails to explain anything but the most myopic selection of data, clinical facts, or interventive predictions. Phlogiston was a better basis for physics and humors a better basis for medicine than is the attempt to explain all of aging on the basis of insulin and IGF’s.
4. Another theory has it that aging is a “quasi-program” (Blagosklonny), a continuation of the development program. Do you think this is plausible/correct? Does it conflict with the telomere theory?
A. Aging certainly isn’t merely something that “happens”, but I have a hard time fitting it into a single teleologically loaded word such as “programmed” or even “quasi-programmed”. Once we pick a loaded word like that, people (on both sides of the argument) stop thinking. It reminds me of the problem that occurs when we label (for example) penicillin as an “antibiotic”. We then stop thinking reasonably and begin to assume that it can’t be an anti-viral, anti-chlamydial, or anti-fungal agent. As you may know, penicillin is an excellent agent for causing seizures if applied to the vertebrate brain after removal of the meninges, yet no one thinks of it that way. In regard to aging, however, I would say that aging is NOT a continuation of “the” developmental program that takes an organism from zygote to adult. I would, however, say that aging has advantages to species adaptation and survival. Once again, however, I deprecate the use of the word “programmed” simply because it carries unintentional denotational baggage and misleads the discussion into the idea of teleology, as though nature “chooses” to have us age. Nature has no “intentions” and doesn’t “program” what happens to biological systems. That is wobbly thinking of the worst sort and makes me suspect that humans are incapable of facing reality at all. Nature simply is: aging occurs because some species that age are a bit more likely to survive (as species) that others that don’t. Things that survive, survive. That’s all there is to evolution.
5. What would you say would count as evidence against the telomere theory of aging?
A. There is no evidence against the telomere theory of aging, but there are a great many people who don’t understand the telomere theory of aging. They start with naïve misunderstandings, erroneously attribute them to “the telomere theory of aging”, find irrelevant counter-examples, and then declare victory. The most common example is telomere length. People note that some mouse varieties have longer telomeres and shorter lifespans than humans and conclude that the telomere theory of aging is wrong. The telomere theory of aging would actually say that telomere length per se has absolutely nothing to do with aging in cells or otherwise. Cell aging is NOT related to telomere lengths but to CHANGES in telomere length. In my book, I’ve cited several other examples of naïve criticisms, often based on either an ignorance of the theory or an ignorance of human pathology, but there are several other similar “strawman arguments” made that are not so much “evidence against the telomere theory of aging” as they are evidence against the knowledge and the logical abilities of those who espouse them.
6. Would you agree that interventions that result in good health, for example exercise or fasting, result in slower telomere shortening, and that conditions that cause worse health, say obesity or smoking, increase telomere shortening?
7. You state in your book that within the next decade or two, we will be able to lengthen the human lifespan to perhaps several centuries. What is the ground for such optimism?
A. Theory, cell data, tissue data, and organism data. That includes both animal and human studies.
8. Is there currently a good way to lengthen telomeres or activate telomerase? Is there good evidence that TA-65 works?
A. There is fair evidence (not “good”, just “fair”) that TA-65 works in humans.
9. It seems to me that interventions that increase autophagy, such as intermittent fasting or the use of autophagy promoters like hydroxycitrate or resveratrol, are the best way we currently know to increase turnover of damaged molecules and hence to counteract the aging process. Would you agree?
10. You emphasize in your book that cell division and not passage of time causes aging. Yet the accumulation of iron (and to a lesser extent other metals) promotes aging and disease, an effect which could be ascribed to the passage of time. The human body has no means of excreting excess iron. Wouldn’t this issue need to be dealt with in addition to lengthening telomeres?
A. Not true. The human body DOES excrete iron, it just has no ACTIVE mechanism for excretion and it can’t excrete excess iron beyond a fixed amount. There is passive excretion in both menses and stool, which roughly balance intake over the lifetime, but there is an overall imbalance if the menses are too great (iron loss) or if iron intake is even slightly too high (iron gain). In most healthy adults (even in old age) the passive loss of iron is sufficient to prevent an overall iron saturation.
Notes: Calorie restriction is currently the most robust means of increasing lifespan, and much of its efficacy appears to be due to increased autophagy, which breaks down and recycles damaged molecules. (Question 9.) Unfortunately, men and post-menopausal women do not have menses, and many adults have far too much body iron, as documented in my book. (Question 10.)