Everyone seems to “know” that telomeres have something to do with aging. The internet even has pop-up ads about foods that lengthen your telomeres, with the unstated assumption that will make your younger, or at least healthier. Inquiry shows, however, that not only do most people have no understanding of the role of telomeres in […]
Aging and Disease: 2.2 – Cell Senescence, Telomeres
Everyone seems to “know” that telomeres have something to do with aging. The internet even has pop-up ads about foods that lengthen your telomeres, with the unstated assumption that will make your younger, or at least healthier. Inquiry shows, however, that not only do most people have no understanding of the role of telomeres in aging, but neither do most researchers, academics, or clinicians. The result is that many have an unfounded faith in telomeres, while others scoff at the idea that they have any value whatsoever. In fact, both groups are naïve, albeit for different reasons.
The contrarian in me is tempted to assert that “telomeres have nothing to do with aging”, just because people expect me to say that telomeres cause aging, which they don’t. Telomeres play an important role. To say that telomeres have nothing to do with aging is inaccurate, but it’s just as inaccurate to say that telomeres cause aging. To give an analogy, we might say that your entire life is determined by your genes, which is inaccurate, or that genes play no role in your life, which isn’t true either. As with most things, the truth is complicated. Were we to be accurate we might say that telomeres play an important role in the incredibly complex cascade of pathology that we see as aging, indeed a critical and irreplaceable role, but telomeres do not cause aging any more than does any other facet in that intricate web of pathology. Aging is not simply telomeres.
Telomeres have a lot to do with how aging works, but telomeres don’t cause aging.
Causation is a slippery concept, despite the assumption that it’s concrete and well-defined. Causation might apply to billiard balls and the laws of motion, but causation becomes misleading when we apply it to multifactorial events, let alone to complex webs of biological mechanisms. This definitional fuzziness is blithely ignored by both those who ask about causation and those who provide an answer.
To move the discussion to history, for a moment, if I asked for the cause of the American Revolution, there might be a thousand answers that were relevant and appropriate (and not necessarily overlapping). We might focus on taxation, representation, the cultural and geographical distance, any number of specific “flash points”, any of several dozen key players on either side of the Atlantic, etc. Pretending there is “a” cause of the American Revolution presupposes that we already share not only a common framework for the discussion, but common assumptions about what constitutes a cause, and (probably) a great many unexamined prejudices as well. In short, most discussions about causation start with the assumptions that already presuppose a narrow answer. Not a good point to begin understanding.
This is equally true of biological causation. For example, what causes cancer? Is it your genes? Is it down-regulated DNA repair mechanisms? Is it cosmic rays, oxidative damage, or “carcinogens”? It depends on what you are asking. All of these contain an element of truth (and supportive data), but none of them are “the” cause of cancer unless you specify what you are asking and what you want to discuss. If you are a genetic counselor, genes are the focus. If you work for the EPA, carcinogens are the focus. You choose to narrow down your focus but doing so prevents an understanding of the broader question of how cancer occurs and why.
In the case of aging we find the same naiveté. The “cause” of aging depends on your assumptions, why you are asking, and how myopically you look at the process. In short, the question often presupposes the answer. As the Romans once said “Finis origine pendet”. The End hangs on the Beginning, or as too often the case (and using more modern phrasing), garbage in, garbage out. If you already presuppose the answer, then why are you asking? To truly understand how aging works, you need to erase your assumptions, step back, and look at the complexity without blinders or preconceptions. Looking at aging without preconceptions about “the” cause is almost always too much to ask.
There is, however, a more practical approach to understanding aging and the complex cascade of pathology that results from the aging process. Rather than looking for causes, look for effective interventions. If we ignore the deceptive question of causation for a moment and focus on intervention, then telomeres come to the center stage. It’s not that telomeres are in any sense the “cause” of aging, but telomeres are, without doubt, the single most effective point of intervention in the aging process and in age-related diseases.
Telomeres lie at the crossroads – from an interventional perspective – of everything going on in the aging cell. To extend the crossroads analogy, all the roads that lead to aging enter the crossroads of telomeres and all the roads leading toward age-related disease leave that same crossroads. The entire road system – that complex web of pathology that we call aging – consists of myriad highways, county roads, local by-ways, and even walking paths, but almost every one of them, eventually, passes though the same crossroads: the telomere.
Telomeres don’t cause aging and they are not the be-all-and-end-all of the aging process, but they do function as a pivot point, a sine qua non of age-related diseases, and – most importantly of all – the most efficient place to intervene.
Having put telomeres in a more reasonable perspective, what DO they do?
In an odd, but almost accurate sense, you might say that no one really knows. That’s true in two senses. The first sense is that there is simply a great deal that we’ve come to know about telomere mechanisms in the past few decades and there is doubtless a great deal more yet to find out about telomere mechanisms. That first sense, however, is true of everything: there’s a lot we don’t know and anyone who thinks otherwise is probably still in their teen years or has managed to get through life with their eyes (and their minds) closed. The second sense, however, is more specific to telomeres, the aging process, and age-related disease. This second sense is worth exploring, if only to realize the specific gaps in knowledge and how they might impinge on our ability to intervene clinically. This involves how telomeres affect gene expression. What we don’t know (for certain) is the linkage mechanisms, despite discussions about T-loops, sliding sheaths, and all the accompanying data involved over the past two decades. It’s still a bit of a black box. What we do know (for certain), is that telomere shortening changes gene expression (see figure 2.2a), and we do know (for certain) that when we reset telomere lengths we reset gene expression (see figure 2.2b).
We know that this change in gene expression is related to overall shortening and that the change in gene expression is more closely related to the shortest telomere than to the average telomere. We also know that all of this has nothing to do with telomeres “unraveling”. As we discussed before, they don’t unravel. It’s merely a pleasant myth based on the shoelace analogy. Telomeres may function a bit like aglets, but the chromosomal shoelace never unravels. Finally, we know that the absolute length doesn’t determine the changes in gene expression: it’s the relative telomere length that sets the pace of cell aging. Again, this is just the most common misconception, and one that causes inordinate confusion among researchers.
Once telomeres shorten, we know that gene expression changes not only on the same chromosome, but on other chromosomes as well. We know that the changes are progressive and subtle if you only look from one-cell-division-to-the-next (with the associated loss of base pairs). Yet over multiple cell divisions and thousands of base pair losses, these changes in gene expression add up, altering gene expression just enough to have effects upon DNA repair, mitochondrial efficiency, free radical production, lipid membrane competency, protein turnover, and myriad other processes that we associate with aging.
As we will see later in this series, it is this loss of telomere length and the crucial changes that it causes in gene expression that underlies aging and age-related disease, as well as explaining many other diseases, such as the progerias. It also explains why, when telomeres are preserved, cells gain indefinite proliferative potential whether in vitro or in vivo: they are, in common parlance if certainly not in fact, immortal.
Finally, all of this explains why, when we re-extend telomeres, whether in vitro or in vivo, we reset gene expression and not only allow cells to become fully functional again but allow the organism to become functional as well. In short, it explains why and how we may prevent and cure aging and age-related disease.