Geroscience recently published a long two part discussion with Michael Fossel. He is among the more prominent advocates for treating aging as a medical condition from the past few decades, and has written a couple of books on the topic. As a very brief summary of his views, I'd say he is fairly narrowly focused on telomerase therapies and telomere lengthening as a mode of treatment. This isn't because he sees telomere erosion, the reduction in average telomere length in tissues over the course of a life, to be a cause of aging. Rather he sees it as a convenient point of intervention that might at least partially reverse many of the epigenetic changes that occur with aging.
Epigenetic decorations to DNA adjust the pace at which specific proteins are produced from their genetic blueprints. Cellular machinery is controlled by the amounts of various proteins that are present in the cell: more or less of a given protein and the machinery acts in different ways. The internal activity of a cell is a highly dynamic feedback loop running from protein production to protein activity to epigenetic change to protein production again, with thousands of proteins participating and interacting with one another. It is enormously complex, and patterns of epigenetic markers are constantly changing in response to the circumstances a cell finds itself in. Some of these changes are reactions to the rising levels of metabolic waste and molecular damage that cause aging, and can in and of themselves be either helpful or cause further harm.
A number of factions within the research community are interested in trying force a reversal of age-related epigenetic changes: to make cells act in more youthful ways, overriding their reaction to damage and dysfunction in tissues. The fact that stem cell therapies can work even when the delivered cells die, and the only outcome is signaling that alters native cell behavior for some period of time, demonstrates that there are gains to be obtained in this sort of approach. It is nonetheless not really rejuvenation. It doesn't address the causes of aging, it is not repair in that sense even if can spur greater tissue regeneration and stem cell activity. It is instead something more akin to revving up a damaged engine - with all of the obvious downsides even if goals are achieved in the short-term.
Fossel isn't the only one advocating telomerase therapies. Maria Blasco's group is very much in favor of this path to treatment of aging, and accordingly telomeres and telomerase are found in the Hallmarks of Aging. Thinking of telomere erosion as a cause of aging and acting accordingly is, I think, the wrong path, however. Average telomere length in a tissue is a function of (a) the rate at which somatic cells divide, losing a little of their telomere length each time until they self-destruct or become senescent, and (b) the rate at which the stem cells supporting that tissue provide fresh somatic cells with long telomeres. So average telomere length is clearly secondary to declining stem cell activity, and it is well known that stem cell populations decline and falter with age.
When a lot of people look it aging, they view it in a very simplistic way: "Well, things fall apart, what do you expect?" You're accumulating amyloid, tau tangles, your collagen and elastin break down. But they're thinking about it mechanically, not biologically. I'll give you an analogy: I have a beautiful picture of a 1930 Duesenberg, and the car looks absolutely gorgeous - spot free, runs smoothly. If compare that to my five-year-old car, mine is in much worse shape. But the reason the 1930 Duesenberg looks fantastic is that five generations of absolute fanatics took care of it.
What happens with humans is that our rate of turnover comes down with age. If you look at beta-amyloid in regard to Alzheimer's disease, for example, you find that the pool of beta-amyloid is dynamic. It's continually being picked up, brought through the cell membrane, broken down, reconstituted, rebuilt, and put out again. But if you measure the rate of turnover in, for example, microglial cells with age, you find that the more senescent a cell is, the slower all of these turnover processes are - the rate of capture, the transmembrane translation, the rate of degradation. It's not that beta-amyloid denatures and therefore you get plaques. Instead, as the rate of turnover goes down, the percentage of denatured molecules goes up.
This is true throughout the entire human body. Everything that you think of as aging or age-related disease is a dynamic process, and all of those processes slow with age. The Duesenberg doesn't do well because it was well-made or because it had "great genes". It's the epigenetics, the turnover rate, that counts. And that's why telomeres matter - telomeres per se aren't important, but they modulate a slew of genes controlling turnover rate.
The mechanism of aging is a cascade of changes. Let's take Alzheimer's, for example. Why does Alzheimer's occur? Well, it occurs because the neurons die. Why does that happen? Well, because of the beta amyloid, and the tau tangles, and the changes in mitochondria and the oxidative damage. Well, what's upstream of that? I would argue it's because the microglial cells have changed their behavior. And why did that happen? Because the telomeres were shortened and now the pattern of epigenetic expression is playing a different tune. Why did that happen? Well, because the cell divided.
Then it gets messier and brings you back to clinical medicine. For example, we know that the rate of microglial cell senescence - that is, microglial cell divisions - goes up in patients with closed head injury and infection. So is that why you find that some patients are people with viral infection, bacterial infection, fungal infection, closed head injury? Well, again you have to go back and ask yourself what you're exposing for underlying genetic risks. You could also ask why the cells are dividing in the first place, if that's how far up you want to trace it.
I would never say that telomeres cause aging - they don't! The question I'm asking is, out of this whole cascade of changes, where's the single most effective point of intervention? I don't think it's preventing infection or preventing closed head injuries. I think the more effective point of intervention has to do with changing the pattern of gene expression. But rather than going after gene by gene by gene, rather than approaching an orchestra instrument by instrument, I would rather go to the conductor and say, "Play this tune." And that's where the telomere comes in.
If you asked me when we would first able to reverse human aging, technically I'd have to say it already happened back in 1999. That was when we showed in the lab that when you reset the telomere length in individual human cells like fibroblasts, you reset the pattern of gene expression, and then they act like young cells. Alright, but that's cells. Let's get a little more realistic: what about human tissue? There, the answer is the year 2000, when someone showed that you could grow young human skin cells. And likewise you can do the same thing with endothelial cells, vascular structures, bone, and a number of other tissues. But if you look at the data on the supplement TA-65 and a number of other things, it's just not impressive. It is suggestive and intriguing, though.
There are at least four ways, probably five, that we can reset telomeres in patients. The problem is that we need techniques that allow us to actually do that. Ronald DePinho did some really nice work seven years ago, but what he'd done was to alter the germ cell line so that he could turn telomerase on and off. I can't do that to you! Then Maria Blasco did the same thing with gene therapy. And the viral vector she used has been used in humans already, so we can actually do this now.
There are a couple of odd variables. Let's say I put a telomerase gene into one of your cells and it resets your telomeres. The first question is, how long does it stay there before the cell tears up the little plasmid that I put in there, because it's not on your chromosome? The answer is that it gets torn down at a certain rate that's a little hard to predict, since it depends on which cells and which species you're looking at. But it also depends on how fast your cells divide. If I put one little plasmid into a microglial cell and it divides, now I've got one cell with the plasmid and one without, or two with half a plasmid. So if this happens every time your cells divide, the more rapidly they divide, the less they have the telomerase. It's not like I've made you immortal - all I've done is reset your telomeres and gene expression, and they will un-reset again over time.
I actually see this as an advantage in several ways. One of the academic fads in the last twenty years (that's not well-substantiated) is that telomerase causes cancer. It really doesn't, but it is permissive of cancer. Even then, telomerase's effect on DNA repair means it's a genomic stabilizer which decreases the rate of new mutations. That doesn't mean telomerase is totally safe though. I think of it as three different zones a cell can be in. If you have long telomeres, you repair DNA really quickly. If your telomeres are short enough, the cell can no longer divide, so it's damaged, but it's not a complex problem. But if they're a bit less short, your cells are still dividing but you're not repairing damage - a cancer disaster. Most cancers maintain their telomeres just long enough that they remain unstable from a genetic standpoint, but not long enough that they can repair. So if I give you telomerase, I want to make sure that I either give you a lot, enough to get through that risk zone, or none at all.