Michael Fossel Michael is President of Telocyte

September 20, 2017

Genes and Aging

Several of you have asked why I don’t update this blog more often. My priority is to take effective interventions for age-related diseases to FDA phase 1 human trials, rather than blogging about the process. Each week, Outlook reminds me to update the blog, but there are many tasks that need doing if we are going to get to human trials, which remains our primary target.

In working on age-related disease, however, I am reminded that we can do very little unless we understand aging. Most of us assume we already understand what we mean by aging, but our assumptions prevent us from a more fundamental and valid understanding of the aging process. In short, our unexamined assumptions get in the way of effective solutions. To give an analogy, if we start with the assumption that the Earth is the center of the solar system, then no matter how carefully we calculate the orbits of the planets, we will fail. If we start with the assumption that the plague results from evil spirits rather than Yersinia pestis, then no matter how many exorcisms we invoke, we will fail. We don’t fail because of any lack of effort, we fail because of misdirected effort.

Our assumptions define the limits of our abilities.

When we look at aging, too often we take only a narrow view. Humans age, as do all the mammals and birds (livestock and pets come to mind) that have played common roles in human culture and human history. When most people think of aging, they seldom consider trees, hydra, yeast, bacteria, or individual cells (whatever the species). Worse, even when we do look at these, we never question our quotidian assumptions. We carry our complacent assumptions along with us, a ponderous baggage, dragging us down, restricting our ability to move ahead toward a more sophisticated (and accurate) understanding. If we looked carefully, we would see that not all cells age and not all organisms age. Moreover, of those that age, not all organisms age at the same rate and, within an organism, not all cells age at the same rate. In short, neither the rate of aging, nor aging itself is universal. As examples, dogs age faster than humans and, among humans, progeric children age faster than normal humans. The same is true when we consider cells: somatic cells age faster than stem cells, while germ cells (sperm and ova) don’t age at all. So much for aging being universal.

The key question isn’t “why do all things age?”, but rather “why does aging occur in some cases and not in others, and at widely different rates when it occurs at all?” The answer certainly isn’t hormones, heartbeats, entropy, mitochondria, or free radicals, for none of these can explain the enormous disparity in what ages and what doesn’t, nor why cells age at different rates. Nor is aging genetic in any simplistic sense. While genes play a prominent role in how we age, there are no “aging genes”. Aging is not a “genetic disease”, but rather a matter of epigenetics – it’s not which genes you have, but how those genes are expressed and how their expression changes over time, particularly over the life of the organism or over multiple cell divisions in the life of a cell. In a sense, you age not because of entropy, but because your cells downregulate the ability to maintain themselves in the face of that entropy. Cell senescence effects a broad change in gene expression that results in a gradual failure to deal with DNA repair, mitochondrial repair, free radical damage, and molecular turnover in general. Aging isn’t a matter of damage, it’s a matter of no longer repairing the damage.

All of this wouldn’t matter – it’s mere words and theory – were it not for our ability to intervene in age-related disease. Once we understand how aging works, once we look carefully at our assumptions and reconsider them, our more accurate and fundamental understanding allows suggests how we might cure age-related disease, to finally treat the diseases we have so long thought beyond our ability. It is our ability to see with fresh eyes, to look at all organisms and all cells without preconceptions, that permits us to finally do something about Alzheimer’s and other age-related disease.

Only an open mind will allow us to save lives.

 

August 10, 2017

Progeria and Telomerase

Recently, John Cooke at the Houston Methodist Research Institute, showed that telomerase, when expressed in cells from progeric children, caused a “substantial physiologically relevant and meaningful effect on the lifespan and function of the cells.” As many of you know, progeria is a disease in which young children appear old, with baldness and osteoarthritis, and usually die of advanced cardiovascular disease, such as heart attacks, typically around age twelve. In short, they appear to have extremely rapid aging. Cooke’s results suggested that telomerase might offer a therapy. Oddly enough, both Cooke and the media described this finding as “surprising”.

While these results are promising, they are hardly surprising. In 1996, I published a book going into this prospect in detail, then wrote the first medical papers on this the medical potential in JAMA in 1997 and 1998. This was followed up with a medical textbook which explored the entire area in 2004, and another book in 2015 that described the medical potential of telomerase. What is truly surprising is not the most recent results, but that anyone finds the results at all surprising.

While not actually surprising, they present a bitter irony, in that any number of deaths, including deaths of progeric children, might have been prevented and may still be prevented if we only understand and act upon what we have known for two decades and which Cooke’s results only highlight again.

The irony – and my exquisite personal frustration – is that I proposed this approach annually in our global meetings for progeric children, starting twenty years ago. For about a decade, beginning several years before the turn of the millennium, I had been part of the annual global reunion of progeric children. Each year, we gathered with perhaps three dozen progeric children and their families from around the world, giving them a chance to meet one another, to talk with experts, and … to feel normal among other children and families who had the same problems. In 1999, among those progeric children was a young boy, whose parents were both physicians, and who were desperate to find a cure for progeria. Although I explained the potential of using telomerase as an intervention, they founded the Progeria Research Foundation and aimed it solely at genetic markers rather than epigenetic intervention. They managed to get significant funding through the NIH, fund raising, and government contacts in order to fund a set of studies that localized the genetic error responsible for progeria. As I predicted, none of the subsequent therapies based on their approach have had any effect on the disease. Worse yet, and like all the other progeric children I have known over the years, their son died of progeria. Had we gone straight to telomere-based interventions rather than taking the detour, many progeric children – not merely their son — might have been treated more effectively.

John Cooke and his colleagues have done well to show that they can reverse the problems seen in progeric cells, yet others have gone further. Maria Blasco’s group, for example, has shown that she can not merely reset aging in cells, as Cooke’s group has, but can do the same in animals. Moreover, we are collaborating with her group to take this approach in our upcoming human clinical trials next year, initially aiming at Alzheimer’s disease.

The fact that this comes as a surprise, given what we have known about the potential of telomerase for more than 20 years is a tragic example of wasted opportunities, wasted funding, and wasted lives. Telomerase was shown to reverse aging in cells 20 years ago; telomerase showed its value in animals 5 years ago; Telocyte is ready to show the benefits of telomerase in human trials next year.

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