Epigenetic versus Genetic Disease

• Age-related disease
• APOE4
• Telomerase

Last week I attended a global conference on aging research. The presentations were professional and thoughtful, as befits an organization of researchers with impeccable academic and clinical credentials. These are bright, well-educated people who work hard to understand not only the basic science that underlies aging, but the possible interventions that might cure age-related diseases. My role was to consider becoming their executive director and to discuss my thoughts on how to improve — and ensure the viability of — the organization.

Oddly enough, my biggest fear was that they might find themselves side-lined and outmoded by the plethora of advances that are leading the way, advances that promise to revolutionize both our understanding of aging and our ability to treat disease. I had the nightmarish image of a group of well-meaning and well-trained researchers who are blithely marching off the cliff en masse, happy and blind, certain of their small (and ultimately unimportant) piece of the aging puzzle.

The problem is that science changes.

Science has a history of progressing in straight lines until reality abruptly intrudes. We happily refined the epicycles needed to prove a geocentric universe until Galileo substituted a heliocentric universe. We happily refined classical physics until Einstein and quantum mechanics showed us a more complex reality. At the moment, in biology, we happily refine the genetics of disease, while most age-related disease is — as it turns out — actually epigenetic.

Whether we look at the role of APOE4 in Alzheimer’s disease, or the role of cholesterol metabolism is atherosclerosis, a careful view of the literature (and the pathology) shows us that these and other age-related diseases are not genetic in the classical sense. We might reasonably call sickle cell disease genetic, but Alzheimer’s disease is epigenetic. Where genetic diseases are relatively simple to understand, epigenetic diseases are a bit more complex.

An analogy that might help understand the critical difference can be found in my new book, The Telomerase Revolution. Imagine a large lake on which we speed back and forth during our lives. A few of us, unfortunately, have exposed rocks — genetic diseases — that tear out the bottom of our boat, ending our lives. All of us, however, have hidden rocks as well — epigenetic diseases — that are innocuous enough unless we lower the water level. In the case of aging, exactly such a lowering occurs: as telomeres shorten, they change the pattern and extent of gene expression. It is this epigenetic change — lowering the water level — that results in our increasing risk of disease as we age.

Now in the case of a strictly genetic disease — such as sickle cell, we might reasonably ask how we can “fix” the gene. In the case of epigenetic disease — such as Alzheimer’s — however, the problem is not the hidden rocks (the various alleles that associate with Alzheimer’s, such as APOE4), but the fact that the water level is too low. The way to cure Alzheimer’s disease is not to find each and every rock and try to “fix the gene, but to simply raise the level of the water again.

This is precisely the aim of genetic therapy aimed at telomerase.