DNA Methylation: an Epigenetic Aging Clock?

How does the body know how old it is? Our metabolisms change as we get older, even though our DNA doesn’t change. Different genes are activated at different times of life, and the timing of gene expression is what controls growth, development, sexual maturity, and perhaps aging as well. The body keeps accurate track of how old it is, though there has been no scientific agreement about where the clocks are, or how they work. Recently, some biologists have suggested that one such biological clock might reside in the epigenetic state of the DNA. If this is true, epigenetics will become an attractive, though challenging, target for anti-aging research.

An aging clock is the holy grail of anti-aging medicine. The body must have some way of knowing how old it is, a master reference that controls many aspects of the metabolism that can make us grow pubic hair at some time of life and grey hair at another time. (Aging is an active process, and not merely a matter of the body becoming damaged, or wearing out, as I have written previously.)

If we knew where the body kept its “clock”, then perhaps we could target the clock itself with biochemical interventions. We would not just be able to slow the progress of aging, but reset the clock to an earlier age.

I have written about telomeres as an aging clock. Telomeres are chromosome tails that are truncated with each cell division, so that they become shorter with age. Telomeres have all the characteristics of an aging clock in humans, and already therapies are being targeted toward promoting the enzyme telomerase and elongating our telomeres.

But there are other animals that have plenty of telomerase, and don’t lose telomere length over their lifetimes, and still they get old and die on a reliable schedule. So we know that telomeres are not the only aging clock. There are evolutionary reasons as well for believing that probably there is more than one aging clock at work in most higher organisms, including humans, (otherwise, it would be too easy to evolve away from aging, toward unlimited life span).

I have recently read about another candidate for an aging clock based on epigenetics. Genes are in control of every aspect of the body’s biochemistry, but different genes get turned on and off in different times and places in the body. In fact, 80-90% of the body’s genes are turned off in the average cell, at any given time. The choice of which genes to express is made from moment to moment by specialized promoter and inhibitor molecules.  These are responding to complex networks of chemical reactions and nervous signals as well that serve as a kind of neuro-chemical computer.

But there is also a more persistent aspect to the control of gene expression, and this is methylation. DNA is decorated with methyl groups, small molecular add-ons that act like “Do Not Disturb” signs for the underlying gene. A gene that is decorated with methyl groups is passed over, and not expressed. Patterns of methylation are programmed into the genome at birth, and they are known to change over a lifetime. The new idea is that these changes can constitute a reference, like a clock face that informs the cell about the body’s stage of life, so that it can appropriately adjust its gene expression, and thence its entire metabolism.

Methylation is controlled in turn by a set of enzymes called, appropriately enough, methyl transferases. There are “de novo” transferases that program the embryonic genome before birth, and then there are “maintenance” transferases that are active through the lifetime, assuring that the methylome decoration pattern is age- and tissue-appropriate.

Why does methylation make a plausible clock for aging and development?

Methylation patterns are important – they control gene expression. Mutations in the methyl transferase genes cause serious, usually lethal, defects.  Several of the diseases of old age, including diabetes and Alzheimer’s, are known to be associated with aberrant patterns of methylation.

Methylation patterns are persistent. They can last for years.  In fact, methylation patterns are copied when DNA is copied, which is to say whenever a cell is replicated.  Epigenetic patterns can persist for several generations, and epigenetic inheritance is thought to be mediated through patterns of methylation.

Gene expression changes during development and maturation, and it is plausible that this is accomplished through changing methylation patterns. And gene expression is known to change at advanced ages. The new hypothesis is that perhaps altered patterns of methylation are a deep cause of the disabilities and altered metabolism that come with age.

It is likely that some of the change in methylation patterns over time are random and haphazard, and can cause trouble; and other changes are programmed and determined, and these definitely cause trouble.

Three key experimental facts

1. In general, we lose more methylation than we gain over time.  DNA from older animals is less methylated than from young animals, though there are also some regions of the DNA where there is more methylation with age. Ref  In a recent study, it was shown that people with less total methylation were more frail and sickly at the same age. Ref

2. Gene methylation patterns were compared in identical twins when they were very young, and when they were older. Methylation patterns were very similar in young twins, but diverged markedly over time. Ref  Could it be that some of the body’s loss of function with age has to do with a haphazardness in the way that methylation changes over time?
3. Fruit flies with an extra dose of methyl transferase in their genome lived up to 58% longer than control flies. Conversely, when one copy of the methyl transferase gene was deleted, flies lived only 3/4 as long. Ref.

How difficult will it be to learn to reset the clock?

The idea that methylation patterns could be an aging clock presents an opportunity and a challenge for anti-aging medicine. If the clock hypothesis pans out, we will have to learn two things: First, to read off a strand of DNA, which places are methylated and which are not. There is already good technology for acquiring this information, but it will have to be automated and far more efficient in order to create a detailed map.  Second, we will have to learn how to impose a pattern of methylation on a strand of DNA in vivo, without otherwise disrupting the function of the cell or its nucleus. This will mean acquiring a new language, the language of methyl transferases that accurately locate a place on the genome to do their decoration. This may be a decade-sized challenge for the current biochemical state of the art.

But if we’re really lucky, it will turn out that humans, like flies, respond well to a dumb, across-the-board increase in methylation.  Flies have just a single methyl transferase that is active in their adult lives, and extra copies of the gene for that molecule was enough to create a whopping boost in life span.  The methyl transferase system in humans is more complicated, but it will still be far easier to engineer a general increase in methylation than to copy youthful methylation patterns in detail.  This question could be posed in research project that we know how to do now.

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Much of the technical information for this blog post came from this paper in Rejuvenation Research last fall.