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
- 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
- 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?
- 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.
Much of the technical information for this blog post came from this paper in Rejuvenation Research last fall.
We might draw encouragement from the story of “sirtuins”. This is a family of chemicals including resveratrol, the anti-aging component of red wine. They are named for their ability to activate the gene called SIR2, and SIR stands for “silent information regulator”. SIR2 works by a different mechanism from methylation, but its effect is also to turn genes off. The point is that there is a precedent for the idea that blindly turning genes off can extend life span.
Thank you for the science blog, I am doing a research project on DNA methylation, this is the most interesting facts I have found so far!!!
The clock is inside your eyes
Epigenetics controls aging the same way it controls development, by making global changes (often chromosome specific – an entire region of a chromosome may become demethylated upon aging (Chambers,2007). Stuart Chambers attributed this to ‘epigenetic dysregulation’, but though I’m sure there’s a stochastic element in the process (any biological process) it is more likely programmed, a normal part of development. Chambers et al noted that just before the time (and during) that DNA damages start to accumulate there is a down-regulation, in hematopoietic stem cells, of DNA repair enzymes and chromatin remodeling proteins are down-regulated. Now these chromatin remodeling proteins include SIRT1 mentioned, a histone de-acetylase) by an earlier reader. SIRT1 changes the chromosome’s epigenetic state, a histone deacetylase (acetyl groups added to lysine residues on the histones that form the nucleosome core),usually make the chromosomal region the operate on have an ‘open to transcription and repair’ state. I don’t believe there’s a clock, but probably many clocks -an instance of this clock was given in last weeks Science showing how the buildup of a micro RNA (let-7) that is controlled by the heterochonic gene lin-41 result in neurons losing the ability to regenerate (in a step-by-step manner). As the nematode that bears this mechanism – purposely shifts to a less resilient form the authors of a peice about this work in the same issue of Science wonder what the cause for this is – it become a mystery only if you don’t understand that the ’cause’ for this is the make the worm adequate for reproduction and that’a about it – otherwise get it ready to die. Then there’s no mystery -even if we don’t understand the evolutionary basis – Stuart Chambers (and Rossi before him) show, if you use Occam’s razor, that the various stages of post-adult development (including middle- and old-age) are the result of changes in the regulation of the cells genes – now whether this is intrinsic to the cell or mediated by exogenous factors is another matter.
Guess not. http://www.epigeneticsandchromatin.com/content/6/1/36. But this is progress.
Surely someone has harvested regular and even stem cells anf frozen them for a time and then reintroduced when organism is old and then assessed gene function in reintroduced cells after a time and also checked epigenetic state?
Surely…send me a reference!
It seems clear to my understanding that “epigenetic drifts” are at the root of cancer and degenerative diseases seen rather in late adulthood. Epigenetic changes in DNA methylation which tend to be uniform in blood and tissue cells across individuals are a typical sign of the existence of a “clock”. It occurs to me that dna methylation maybe tightly close to the general antioxidant status in a particular individual and directly correlated to the nutritional status too. As aging also affects negatively the absorption of vitamins from food. There is a theory that may explain why DNA methylation suffers epigenetic drifts and it’s called Triage Theory. As the general (global) status of methylation is reduced with age, the body tends to selectively ” drift” attention from some types of cells to others more connected to the short term survival of the person.
Quite an interesting subject…
People call it “drift” when they think it is random–something that Evolution tried to avoid but couldn’t. My perspective is that there is also an epigenetic “clock”, which implies that Evolution made it that way on purpose.
I champion the idea that aging is a purposeful, timed program of self-destruction. Although this is still a minority view, it is gaining ground.
This thread is old but I wished to log here what I just learned about the crosstalk between the DNA methylation and the microbiome epigenetic regulation which I found interesting and probably very much known to the experts here. Maybe this is also important as potentially impacting the panel of our anti-age interventions.
“The core human gut microbiota contributes to the developmental origin of diseases by modifying metabolic pathways. To evaluate the predominant microbiota as an epigenetic modifier, we classified 8 pregnant women into two groups based on their dominant microbiota, i.e., Bacteroidetes, Firmicutes, and Proteobacteria. Deep sequencing of DNA methylomes revealed a clear association between bacterial predominance and epigenetic profiles. The genes with differentially methylated promoters in the group in which Firmicutes was dominant were linked to risk of disease, predominantly to cardiovascular disease and specifically to lipid metabolism, obesity, and the inflammatory response. This is one of the first studies that highlights the association of the predominant bacterial phyla in the gut with methylation patterns. Further longitudinal and in-depth studies targeting individual microbial species or metabolites are recommended to give us a deeper insight into the molecular mechanism of such epigenetic modifications.”
Gut Microbiota as an Epigenetic Regulator: Pilot Study Based on Whole-Genome Methylation Analysis Kumar H, Lund R, Laiho A, et al. MBio. 2014;5(6)
Qin Y, Wade PA. Crosstalk between the microbiome and epigenome: messages from bugs. J Biochem. 2018;163(2):105-112
Very interesting Albedo. I know gut microbiota affect our health, it’s new to me that they also regulate our epigenetics. Still besides taking probiotics and prebiotics, we know not much more how to manipulate microbiota to better our health.
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