Epigenetics of Aging, and Prospects for Rejuvenation

joshmitteldorf.scienceblog.com/2016/05/09/epigenetics-of-aging-and-prospects-for-rejuvenation/

May 9, 2016
Last week, I attended the tail end of a Keystone conference on Epigenetic Regulation of Aging , followed by a oneday brainstorming session to kick off a project called GILGA-mesh, intended to take this bull by the horns. Though
the subjects of the two days were virtually identical, the approach and attitudes of the scientists in attendance set
very different tones. Both days featured smart, creative and careful scientists, but they saw the same material
through different frameworks. Sometimes philosophy makes a difference.
For readers who know me less well, I should introduce my perspective: I believe that aging is an evolved epigenetic
program. When we are young and growing, particular genes are turned on and off with exquisite timing to determine
the growth and development of bones, muscles, and organs. When we are old, the program continues, more slowly
and more diffusely, but inexorably nonetheless. Genes are turned on that destroy us with inflammation and cell
senescence and auto-immunity and programmed cell death, while the systems that protect us from pathogens and
from free radical damage are gradually shut down. Evolution has left nothing to chance.
[I first wrote an academic paper about this idea in 2013, excited by a paper by Aviv Johnson on methylation, but
unaware that Tom Rando had written on the same lines the previous year. Jeff Bowles had hinted at similar ideas in
a paper more than a decade earlier. Soon the field was broken wide open by the work of a bio-statistician.
Steve Horvath ran a computer analysis on thousands of genes as they are expressed in young and old humans,
and produced an epigenetic clock that could accurately report how old a person using measurementis of
methylation in 353 DNA sites in particular.]

Background
Epigenetics is a new science in the 21st century. All the cells in one body have the same DNA (pretty much), but
differernt genes are expressed (translated into proteins) in different tissues and at different times, and this is what
controls the bodys metabolism. In fact, only 2% of our DNA is genes, and 98% determines how the DNA is folded
and spooled, opened and closed at particular times and places, and this in turn controls gene expression. We are
2% genetic and 98% epigenetic.
There is a language called the genetic code which determines how genes are translated into proteins. It was
decoded by Francis Crick and others in the 1950s. It is as simple as it can be, and is completely understood.
There is another language, the epigenetic code that determines gene expression. It is anything-but-simple, with a
convoluted and self-referential syntax that we are just beginning to understand. The epigenetic code starts with
signals embedded in the DNA that serve as start and stop codons. The stretch in between comprises a piece of a
gene, a kind of Gutenberg movable type that is transcribed from the chromosome and then spliced and combined to
form functional RNAs and proteins. The complicated part of the epigenetic code is implemented as a pattern of
methyl and acetyl groups. These are little chemical decorations that attach to the DNA and to the histones (spools
around which DNA is wound up in the cell nucleus for safe storage). The methyl and acetyl groups are continually
being attached and removed according to instructions that come from within the cell and other instructions that are
passed through the blood. It is the methyl and acetyl groups that determine how the DNA is folded and spooled,
which effectively turns particular genes on and off as needed.
The part of the epigenetic code on which we have the best handle at present is called methylation of CpG islands.
Long stretches of DNA have CGCGCGCG on one strand, complemented by GCGCGCGC on the other. Often

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the Cs in this region get an extra methyl group, turning from cytosine to 5-methylcytosine. Then this stretch
becomes a repressor region, a signal to NOT express the adjacent gene.
DNA methylation can be persistent, turning a gene off for decades at a time. When a cell divides and its DNA is
copied, the methylation pattern can be copied with it. This accounts for some of the persistence of epigenetics, and
the way gene expression can be inherited across generations.
DNA methylation has been appreciated for 30 years, but two recent developments make the subject attractive and
accessible to research. (1) There is now a simple lab/computer technique for reading the methylation pattern from
DNA. It relies on commercially available, automated machinery for PCR to sequence a full genome before and after
chemical modification of the methylated Cs. (2) There is now a simple lab/computer technique for changing the
methylation state of any chosen target site in the DNA. It is based on CRISPR technology that is taking genetics
labs by storm the last two years.

from Hannum et al., 2013, Genome-wide Methylation Profiles

Epigenetics and aging

Three years ago, Horvath demonstrated that there are specific patterns of methylation associated with particular
ages of the body. Its not just that the fresh, clear pattern of youthful gene expression becomes muddied and
random with agealthough there is some of that. But its also true that some genes that are active in youth become
inactive as we get older and (especially) that other genes that were suppressed in youth become activated in old
age. What Horvaths paper says is, show me methylation pattern of a persons cells, and I can tell you how old
s/he is.

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Is epigenetics a cause or effect of aging?

The correlation between aging and epigenetic status is established beyond dispute. But what does it mean? This
is the big question. Most researchers think of the body as programmed by evolution to be as strong and healthy as
possible. So, when different genes are expressed in old age, they find it natural to assume that the body is
protecting itself in response to damage that it has suffered over the years. We express different genes when we are
older because we need different genes when we are older. This was the predominant attitude at the first conference
(where I was present just for the last day).
The other possible interpretation is my own, and it has become common among those who are closest to the field of
epigenetics. It is that epigenetic changes with age are means of self-destruction. The body is programmed to die,
and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes. This idea flies in the
face of traditional evolutionary theory. (How could natural selection prefer a genome that destroys itself and cuts off
its own reproduction?) Nevertheless, the evidence for this hypothesis is robust. The genes that are turned on dont
protect the bodyquite the opposite. Genes for inflammation are dialed up. Genes for the bodys defense against
free radicals are dialed down. Cell turnover is dialed down. DNA repair is dialed down. The mechanisms of
programmed cell death (apoptosis) are strengthened in healthy cells, at the same time that they are perversely
weakened in cells that are a threat to the body, like infected cells and cancer cells.

How will we determine who is right?

In my opinion, the existing evidence heavily favors the hypothesis that aging is caused by epigenetic changes,
rather than the other way around. When we look at the kinds of changes that occur, they seem to be pouring fuel on
the fire, not putting it out. Protective genes are turned off and inflammatory genes are turned up. I also think that
parabiosis experiments provide a strong clue. Three researcher groups (at Stanford Harvard, Berkeley) have
shown that injecting blood plasma from a young mouse into an old mouse makes the old mouse healthier, and
relieves some problems associated with age. The blood plasma contains no cellsonly signal molecules that are
the product of gene expression. This is powerful evidence that youthful gene expression is supporting a strong and
youthful body, and (conversely) that the kind of gene expression that characterizes old age is not doing the body any
good.
But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating
effect.

My proposal
As of now, the GILGA-Mesh project is dominated by numbers geeks (like me) who practice the Google approach to
bioinformatics. Huge databases of gene expression are screened for epigenetic candidates that seem to be wellcorrelated with good outcomes. I think what we need is an infusion of biolochemists who understand something
about the bodys signaling networks, and can orient us toward upstream and downstream molecules. Heres my
proposed program:
1. Repeat Horvaths (human) analysis for mice. In other words, identify several hundred places where
methylation is different in young and old mice.
2. Determine which genes are associated with these regions. (Map needed for this should already be
available.)

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3. Look at the set of genes and identify transcription factors. These are likely to be upstream, in that they
control other genes.
4. Start with old mice. Use CRISPR to change the methylation status in a handful of promoter regions that
control transcription factors, making them match the methylation status of young mice.
5. Measure metabolic functions to see if the old mice are more healthy or less after these procedures. Look
particularly for changes in inflammation, propensity for cancer, and especially life span.
If this experiment goes as I expect, we will be ready for rejuvenation experiments in humans.

How does the body know how old it is?

Even further upstream, is there a central master clock that dictates the bodys epigenetic expression, and thereby
determines our biological age? Logically, it seems that the body would need an accurate clock to time the events of
growth and development. Evolution likes to re-use the parts she has created, and it would not surprise me if the
developmental clock morphs into an aging clock.
I have reasoned that there are two possibilities. It may be that there is a timekeeper, probably in the neuroendocrine regions of the brain, that controls the processes of development and aging. This possibility is supported
by works of Kasper Daniel Hansen and Claudia Cavadas. If this pans out, it would present the handiest target for
true rejuvenation in humans. But it also may be that epigenetic expression itself is a kind of clock that is diffused
through the body. Todays gene expression includes transcription factors that control tomorrows gene expression,
and so epigenetic state may be a feedback loop, or self-contained clock. This may also be a target for rejuvenation,
but a little accessible, harder to address or to tinker with.
Random notesother things I learned last week
I was tickled to find how many members of the GILGA-mesh team already support the
programmed aging perspective that I have advocated. I was particularly gratified to receive encouragement from
Caleb Finch, a grand old man of the field who wrote the
encyclopedia of aging in 1990, and continues a very active research program today.
From Finch, I learned that infections in childhood and even in the womb can have a serious effect on diseases of old
age, decades after the fact. He hypothesizes a lifelong burden of inflammation. Evidence includes an elevated
incidence of heart disease for the cohort born just after the influenza epidemic of 1918.
I was chagrined to learn that air pollution, especially particulate matter, is associated with increased risk of dementia.
This poses a personal dilemma for me, as I plan to spend the summer at the lab of Meng-qiu Dong in Beijing.
I learned that hospital errors are the third leading cause of death in the US, accounting for about 10% of all deaths,
about the same number as smoking. Maybe you already read that in the New York Times.

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