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7.10 Extension lecture: Aging - Part 1

Course video 58 of 59

This week we’ll bring together much of what we’ve learned in previous weeks of the course, to understand how the epigenome is affected, and can also affect, cancer development and progression. We’ll then go on to discuss the potential therapeutic benefits that can come from using epigenetic biomarkers, and targeting epigenetic modifiers in cancer.

While the human genome sequence has transformed our understanding of human biology, it isn’t just the sequence of your DNA that matters, but also how you use it! How are some genes activated and others are silenced? How is this controlled? The answer is epigenetics. Epigenetics has been a hot topic for research over the past decade as it has become clear that aberrant epigenetic control contributes to disease (particularly to cancer). Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. It has also become clear in recent years that epigenetic modifications are sensitive to the environment (for example diet), which has sparked a large amount of public debate and research. This course will give an introduction to the fundamentals of epigenetic control. We will examine epigenetic phenomena that are manifestations of epigenetic control in several organisms, with a focus on mammals. We will examine the interplay between epigenetic control and the environment and finally the role of aberrant epigenetic control in disease. All necessary information will be covered in the lectures, and recommended and required readings will be provided. There are no additional required texts for this course. For those interested, additional information can be obtained in the following textbook. Epigenetics. Allis, Jenuwein, Reinberg and Caparros. Cold Spring Harbour Laboratory Press. ISBN-13: 978-0879697242 | Edition: 1

Skills You'll Learn

Cancer, Molecular Biology, Cancer Epigenetics, Dna Methylation

Taught By

Dr. Marnie Blewitt
Head, Molecular Medicine Laboratory

Transcript

Hi everybody.

So what I wanted to do in this set of two lectures was to provide you a small

extension on the work that we've already covered, and

this is going to be on Epigenetics and aging.

So for decades really,

this has been a a topic of conversation within the epigenetics community.

It's part of what happens during aging, that actually genes are switched off

epigenetically or switched on epigenetically in an aberrant fashion.

But it's really only been probably in the last five years or so, or in recent times,

that we've had a real advance in terms of understanding what does happen when aging.

So still a very new field in terms of the amount of data that's out there, and

it's definitely incomplete.

But it's at the point where we can start to make some sort of generalisations, and

so that's what I'd like to talk you about today.

So we're going to first think about what are the hallmarks of aging?

In the epigenetics and

cancer lectures in week seven, we think about what the hallmarks are of cancer,

and similarly people have come up with hallmarks of aging.

These include epigenomic changes, in other words changes to the epigenome, or

changes that occur to the epigenetic state genome-wide.

We're going to go through a brief summary of the epigenomic changes that occur

in aging.

And then talk about how these relate with the changes that occur

in cancer, which often happens when you're getting older.

And then we'll think about how is it these epigenetic abnormalities occur in

the first place, and what are the effects of having these epigenetic abnormalities.

And finally, we'll think about whether or

not this understanding of the epigenetic changes that occur with aging leads to any

potential therapeutics which might halt aging, or at least slow down aging.

Something that really is obviously of interest to all of us.

So in the first lecture, I'm just going to go through the hallmarks of aging and

some summaries.

And then in the second lecture,

we'll deal more with the specifics of the epigenetic changes with age.

So in this picture, you can see many of the hallmarks that you and

I would think of as being the hallmarks of aging.

You can see that a man has become bald with age, this is fairly common.

You can see there's grey hair, this is extremely common, and

I'm sporting a lot of grey hair now, as well as most people do as they get older.

You can see that the skin is becoming wrinklier as the elastine that's normally

found in the skin is expressed less, and so that the skin has more stretchy-ness.

You can see in the knuckles of the man that he has inflamed knuckles,

probably arthritic knuckles.

And this is again, inflammation is something that occurs commonly with age,

as does a slower ability to heal from many different wounds or

insults, and many other hallmarks that you can think of.

That we think of as being the phenotypes or in other words,

the visual effects of aging.

But what do we describe in terms of the scientific hallmarks of aging?

So the hallmarks that I've got listed on this slide,

here, have been defined by features that first occur in normal aging.

Second of all, they accelerate aging if you enhance these features.

And thirdly, not always but where it's been able to be studied,

they can slow down aging if you can prevent this particular hallmark.

Now this third part is in brackets because you can't if the studies haven't always

been done, and secondly, it's actually a big ask to ask us to slow down aging.

So this is somewhat of an optional part of the hallmark.

We can't always slow down aging, but certainly accelerating aging,

if we enhance any of these features,

is something that happens in everyone of these cases.

So what you'll notice is in striking up here is one of the major hallmarks of

aging, epigenetic alterations.

We also have genomic instability,

and you'll remember there's a relationship between epigenetic changes and

genomic instability that we spoke about right back in week one of the course, and

again, of course, in week seven when we talk about cancer.

We also know that there's telomere attrition.

So those of you that have done a little bit of biology will know that telomeres

are the ends, the caps of each of the chromosomes.

These caps have repeats.

Many, many copies of a particular repeat,

that are bound to by an enzyme called telomerase.

And we have these repeats because DNA polymerase is actually unable to bind

to the very end and replicate the very end of a chromosome.

It replicates almost the end, and so what happens is and

this is just a bi chemical feature of the enzyme.

So what happens is if you have these repeats,

then slowly over time with more cell divisions you lose

one of these subsets of the, one of these units of the repeats.

So over time you have fewer and fewer telomeres, and therefore there's telomeres

attrition as the cell divides more and obviously as the organism is aging.

And eventually you get to the point where they're no more telomere caps, and

therefore you start eating into the actual coding regions of the genes.

And this has obviously a consequence for aging.

And it's a telomerase enzyme that can actually add these telomere repeats

back again.

So if you over express telomerase,

you can in fact increase the life span of an organism, and certainly of cells.

And it's only some cell subsets that express telomerase.

For example, the primordial germ cells where we need put the telomere

caps back on again, so that we can have totipotency for the next generation.

We also include up here the loss of proteostasis, and

this just means that the ability of proteins to be made and

degraded at the right rate is all of sudden upset.

What we know is we can actually class these hallmarks in different ways.

The first one being those that cause the damage, so

these ones that I've described so far, which include the epigenetic changes,

are the ones that are always deleterious, they always cause harm.

So if you have epigenetic changes that aren't appropriate,

this could cause problems for the cell.

This may, indeed, result in genomic instability.

You can have telomere attrition, this is always a bad thing, and

you can have loss of proteostasis.

But these causes of damage then lead to the cell making particular responses.

The cell wants to try and

respond to these changes to protect itself from these changes that are occurring.

These include change nutrient sensing.

So this means a change of working out whether or not there is enough

food around, whether or not, and therefore responding inappropriately.

But normally for these responses that we've got grouped here,

if they have a small amount of these changes, it's actually beneficial.

It protects the organism.

The problem with aging is that as these progress,

you go from a small amount of these things that it's beneficial to a very high amount

of these things, and that's when it causes problems.

So, for example, if we think about cellular senescence or

cell senescence, what this means is that the cells no longer divide,

and they're not very active, but they don't die.

So they sit around in a tissue, for example, and take up some of the space but

they're not actually functional.

It's protective when you have a small about of this because it means that,

because it tends to happen if you have some sort of a genetic insult

which could otherwise result in cancer.

So it's protective because it's stopping this cell from dividing in an out of

control manner like you would have occurring in cancer.

But, when you have a large amount of cellular senescence, it's indeed damaging,

because it means that the tissue is no longer going to function as it should,

because you have many cells not actually working as they should.

Senescence is one of the the hallmarks of aging.

It's also one of the cases where people study the epigenetic changes because

getting senescent cells is easier than having very aged cells.

So some of the work that's come out has been comparing senescent cells to normal

cells rather than aged cells with normal cells.

And this is one of the issues with trying to come up with summaries of what

happens in an aged cell, when actually we're looking at senescence instead.

What I said is senescence occurs

particularly if you have an insult that might otherwise result in cancer.

And in fact we know that some oncogenes, for example, oncogenic ras,

what it does, if you have in an otherwise normal cell, is it causes senescence.

But it's only if that cell has some other problem,

some other first hit if you'd like.

Maybe genomic instability, but then if you add ras activation on top of that,

that's when you'll result in tumour agenesis.

And so cellular senescence is really intricately involved in and importantly

involved in protecting the body from the damages that could otherwise occur.

Just as we're talking about with these particular features here.

So then if you have these responses to damage occurring at a high level,

what ends up happening is that you end up with the phenotypes of aging.

So these include an altered intercellular communication.

In other words, how the cells actually talk to one another.

But in particular stem cell exhaustion, and this is an easier one to explain.

So we know that as people get older, they don't heal as fast as they used to.

So we know that, for example,

if you had your grandparent who got a cut on their arm, its going to take them a lot

longer to heal that cut than it would to a baby or even a teenager.

And that's because the way that you heal skin cells is that you have the stem

cells, the resident stem cells, and progenitor cells that exist in the skin,

the epidermal progenitors in stem cells, they divide and create new skin cells.

But if the stem cells are exhausted, that is if they no longer want to divide as

much as they should then that can't happen as quickly as it might have done.

And in the extremely aged populations,

perhaps, they don't really repair these things at all anymore and

no longer repair the skin because the stem cells are completely exhausted.

So this is one example of stem cell exhaustion, and

it's one of the phenotypes of aging.

We know that we no longer respond appropriately, also, to insults,

for example.

Elderly patients tend to be more anaemic.

They tend to have fewer red blood cells, or

they tend to respond slower to bleeding events because their blood

stem cells are less able to reproduce and proliferate and produce their progeny.

Which are all of them mature blood cells that are found in the body.

So these are the hallmarks of aging, and as I said, what we're going to focus on

today are these epigenetic alterations and what we know of those.

So, what I want to do for the end of this first lecture is talk

about something that I think is really important to think about, and

that is the variability of what happens in aging.

So, as I said before, there have been many studies now performed

in fairly recent years on the changes that occur in epigenetic state with age.

But, while there have been many of them they don't all fit together, and part of

that, we believe, is because the changes are relatively variable within one tissue.

Say, for example, if we took the liver of an elderly patient.

Each cell within that tissue might have slightly different epigenetic changes.

And then if we compared between the livers of multiple patients, elderly patients,

they would be different changes between these patients, between people as well.

So these changes are hypervariable.

And so what's been proposed is that one reason we might have

the epigenetic changes is because of epigenetic drift.

And what epigenetic drift really means is that you might have some epigenetic

mistake occurring, randomly, and that epigenetic mistake is perpetuated

because of the heritability of epigenetic marks.

But that epigenetic mistake could go in either direction.

You might activate a gene or repress a gene because of an epigenetic mistake.

And, similarly,

where that epigenetic mistake occurs could occur anywhere in the genome.

And so what ends up happening then is that you have highly variable nature

of the epigenetic mistakes that are made.

And so, if you think about a tissue, you then have a mosaic,

you have some cells that have the mistakes, and some cells that don't.

And the mistakes might be different in each of those scenarios.

So this means that while we can come up with summarised versions

of what might happen with aging in terms of the epigenetic effects,

these are just summarised versions.

So aging may not have really specific concerted effects on epigenetic state.

They might not have really strong features that we can call out and

say this always happens in aging.

But rather what we probably should think of is that

epigenetic state becomes more variable with age.

So there is some evidence for this, and this comes from studies,

again, of identical twins.

We've spoken about studies of identical twins earlier in the course.

So using methodologies we've been able to look at DNA methylation

throughout the genome, so genome wide methodology.

They found in young identical twins there are relatively few epigenetic differences.

So they're genetically identical and

they're largely epigenetically identical as well.

In fact, the differences that you can find between identical twins,

young identical twins, it's actually very difficult to find these differences,

and the differences that occur are only slightly larger than the technical

variation that you see in the methodology itself, so incredibly difficult to find.

Whereas when you use the same methodology and look at older identical twins,

in fact, aged identical twins, usually they're not the same twins but

elderly identical twins, they seem to have more marked epigenetic differences.

So this suggest that over time,

you have some sort of epigenetic drift that occurs, and that this drift may occur

partly because of this stochastic change in epigenetic state, as I discussed.

But maybe also because of some influence of the environment.

So, as I said I think this gives some evidence towards the epigenetic drift

theory, and this is interesting and important to keep in mind in terms of what

we talk about regarding the epigenetic changes that we see.

So in the next lecture we'll talk about more specifically the epigenetic changes

that we can find fairly consistently in aged cells.

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