Thank you for coming to this lecture. Today we're going to talk about the
biology of
aging, right, which is a topic that myself
and some other researchers in the Bio-
sciences Department at Kent
as well as a whole community of
scientists worldwide
are interested in, OK, and it's something
that most
most of you will also have a vested
interest in because
you yourselves will age and you will know
lots of people at different ages
And it doesn't just,
it's not a process that only happens to
humans, it also happens in other species
and here we have the honey bee. At the
center is the queen bee
who lives for around about six years
whereas her workers
only live for about six weeks so within this
one population that
has exactly the same genetic background
is a huge discrepancy
in the amount of time that an individual
can live for so what scientists are
interested in,
in bees and in other species, is trying
to find what it is, what are the
differences
between those that are living for a long
time and those that are not
and trying to use these to understand
the aging process and perhaps trying to
find ways that we can
intervene in it. So back to humans now
for a moment.
This is a picture of my son with his dad,
and his granddad,
and his great granddad, and he was lucky
enough to meet
his great granddad, which not everyone is, and this is because his great granddad
lived
till he was 96 but he lived a very happy
and very healthy life, which is the most
important thing,
at least in my opinion, and
I think a propos here is an example
of how most people would like to age.
They would like to be, they would like to
live as long as they are independent
and healthy and happy, and that's what we
try and do
as aging researchers. We're not
interested in just trying to
indiscriminately make everyone live for
hundreds and hundreds of years in a
decrepit state.
What we want to do is we really want
to do away with this portion
of ill life that a lot of elderly people suffer at the end of their lives
and instead,
you know, we want to improve the amount
of time that people are healthy
during their life span, right and,
as a result of that, there may well be a
number of years that are added to the
end of life,
OK, but hopefully most of these will be
healthy ones.
And there are examples in nature that
make us think that this could be
possible
because they're actually species that
don't seem to age
at all, and this is one of those, this is
a Freshwater Hydra,
It's really quite beautiful. You see it
floating around in the water.
Tiny little thing, but if scientists
isolate populations of this species from
the wild,
which presumably would have a whole
range of different
ages in them, and then they take these
populations into the lab,
they don't seem to age at all, and they,
a few of them die, but really they seem
to go on for a very long time.
OK, so there's something about this process of aging that doesn't mean that
happens, has to happen
So as well as this Hydra,
scientists tend to study a range of other
different species
and this is because aging studies in
humans tend to be very long
and often quite expensive to do.
So what scientists do is they use model
organisms
so this can range from the baker's yeast
so this is the same yeast that's used for
making bread and for brewing beer
called Saccharomyces Cerevisiae, a very basic organism
but we also use C. elegans, which is an nematode worm.
The fruit fly, which can be found on any fruit bowl.
This is Drosophila Melanogaster, and then you've got the mouse,
Mus Musculus. And there are a number of advantages to using these organisms
and one of the main ones is that we
know their whole genome.
Their genomes have all been sequenced,
right, so we can do really good genetics
on them,
and the populations of each one of
these is homogeneous,
right, which again, when you're dealing with
humans, there's much more variety to contend
with.
Much faster to do aging experiments in
these organisms,
so for example a worm will only
live for three weeks,
the fly for about three months,
it also make these experiments a lot
cheaper to do in the lab.
But the important thing to remember is
that all of the species, what we learn in
these species, can be related
to humans because lots of the genes and
lots of the pathways
that scientists studying are the same
in these organisms as they are in humans.
So I'm going to give you one example now
from my own research and this is the
nematode worm, Caenorhabditis elegans,
or C. elegans for
short and here you can see it crawling
around,
this is a picture from the lab, and it crawls
around in bacteria,
that's what it grows on. In the wild you
can find it in compost,
composting fruit, but in the lab we grow
it on small agar plates which have been
seeded with a little bit of
E-coli bacteria. The worms crawl around
in that quite happily.
The biggest one that you can see here in
the middle is an adult
and it's now producing eggs, and it's a
hermaphrodite so it produces both the
eggs
and the sperm which self-fertilize to go on to produce
embryos. And during its lifetime its going to lay around about 300 embryos
over about five days, OK, so you get a lot of
worms very fast.
And then these eggs, they're laid onto the
plate and they hatch and they develop
through four larval stages
until they become adults themselves
again and start the reproductive cycle
all over. There are round about 20,000
protein-coding genes in the worm, so
this means the
genes that we know what protein is
incubating code for, and these have been mapped to
a lot of different pathways which a
conserved through from
worms all the way up to mammals in a
lot of cases.
These animals only live for three weeks
so I can do an experiment in the lab in
under a month
in an effort to find out the effect of
something on aging
and they come with a really good tool kit,
especially for genetics. It's possible to
knock out genes in this worm,
and it's possible to increase the
expression of genes in these worms
so you can actually look at the
detailed function of individual
individual genes. And of these
20,000 protein-coding genes that it has,
about 75 percent
of them a similar to genes that found in
humans.
So they live for about three weeks
but after the reproductive part of their
life is over, so that first five days
of adulthood,
what happens to them. Well,
the kinda crawl around on the plate a bit,
they start to slow down
and if you start to look at them really
carefully you can actually look at lots
of
markers of aging and some of these are
muscle degeneration, or fat
accumulating
in their body wall muscle. Their skin gets a bit thicker.
You can see that their food, the bacteria,
starts to clog up their gut
and slow down their digestive
system. Their neurons branch,
and they form tumors in their uterus
and also you have some accumulation
of yolk from the embryos in the
intestine as well.
So let's have a look at the video
and on the left we have a young worm
you can see, it's crawling around the plate
really happily and on the
on the right is an old worm, so when you
prod it
with the worm pick, that's what we call the tool that we scientists use to
manipulate these animals,
if you prod it, it barely moves at all.
It actually looks a bit dead in this
picture but I can assure you that it's
not,
it's alive, I looked at it very carefully and
the microscope.
But this just gives you an idea of what
we're looking at.
But what we do, is we generate life span
data
so we generate life span curves, as we call them, right,
So we start with a population of around
about 100 worms on a plate,
and every day, or every two or three
days, we look at them
and we determine whether each one is
dead or alive by poking it with that worm
pick,
and that's what each point on this
graph is.
So every day we figure out the
percentage of worms that is alive.
So for quite a long time at the beginning,
everybody's alive in that population,
nobody dies, but then at some point in
the middle
starts to drop off pretty fast, so
WT stands for wild-type which is a normal
worm.
So this is the normal worm's life
span, on average around about three weeks,
OK, but then what we do is because we're
trying to understand the
genes that are involved in this process,
is we start playing around with the worm's
genome, and
we start making genetic mutations OK, and
this is a repeat of
an experiment that was done by
Cynthia Kenyon in the early nineties
which really kick-started the aging
fields, particularly in C. elegans.
And what she did, was she made
a point mutation in the gene called Daf-2
and she found
that with the worms that carried this one
mutation, so this is one
tiny change their genome, lived for twice
as long
as those that were pretty much normal,
that didn't have this mutation. And she
found
that also if you combine this mutation
with another one, called Daf-16,
this effect went away, and myself
and others
are extremely interested in trying to
understand what it is
about this genetic mutation and about
this one here that
relates to it that is actually
responsible for this effect on life span.
And one of the reasons for this is that
this gene,
this Daf-2 gene, is actually the worm
equivalent of the human insulin receptor
so it's its conserved, it's the same. There
is an equivalent of Daf-2 in flies and in
mice
and also in humans, and this one
gene,
which is a receptor gene, is at the top
of a pathway
at the top of a signalling pathway,
and the details of this are not important at the moment, this is something that you will learn
about
as you go through your undergraduate degree at Kent, but these
pathways are conserved throughout the
species.
So what we learn in the worms about
the role of this pathway in life span
can also be applied to the flies, to
the mice
and ultimately also to humans. And another
really impressive thing about these long-lived worms, so these worms with this one
genetic mutation in the Daf-2 gene,
is that not only are they living twice
as long, but they're also incredibly
healthy.
They're moving really happily around the plate for a really long time
into their life span, much longer than
a normal worm.
So they don't seem to be suffering
from the muscle degeneration,
something that could be related to human
Sarcopenia, and they're
not suffering from the accumulation of
lipids in their body wall muscles,
they're not getting as many tumours in
in their uterus, and their neurons aren't branching as much.
And we can relate all of these
things, or we can try to relate these things
to the human
aging condition. So what we're doing,
going back to the earlier point,
is that what we're trying to do is not
have this portion of ill health at the end
of life, but not only extend life
span
and also increase the amount of time
that an individual is healthy for.
Thank you very much for your attention.
