VOICE OVER: Why do some animals live so much longer than others?
And what is it that causes the variation in the ageing process?
One theory suggests that somatic mutations
— changes that accrue in our bodies over time, could be part of the answer.
ALEX CAGAN: So there's you know good reason to suspect that somatic mutations that are altering
the DNA could be having deleterious effects on cellular function that could lead to breakdown
and kind of consequences that we see in ageing.
VO: But this theory doesn’t necessarily align with what we see in the animal kingdom.
For example somatic mutations are known to cause cancers which can in turn reduce lifespan
— and so it would stand to reason that larger animals with more cells to mutate —
might have a higher chance of developing cancer somewhere in their body and thus have lower
lifespans. But in fact the opposite is often true. With a few notable exceptions, larger animals
often have far lower rates of cancer than smaller ones - a phenomenon known as Peto’s paradox.
ALEX: Everything we know about somatic mutations and cancer
we would expect that the more cells you have the higher your chance of
cancer because you just have more cells where you could be unlucky and accumulate somatic mutations.
VO: What’s more - some of the longest lived animals in the world are also the
largest despite having so many cells which could be deteriorating through mutations.
If somatic mutations are linked to ageing, then something else must be going on - and
now a team of researchers have delved into the somatic mutation rates of a range of
mammals for the first time - in the hopes of finally unraveling some of these mysteries.
VO: Somatic mutations can be caused by lots of things,
like errors in DNA replication or exposure to mutagens like ultraviolet radiation.
Despite being very common, their effects are still not fully understood.
ALEX: The most well-known consequence that's very well established is cancer, but what's less
well understood and still debated is whether somatic mutations could be playing other roles
uh crucially for example what is the role of somatic mutation in ageing? Because we know that
as we age we're accumulating somatic mutations but kind of the key question in the field is
are these a consequence of ageing or a cause of ageing.
VO: Alex and his colleagues wanted to measure the rate these somatic mutations were acquired,
not just in humans, but across as wide a variety of mammals as possible.
So they set about collecting tissue samples.
ALEX: so we work with a variety of partners including the London Zoo so ZSL Institute
and the CSIP which is the Cetacean Stranding Investigation Program who i'd never heard
of before but they're essentially like CSI for cetaceans or whales and so we work with
partners like that and different zoos to collect tissue samples opportunistically from when animals
have died from other causes and so we wanted to get a tissue type that we could compare across
mammals because we know from human studies that different cell types in the body have different
mutation rates. And so to compare across species we wanted to pick one cell type and we settled
on intestinal crypts which are these small kind of crypt-like structures that line the intestine
and so basically by sequencing these intestinal crypts from 16 different mammalian species
and 56 different individuals and knowing the age of those animals when they died we could
count and say okay in this harbour porpoise that's you know x years old there are this
many mutations while in this mouse you know that's maybe a few months old we count this
many of mutate number of mutations and then we can figure out the mutation rate across
these different species and see to what extent they are similar or to what extent they vary.
VO: Their results allowed them to investigate whether mutation rates can help explain
Peto’s Paradox - the curious observation that larger animals don’t appear to develop
more cancers despite having more cells to mutate. And it turns out that – size is
actually a fairly poor predictor of the rate of somatic mutation.
For instance cows, giraffes and horses weigh much more than an average human,
but their somatic mutation rates don’t follow the same pattern.
It’s clear that having more cells doesn’t mean you have a higher chance of developing cancer,
but the weak correlation between body mass and somatic mutation rates across species
suggest that lower mutation rates are not behind this - and that large animals,
like elephants, must have another trick for lowering their cancer risk.
However, there was one factor which seemed to correlate strongly
with somatic mutations, a factor that is very relevant to ageing: lifespan.
ALEX: By far for us the most striking finding
was we found this strong inverse correlation between lifespan and somatic mutation rate.
VO: For example, the naked mole rat is about 23 thousand times smaller than a giraffe,
but they both live for around 20 to 30 years. And this new research presents an explanation for such
similar lifespans in such different creatures - they have nearly identical somatic mutation rates.
ALEX: And so what that tells us is that somatic mutation rate is evolutionarily constrained,
so there's some reason that evolution is shaping somatic mutation rate
um to be similar at the end of lifespan across species and this is consistent with the somatic
mutational theory of ageing that somatic mutations play a causative role in the ageing process.
VO: Across the animals tested - somatic mutation rates proved a reliable predictor of lifespan,
and that provides strong evidence for the theory that somatic mutations
are a cause of ageing, not a result of it. But the team isn't finished yet,
they want to expand their study as far and wide across the tree of life as possible.
ALEX: From evolutionary theory and what we're seeing in mammals species with longer lifespans
seem to have lower mutation rates so if we can start to understand how species with even longer
lifespans than humans are maintaining their genome integrity and lowering their mutation rate there's
a potential to kind of learn from the solutions that nature and evolution have already found
uh to potentially find ways to lower the somatic mutation rate. You know whether
that will one day be possible I don't know but in principle if one could lower the somatic
mutation rate that could be a very effective way to do things like lower cancer risk or
you know slow the ageing process but so that's you know that's kind of the moonshot
far future thinking of how this kind of research could potentially be relevant.