Switching off Grb10 in the brain results in what might sound like a rather impressive, kick-ass kind of a mouse. It maybe even seems odd that this gene is normally switched on in the brain. Wouldn’t mice that switched off Grb10 be the butchest, most successful mice? Actually, it’s more likely that they’d be the mice most likely to get themselves beaten up. There are a lot of mice in the world, and they encounter each other pretty frequently. It pays to recognise when you are out-gunned.
When the Grb10 gene is switched off in the brain, it’s like a bad Friday night for the mouse. Let’s put this in human terms so we can see why. You’re down the pub when a person twice your size and all muscle knocks against you and you spill your pint. When this gene is switched off, it’s as if you have a friend next to you who says, ‘Go on, you can take him/her, don’t wimp out.’ We all know how badly those scenarios tend to play out. So let’s end this chapter by raising a cheer for imprinted Grb10, the gene that likes to say, ‘Leave it mate, it’s not worth it.’
Chapter 13. The Downhill Slope
I guess I don’t so much mind being old, as I mind being fat and old.
Time moves forward, we age. It’s inevitable. And as we get older, our bodies change. Once we’re past our mid-thirties most of us would agree that it gets harder and harder to sustain the same level of physical performance. It doesn’t matter if it’s how fast we can run, how far we can cycle before needing to stop for a break, or how quickly we recover from a big night out. The older we get, the harder everything seems to become. We develop new aches and pains, and succumb more easily to annoying little infections.
Ageing is something we are good at recognising in the people around us. Even quite small children can tell the difference between the young and the very old, even if they are a bit hazy on everyone in the middle. Adults can easily tell the difference between a 20-year-old and a 40-something individual, or between two people who are 40 and 65.
We can categorise individuals instinctively into approximate age groups not because they give off an intrinsic radio signal about the number of years they have been on earth, but because of the physical signs of ageing. These include the loss of fat beneath the skin, making our features more drawn and less ‘fresh-faced’. There are the wrinkles, the fall in muscle tone, that slight curvature to the spine.
The growth of the cosmetic surgery industry appears to be relentless and shows how desperate we can be to fight the symptoms of ageing. Figures released in 2010 showed that in the top 25 countries covered in a survey by the International Society of Aesthetic Plastic Surgery, there were over eight and a half million surgical procedures carried out in 2009, and about the same number of non-surgical procedures, such as Botox and dermo-abrasion. The United States topped the list, with Brazil and China fighting for second place[234].
As a society, we don’t seem to mind really about the number of years we’ve been alive, but we dislike intensely the physical decline that accompanies them. It’s not just the trivial stuff either. One of the greatest risk factors for developing cancer is simply being old. The same is true for conditions such as Alzheimer’s disease and stroke.
Most breakthroughs in human healthcare up until now have improved both longevity and quality of life. That’s partly because many major advances targeted early childhood deaths. Vaccination against serious diseases such as polio, for example, has hugely improved both childhood mortality figures (fewer children dying) and morbidity in terms of quality of life for survivors (fewer children permanently disabled as a result of polio).
There is a growing debate around the issue sometimes known as human life extension, which deals with extending the far end of life, old age. Human life extension refers to the concept that we can use interventions so that individuals will live to a greater age. But this takes us into difficult territory, both socially and scientifically. To understand why, it’s important to establish what ageing really is, and why it is so much more than just being alive for a long time.
One useful definition of ageing is ‘the progressive functional decline of tissue function that eventually results in mortality’[235]. It’s this functional decline that is the most depressing aspect of ageing for most people, rather than the final destination.
Generally speaking, most of us recognise the importance of this quality of life issue. For example, in a survey of 605 Australian adults in 2010, about half said they would not take an anti-ageing pill if one were developed. The rationale behind their choice was based around quality of life. These respondents didn’t believe such a pill would prolong healthy life. Simply living for longer wasn’t attractive, if this was associated with increasing ill-health and disability. These respondents did not wish to prolong their own lives, unless this was associated with improved health in later years[236].
There are thus two separate aspects to any scientific discussion of ageing. These are lifespan itself, and the control of late-onset disorders associated with ageing. What isn’t clear is the degree to which it is possible or reasonable to separate the two, at least in humans.
Epigenetics definitely has a role to play in ageing. It’s not the only factor that’s important, but it is significant. This field of epigenetics and ageing has also led to one of the most acrimonious disputes in the pharmaceutical sector in recent years, as we’ll see towards the end of this chapter.
We have to ask why our cells malfunction as we get older, leaving us more at risk of illnesses that include cancer, type 2 diabetes, cardiovascular disease and dementia, amongst a host of other conditions. One reason is because the DNA script in the cells of our body begins to change for the worse. It accumulates random alterations in sequence. These are somatic mutations, which affect the tissue cells of the body, but not the germline. Many cancers have changes in the DNA sequence, often caused by quite large rearrangements between chromosomes, where genetic material is swapped from one chromosome to another.
But as we’ve seen, our cells contain multiple mechanisms for keeping the DNA blueprint as intact as possible. Wherever possible, a cell’s default setting is to maintain the genome in its original state, as much as it can. But the epigenome is different. By its very nature, this is more flexible and plastic than the genome. Because of this, it is probably not surprising that epigenetic modifications change as animals age. The epigenome may eventually turn out to be far more prone to changes with age than the genome, because the epigenome is more naturally variable than the genome anyway.
We met some examples of this in Chapter 5, where we discussed how genetically identical twins become less identical epigenetically as they age. The issue of how the epigenome changes as we age has been examined even more directly. Researchers studied two large groups of people from Iceland and from Utah, who have been part of on-going long-term population studies. DNA was prepared from blood samples that had been taken from these people between eleven and sixteen years apart. Blood contains red and white blood cells. The red blood cells carry oxygen around the body, and are essentially just little bags of haemoglobin. The white blood cells are the cells that generate immune responses to infections. These cells retain their nuclei and contain DNA.
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For a review of this and other surveys on public attitudes to lifespan extension, see Partridge et al. (2010),