Borrowed Time: The Science of How and Why We Age

by Sue Armstrong

‘Ageing is weird from the evolutionary point of view, because what you have is an obviously maladaptive trait.

Like daf-2, chico works high up in the nutrient-sensing network and it triggers the same cascade of events, awakening the caretaker FOXO to go to the nucleus and switch on a battery of protective genes.

the discovery of age-1, daf-2 and then chico – all of them working through the same core signalling network in the different creatures

But what about humans? Does any of this have direct relevance to us?

published a paper showing a strong association between a natural variant of the FOXO3 gene and long life.

the older a person was at death, the later in life they were likely to have suffered their first serious age-related disease – defined as cancer, cardiovascular disease, chronic lung problems, diabetes, dementia or stroke – and the shorter the period of their

total lives they had spent as frail old people.

There is abundant evidence that no such master switch exists.

As of mid-2017, scientists had identified 2,152 genes that affect lifespan

‘ageing is plastic. It's not fixed. It's something that is alterable.’

This is the ‘hyperfunction theory’ of ageing, and it was first suggested in 2008 by biologist and cancer specialist Mikhail Blagosklonny. At its heart is the idea that ageing is driven by the action of normal genes (known in the business as ‘wild-type’ genes), not mutants

‘What the biology is saying,’ explains Gems, ‘is that it's your wild-type genes that are causing pathologies. They bring you into existence; they take you to maturity and then they carry on regardless and they generate pathologies.’

Gems and Partridge point out that many of the classic pathologies of old age involve runaway growth or over enlargement of cells rather than decline and decay.

Hyperfunction theory is not yet mainstream and most genetic research into ageing is still focussed on the nutrient-sensing network.

‘Every time you eat something,’ says Kapahi, ‘your body has to turn that food into protein mass or something, right? That's the job of this molecule, TOR.

We were able to show that when you restrict the diet of a fly, the mechanism by which it's extending lifespan involves TOR. And it's turned out to be true in multiple species now.’

‘A lot [of the difference] is probably to do with the fact that female flies eat a lot more than males do,’

The immune system is less robust in males than females,

Today the mitochondria are such thoroughly integrated elements in our cells that they are accepted as ‘self’ by the immune system. However, when they spill out from ruptured cells, or are themselves damaged by age and the rough and tumble of life, they release molecules reminiscent of their bacterial origins, and these alert the immune system to what looks like a foreign invasion.

Adipose tissue, or fat, is a source of inflammation, too,

Inactive muscle pumps out pro-inflammatory cytokines, while moving muscle makes anti-inflammatory cytokines to maintain equilibrium.

‘All the medical guidelines at the moment just say “Try to be less sedentary”, because we don't know any more than that,’

In older people neutrophils are not as efficient at swallowing and killing – nor at casting their DNA nets – as they are in the young.

Blundering neutrophils are slow to reach their target, which is one reason why wounds heal so much more slowly as we age than they did when we were kids

elderly patients admitted with pneumonia who were already taking statins were less likely to die of their infection than those who were not.

We now feel it's probably more to do with the effects on the immune system, because statins lower the inflammation, improve your neutrophils, and they make [more specialised] T cells function better too.’

Breaking a bone is a traumatic event at any age, but for an elderly person it can be a killer: roughly one in four old people who break a hip will die within a year.

Surprisingly, in those who didn't become depressed, immune suppression was not such a big deal in hip-fracture patients though everyone – depressed and non-depressed alike – became more frail following their falls.

Recalling the stories one hears so often about a couple, married for 40 years or more, where one of them dies and the other soon follows, she commented, ‘They go down with infections; it's nearly always pneumonia. So I always say they die not of a

broken heart, but of a broken immune system.’

the sentinels in elderly people are doing a pretty pathetic job of gathering intelligence. In turn, the populations of adaptive immune cells (both B and T) become depleted from repeated stimulation and proliferation over the years, and the cells’ telomeres shorten, ultimately leading to senescence.

And out in the real world, beyond the controlled and bug-free environment of the lab, this can be fatal. ‘DR animals are usually less good at clearing viruses,’

the effect of this tough regular exercise on the adaptive immune system was remarkable.

the cyclists’ muscles are much more efficient than those of their less active peers at maintaining levels of the growth hormones that keep the thymus going.

‘CMV devotes about 90 per cent of its DNA, or more, to negotiating this very delicate balance with the host,’

Over time our response to CMV comes to dominate the system, with around 10 per cent of all T cells devoted to suppressing this one virus, and up to half of the supply of memory cells being CMV-specific in some elderly people

They found that the primary influence on the functioning of virtually everything they measured was environmental rather than genetic.

the older the pair of twins was, the stronger the effect of the environment and the weaker that of their genes on the behaviour of their immune systems.

CMV positivity modulated more than 50 per cent of all of the immune parameters they measured. It was an enormous, enormous modulator of everything that happened.’

evidence is emerging that CMV may sometimes be beneficial for its carriers. ‘It may even improve immune defence against other infections, as well as the response to vaccination, in an adult population,’

people who are being successfully treated with ARVs showing signs of premature ageing.

disease and death in HIV-infected people with CD4 counts higher than 250 were usually caused by the drugs themselves, or something else unconnected to their viral infection.

‘But then,’ says Hunt, ‘the trial proved the exact opposite: that it was the people who were interrupting therapy that seemed to have an increased risk of heart disease, cancer, liver disease, kidney disease.

“Gosh, you know, the virus is worse for you than the drugs.”’

Even when someone's viral load is undetectable in the blood, HIV is still able to shed particles in the lymph tissue, which is where it holes up indefinitely, largely beyond the reach of ARVs.

HIV has evolved mechanisms for homing in on the cells of the gut, which are particularly hospitable to it, and where there's an initial explosion of virus production to flood the body.

As we age naturally, the pool of naïve CD8 cells – that is, the ones waiting to be trained up – progressively declines, to be outnumbered by the already-trained specialist killers, which are not so good at responding to new challenges. In people with HIV, however, the killer T cells seem to get stuck midway through their differentiation from naïve cells to specialist killers, and they fail to proliferate.

By early 2015, those who had deferred treatment were more than twice as likely as the immediate starters to have suffered a serious illness,

So the question is, does our biology continue to keep step systematically with our chronology once the developmental programme has run its course? If so, is it played out at the level of the individual cells, or the tissues, or our bodies as a whole? And how predictable is it?

There's a species of locust that develops without functional wings if there is likely to be lots of food and little competition in the world into which it's hatching.