Borrowed Time: The Science of How and Why We Age

by Sue Armstrong

In a provocative essay written in 2014 explaining why he hopes to die at 75, the American oncologist Ezekiel Emanuel reviews the evidence of research and concurs with gerontologist Eileen Crimmins of the University of Southern California that, ‘Over the past 50 years, health care hasn't slowed the ageing process so much as it has slowed the dying process.’

He supported his hypothesis by demonstrating that he could increase the lifespan of laboratory mice by up to 30 per cent by giving them drugs to protect them against radiation. He could also increase their lifespan, but not so dramatically, by giving them antioxidants designed to prevent oxidative damage. The relative weakness of antioxidant therapy perplexed Harman for a long time and led him eventually to conclude that most free radicals are generated inside the mitochondria, the cell's batteries, which burn calories to produce our energy and which are impenetrable to compounds introduced from outside. In the 1970s he modified his theory to suggest that the mitochondria might be the body's clock, determining how long we live according to how hard we work our batteries and how much wear and tear they sustain.

Gems doesn't dismiss the oxidative damage theory outright, but says that since the early 2000s labs around the world, including his own, have been ‘testing to destruction’ the theory and its predictions and found them wanting. In the search for truth, scientists have had to wade through a veritable blizzard of data generated by studies in yeast, microscopic worms, fruit flies and mice – the traditional workhorses among model organisms of biological research – which have had their antioxidant defences knocked out or increased by drugs or genetic engineering. ‘The critical issue,’ says Gems, ‘is that if you manipulate the levels of oxidative damage, you should see effects on ageing and on lifespan. And many studies were reported that didn't support that theory. Including human studies… experiments with people taking antioxidant supplements and looking at mortality rates, and it didn't make a difference. In some cases taking antioxidants actually increased mortality rates slightly.’

The oxidative damage/free radical theory was dealt another serious blow in 2009 by researchers working at the Oklahoma Medical Center. Arlan Richardson and Holly van Remmen tinkered with the genes of their laboratory mice so that they produced an overabundance of antioxidants that did a very good job of mopping up free radicals – but without any effect on the lifespan of the mice. They also did the reverse experiment, working with mice that had the genes for two of the most important antioxidants deleted from their DNA. Sure enough, the mice sustained extensive damage to their cells from free radicals, but without this shortening their lifespans – at least not in the mice that avoided developing cancer as a result of the damage.

There were hints in the literature that perhaps senescent cells had some positive attributes, too, and so Campisi and her colleagues took a closer look at them. They found that as well as collagen-chewing molecules and inflammatory cytokines, the secretory substances also include growth factors – molecules that encourage repair and regeneration of tissue. They already knew that in order to heal a wound, our bodies need to mount an inflammatory response (that's why, when you cut yourself, the flesh around the cut goes pink and hot for a while). To test a hunch that maybe senescent cells are actively involved in wound healing, Campisi's team created a transgenic mouse in which these cells expressed a protein that made them glow so they were easily identifiable among other cells in the body. They then made small wounds on the backs of their lab mice and found that, sure enough, senescent cells were clustered at the site of the wounds. When they eliminated the senescent cells, the wounds were very much slower to heal.

In older people neutrophils are not as efficient at swallowing and killing – nor at casting their DNA nets – as they are in the young. But as we saw briefly in Chapter 4, one of the biggest problems with these immune cells is that they lose their sense of direction. When responding to a pro-inflammatory signal, elderly neutrophils zigzag through the tissue towards the site of injury like an emergency crew with a faulty GPS, causing collateral damage as they go. Looking at migratory patterns of neutrophils and their impact on tissues, Lord's team in Birmingham have found that ‘even in healthy elders, the amount of damage caused by neutrophils just wandering around the body looking for infections is double that in a young person’. So when in life does this become a problem? ‘We can pick it up in most 40- and 50-year-olds,’ says Lord. ‘But by the time you're 60 or 70 years old it's really bad. You struggle to find a neutrophil that is moving in the right direction efficiently.’ 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 scuffing knees and elbows in the playground and quickly forming scabs. And they're one reason, too, why old people respond so poorly to infection. In severe infections such as pneumonia, old people's neutrophils are even more disorientated than usual, and the collateral damage they do in migrating to the site is vastly increased – up to five times high...

‘We've known for a long time that, if you look at how much the cholesterol is lowered in people on statins and then their health benefits, there wasn't a really good correlation,’ said Lord. ‘So some people, you put them on statins and their cholesterol doesn't go down very much, in others it goes down a lot, but they all seem to benefit from the drug. 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.’ Large-scale clinical trials are now in the pipeline to determine whether or not statins should be recommended specifically for beefing up the immune system as well as for cardiovascular health.

Interestingly, however, Lord's investigation revealed that the real culprit here was not simply the imbalance between cortisol and DHEAS, but also the effects of clinical depression – a condition that affects more than a third of their hip-fracture patient, and is probably also caused by the hormone imbalance, since this is known to affect mood. Checking everyone's neutrophil activity, they found that in all patients, these vital little fighters were still able to seek out and swallow bacteria, but those in depressed patients were unable to administer the coup de grâce to the engulfed pathogens. 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. But what if the trauma a person suffers is psychological rather than physical? Lord and her colleagues monitored the neutrophil activity of elderly people who had lost a loved one, and found that ‘bereavement is as powerful a stressor as a hip fracture, and it persists. We followed bereaved older adults for a year and their immune systems stayed suppressed.’ 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 researchers also identified one of the factors circulating in young blood that helps to rejuvenate old tissues. This is oxytocin, a hormone produced in the brain and familiar to many people as the substance that aids contraction of the uterus in childbirth. ‘Oxytocin has a direct effect on muscle stem cells,’ explains Irina. ‘It has receptors on muscle stem cells, and without oxytocin muscle doesn't repair well; it does not function well, and it is replaced by fat. With ageing, oxytocin levels in blood decline about threefold and oxytocin receptors become less present.’

A mass of data has also been collected over the years on the Amazonian people's cognitive function, and this is beginning to reveal some very interesting findings about the interaction of genes and environment. Among the Tsimane, APOE e4 – considered the highest single risk factor for Alzheimer's disease in the industrialised world, as we have seen – appears to protect the brains of those who have a high burden of parasitic infections. What's more, this benefit seems to kick in very early: Tsimane children who carry a copy of the APOE e4 gene are generally brighter than those who don't. This mirrors findings from other studies among kids in poor communities in Mexico City and Brazil, who are especially vulnerable to infection, and where those carrying the e4 gene variant seem to have better cognition.

Then in 2010, Janine Cataldo and colleagues at the University of California, San Francisco, published a paper describing how they had systematically analysed the design, methodologies and findings of 43 original, international studies carried out between 1984 and 2009 to try to settle the matter. Significantly, they also looked at the funding and affiliation of the scientists involved to try to eliminate potential conflict of interest in the results – something that, surprisingly, seems to have been overlooked by the journals that published their reports. What was not surprising, however, to anyone who had followed the lengths to which the tobacco industry went to discredit the evidence of a link between smoking and cancer, was that Cataldo and her colleagues found Big Tobacco's fingerprints all over the evidence concerning Alzheimer's. Discovering which bits of research and which scientists the industry had supported was a major sleuthing job. It involved trawling through a massive pile of previously secret internal papers held in the Legacy Tobacco Documents Library that was forced to open its archives when it faced litigation brought by irate customers for personal damages and deaths from smoking. The researchers found that 11 of the 43 studies included in their meta-analysis had been conducted by scientists with links to Big Tobacco, of which only three had disclosed their affiliation. None of the 11 studies found an increased risk of Alzheimer's among smokers – indeed...

a fact sheet from the World Health Organization dated 2014 cites a number of studies from around the world that put the added risk at between 59 per cent and 79 per cent. WHO estimates, furthermore, that around 14 per cent of Alzheimer's cases worldwide are ‘potentially attributable’ to use of tobacco.