Unit 14. Aging

Script 42. Stress and ageing.

A question of attitude

The link between chronic stress and a marker of old age is being disentangled.

Telomers are to chromosomes what plastic caps are to shoelaces - they stop them fraying at the ends. Unlike shoelaces, though, chromosomes replicate themselves from time to time as the cells they are in divide. This shortens the telomere and, after 50-70 such divisions (a number known as the Hayflick limit, after its discoverer), a chromosome can grow no shorter and the cell it is in can divide no more.

That provides a backstop against cancer. The rapidly dividing cells in a tumour soon hit the Hayflick limit and the process is brought to a screeching halt. Which is a good thing. The bad thing is that reaching the limit is one of the markers of old age. You do not want it to happen too quickly, particularly in tissues that have to do a lot of dividing in order to work properly, such as those in the immune system.

It has been known for some time that chronic stress (caring for a child with a protracted illness, for example) causes premature shortening of the telomeres. What has not been clear is whether this is a one-way trip, with each stressful period turning the telomeric ratchet irreversibly. This week, though, at a meeting of the American Association for Cancer Research in Orlando, Florida, a group of researchers led by Edward Nelson of the University of California, Irvine, showed that it isn't. Their research suggests that stress management not only stops telomeres from shortening, it actually promotes their repair.

Dr Nelson drew this welcome conclusion from a previous study that measured the impact of telephone counselling on women who had been treated for cervical cancer. The study found that such counselling worked, both mentally and physically. Women who had been counselled reported that the quality of their lives had improved, compared with those of a control group who had not been counselled. They also showed improvements in the strength of their immune systems.

Given those benefits, Dr Nelson wondered if he could find others, and he re-examined the participants' samples to look at the lengths of the telomeres in their white blood cells (red cells have no nuclei, and therefore no chromosomes). What he found surprised him. Not only did counselling stop telomere shrinkage, it actually promoted telomere growth. Those women for whom counselling had worked (ie, those who reported a decrease in emotional stress) had longer telomeres at the end than they did at the beginning. Their Hayflick countdowns were being reset.

A single such result must, of course, be treated with caution. But another study reported at the meeting, by Elizabeth Blackburn of the University of California, San Francisco (who shared the Nobel prize for the discovery of the enzyme that repairs telomeres), gave some support. This showed that exercise has a similar effect to counselling on the telomeres of the stressed.

If Dr Nelson's work is successfully replicated, it will shine more light on the ill-understood relationship between the health of the mind and the health of the body. For, as he points out, nothing actually changed in the lives of the women in question. They still had cancer, albeit under treatment, and they were still under stress. Nothing, that is, except their attitude. (From The Economist, April 9, 2011)

Script 43. Exercise and longevity.

Worth all the sweat

Just why exercise is so good for people is, at last, being understood.

One sure giveaway of quack medicine is the claim that a product can treat any ailment. There are, sadly, no panaceas. But some things come close, and exercise is one of them. As doctors never tire of reminding people, exercise protects against a host of illnesses, from heart attacks and dementia to diabetes and infection.

How it does so, however, remains surprisingly mysterious. But a paper just published in Nature by Beth Levine of the University of Texas Southwestern Medical Centre and her colleagues sheds some light on the matter.

Dr Levine and her team were testing a theory that exercise works its magic, at least in part, by promoting autophagy. This process, whose name is derived from the Greek for "self-eating", is a mechanism by which surplus, worn-out or malformed proteins and other cellular components are broken up for scrap and recycled.

To carry out the test, Dr Levine turned to those stalwarts of medical research, genetically modified mice. Her first batch of rodents were tweaked so that their autophagosomes - structures that form around components which have been marked for recycling - glowed green. After these mice had spent half an hour on a treadmill, she found that the number of autophagosomes in their muscles had increased, and it went on increasing until they had been running for 80 minutes.

To find out what, if anything, this exercise-boosted autophagy was doing for mice, the team engineered a second strain that was unable to respond this way. Exercise, in other words, failed to stimulate their recycling mechanism. When this second group of modified mice were tested alongside ordinary ones, they showed less endurance and had less ability to take up sugar from their bloodstreams.

There were longer-term effects, too. In mice, as in people, regular exercise helps prevent diabetes. But when the team fed their second group of modified mice a diet designed to induce diabetes, they found that exercise gave no protection at all.

Dr Levine and her team reckon their results suggest that manipulating autophagy may offer a new approach to treating diabetes. And their research is also suggestive in other ways. Autophagy is a hot topic in medicine, as biologists have come to realize that it helps protect the body from all kinds of ailments.

Autophagy is an ancient mechanism, shared by all eukaryotic organisms (those which, unlike bacteria, keep their DNA in a membrane-bound nucleus within their cells). lt probably arose as an adaptation to scarcity of nutrients. Critters that can recycle parts of themselves for fuel are better able to cope with lean times than those that cannot. But over the past couple of decades, autophagy has also been shown to be involved in things as diverse as fighting bacterial infections and slowing the onset of neurological conditions like Alzheimer's and Huntington's diseases.

Most intriguingly of all, it seems that it can slow the process of ageing. Biologists have known for decades that feeding animals near-starvation diets can boost their lifespans dramatically. Dr Levine was a member of the team which showed that an increased level of autophagy, brought on by the stress of living in a constant state of near-starvation, was the mechanism responsible for this life extension.

The theory is that what are being disposed of in particular are worn-out mitochondria. These structures are a cell's power-packs. They are where glucose and oxygen react together to release energy. Such reactions, though, often create damaging oxygen-rich molecules called free radicals, which are thought to be one of the driving forces of ageing. Getting rid of wonky mitochondria would reduce free radical production and might thus slow down ageing.

A few anti-ageing zealots already subsist on near-starvation diets, but Dr Levine's results suggest a similar effect might be gained in a much more agreeable way, via vigorous exercise. The team's next step is to test whether boosted autophagy can indeed explain the life-extending effects of exercise. That will take a while. Even in animals as short-lived as mice, she points out, studying ageing is a long-winded process. But she is sufficiently confident about the outcome that she has, in the meantime, bought herself a treadmill. (From The Economist, January 21, 2012)

Script 44. Rejuvenating bodily organs

Engaging reverse gear

For the first time, a worn-out organ has been persuaded to renew itself.

Regenerative medicine - the idea that it is possible to revitalise old, dilapidated tissue and keep a body going when its organs start to fail - is attractive. Much effort has thus been put into creating and nurturing so-called pluripotent stem cells. These, when appropriately nudged, can be induced to turn into cells of any other type. They might therefore be used for all sorts of repairs. Pluripotent cells, which once had to be extracted from embryos, can now be made routinely from body cells (skin cells, for example). Experiments are going on to see if, when made from the cells of a particular individual, they might be used to repair damage to that person’s organs without (as a transplant from someone else would) attracting the attention of his immune system.

This approach is promising. It would be even better, though, if rather than having stem cells transplanted into it, a degenerate organ could be persuaded to repair itself. Until now, no one has managed to do this. But Clare Blackburn of Edinburgh University in Britain, and her colleagues, have succeeded. As they report in Development, they have treated, in mice, an organ called the thymus, a part of the immune system that runs down in old age. Instead of adding stem cells they have stimulated their animals’ thymuses to make more of a protein known as FOXN1. This is a transcription factor (a molecular switch that activates genes), and for the thymus it turns out to be an elixir of life.

The thymus is the place where the immune system’s T-cells mature. T-cells have various jobs, such as destroying body cells infected with viruses. As an animal grows older, its thymus shrinks and the organ’s internal structure changes. As a result, the supply of new T-cells diminishes. That is why elderly people are more subject than the young to infection.

Dr Blackburn knew from earlier experiments that FOXN1 is important for the embryonic development of the thymus, so she wondered if it might be used to rejuvenate the organ in older animals. To this end, she and her colleagues bred a special strain of mice whose FOXN1 production could be stimulated specifically in the thymus by tamoxifen, a drug more familiar as a treatment for breast cancer.

Wild mice are normally killed by predators before they are a year old, but cosseted domestic versions often make it to two or even three, so Dr Blackburn and her team did their experiments on year-old and two year-old animals, as being roughly equivalent to middle-aged and elderly humans. In year-olds, stimulating FOXN1 production in the thymus caused it to become 2.7 times bigger within a month. In two-year-olds the increase was 2.6 times.

Moreover, when the researchers studied the enlarged thymuses microscopically, and compared them with those from untreated control animals of the same ages, they found that the organs’ internal structures had reverted to their youthful nature. Most important of all, they found, the density of relevant T-cells in the experimental animals’ lymph was twice that of the controls.

This is not a model for a medical treatment. Dr Blackburn relied on specially bred mice for the study. FOXN1 is not naturally sensitive to tamoxifen. But this work does provide an opening for regenerative medicine to exploit because it shows that, in the case of the thymus, stimulating production of a single transcription factor can have an astonishing effect—bigger, certainly, than anything yet seen using stem cells. Whether something similar applies to any other organ remains to be investigated. But Dr Blackburn’s study suggests it might be worth looking. (From The Economist, April 12, 2014)

Script 45. Ageing

Forever young?

A way to counteract part of the process of growing old.

Biologists have made a lot of progress in understanding ageing. They have not, however, been able to do much about slowing it down. Particular versions of certain genes have been shown to prolong life, but that is no help to those who do not have them. A piece of work reported in this week's Nature by Darren Baker of the Mayo Clinic, in Minnesota, though, describes an extraordinary result that points to a way the process might be ameliorated.

Dr Baker has shown - in mice, at least - that ageing body cells not only suffer themselves, but also have adverse effects on otherwise healthy cells around them. More significantly, he has shown that if such ageing cells are selectively destroyed, these adverse effects go away. The story starts with an observation, made a few years ago, that senescent cells often produce a molecule called P161NK4A. Most body cells have an upper limit on the number of times they can divide-and thus multiply in number. P161NK4A is part of the control mechanism that brings cell division to a halt when this limit is reached.

The Hayflick limit, as the upper bound is known (after Leonard Hayflick, the biologist who discovered it), is believed to be an anticancer mechanism. It provides a backstop that prevents a runaway cell line from reproducing indefinitely, and thus becoming a tumour. The limit varies from species to species-in humans, it is about 60 divisions - and its size is correlated with the lifespan of the animal concerned. Hayflick-limited cells thus accumulate as an animal ages, and many biologists believe they are one of the things which control maximum lifespan. Dr Baker's experiment suggests this is correct.

Age shall not weary them

Dr Baker genetically engineered a group of mice that were already quite unusual. They had a condition called progeria, meaning that they aged much more rapidly than normal mice. (A few unfortunate humans suffer from a similar condition.) The extra tweak he added to the DNA of these mice was a way of killing cells that produce P161NK4A. He did this by inserting into the animals' DNA, near the gene for P161NK4A, a second gene that was, because of this proximity, controlled by the same genetic switch. This second gene, activated whenever the gene for Pl61NK4A was active, produced a protein that was harmless in itself, but which could be made deadly by the presence of a particular drug. Giving a mouse this drug, then, would kill cells which had reached their Hayflick limits while leaving other cells untouched. Dr Baker raised his mice, administered the drug, and watched.

The results were spectacular. Mice given the drug every three days from birth suffered far less age-related body-wasting than those which were not. They lost less fatty tissue. Their muscles remained plump (and effective, too, according to treadmill tests). And they did not suffer cataracts of the eye. They did, though, continue to experience age-related problems in tissues that do not produce P161NK4A as they get old. In particular, their hearts and blood vessels aged normally (or, rather, what passes for normally in mice with progeria).

For that reason, since heart failure is the main cause of death in such mice, their life spans were not extended. The drug, Dr Baker found, produced some benefit even if it was administered to a mouse only later in life. Though it could not clear cataracts that had already formed, it partly reversed muscle-wasting and fatty-tissue loss. Such mice were thus healthier than their untreated confreres.

Analysis of tissue from mice killed during the course of the experiment showed that the drug was having its intended effect. Cells producing P161NK4A were killed and cleared away as they appeared. Dr Baker's results therefore support the previously untested hypothesis that not only do cells which are at the Hayflick limit stop working well themselves, they also have malign effects (presumably through chemicals they secrete) on their otherwise healthy neighbours.

Regardless of the biochemical details, the most intriguing thing Dr Baker's result provides is a new way of thinking about how to slow the process of ageing-and one that works with the grain of nature, rather than against it. Existing lines of inquiry into prolonging lifespan are based either on removing the Hayflick limit, which would have all sorts of untoward consequences, or suppressing production of the oxidative chemicals that are believed to cause much of the cellular damage which is bracketed together and labelled as senescence.

But these chemicals are a by-product of the metabolic activity that powers the body. If 4 billion years of natural selection have not dealt with them it suggests that suppressing them may have worse consequences than not suppressing them. By contrast, actually eliminating senescent cells may be a logical extension of the process of shutting them down (they certainly cannot cause cancer if they are dead), and thus may not have adverse consequences.

It is not an elixir of life, for eventually the body will run out of cells, as more and more of them reach their Hayflick limits. But it could be a way of providing a healthier and more robust old age than people currently enjoy. Genetically engineering people in the way that Dr Baker engineered his mice is obviously out of the question for the foreseeable future. But if some other means of clearing cells rich in P161NK4A from the body could be found, it might have the desired effect. The wasting and weakening of the tissues that accompanies senescence would be a thing of the past, and old age could then truly become ripe. (From The Economist, November 5, 2011)