Discovery can help stop emergence of age-related neurodegenerative diseases

As medicine has improved, increasing our ability to treat disease, so our longevity. The deterioration of the body with age, though, is a whole other matter.

But apparently, all that might be needed is some "house-keeping" of the brain, according to research just published in an early edition of the journal PNAS by a Portuguese team from the Centre for Neuroscience and Cell Biology (CNC) of the University of Coimbra.

The researchers might have also solved a 70-year old mystery: how can calorie restriction (a diet with low calories without malnutrition) delay ageing and increase longevity in animals from dogs to mice.

In their new study, Claudia Cavadas and her group have discovered that the key to this diet appears to be its ability to increase autophagy - the mechanism that recycles unwanted molecules in the cells, avoiding their "clogging and malfunction - in the hypothalamus (which has just been identified as the "control centre" for ageing). They also have identified the molecule that controls the process - called Neuropeptide Y (NPY) - raising the possibility that NPY could be used to develop ways to control ageing (instead of just treat its consequences, like we now do).

The discovery can prove especially important to stop the emergence of age-related neurodegenerative diseases - such as Alzheimer's and Parkinson's - a huge step forwards considering that so far science has been incapable of treating, stopping or even fully understanding them. And in a rapidly ageing world a better control of this kind of problems can prove crucial for everyone's survival.

In fact, according to the UN, in less than a decade 1 billion people will be older than 60. In Japan, already more than 30% of the population is older than 60 years old, and in Europe 16% of the population is over 65. So it is clear that our increasingly ageing population needs to be kept as healthy and active as possible, or it will be financially and socially impossible for the world to cope. It is no surprise then, that research to understand and control the deteriorating effects of ageing is now a priority.

One thing that has been clear for a while now is that autophagy (or better, a reduction of it) is at the centre of the ageing process - low levels of autophagy  (so cells with impaired "house-keeping") are linked to ageing and age-related neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases. This is easily explained as autophagy clears the cells "debris" keeping them in good working order. That the process is so important in the brain is no surprise either, since neurons are the cells less able to replenish themselves once one dies/malfunctions.

But about a year ago there was a remarkable discovery that changed the field: hypothalamus, which is a brain area that regulates energy and metabolism, was identified as "the" control centre for the whole-body ageing.

To Cavadas and her group, which have worked on ageing and neurosciences for a long time, this was particularly exciting. Not only they knew that the only proved method to delay ageing and increase longevity - calorie restriction - increased autophagy in the hypothalamus but also that it did the same to NPY and that mice without NPY did not respond to calorie restriction. Furthermore NPY, like autophagy, diminishes with age. All this, together in view of the new role of the hypothalamus suggested that this brain area and NPY were the key to the rejuvenating effects of calorie restriction.

So now all that was left was to join the dots, and for that the researchers started by taking neurons from the hypothalamus of mice and put them growing in a medium that mimicked a low caloric diet, and then measured their autophagy. Like expected autophagy levels in this calorie-restriction-like medium were much higher than normal, unless NPY was blocked, in which case the medium had no consequences on the neurons. So calorie restriction effect on the hypothalamic autophagy appeared to depend on NPY.  To confirm this, next the researchers tested mice genetically modified to produce higher than normal quantities of NYP in their hypothalamus, and found , like expected, higher levels of autophagy.

So calorie restriction seems to work by increasing the levels of NPY in the hypothalamus, which in turn trigger an increase in autophagy in its neurons, "rejuvenating" them and delaying ageing signs. Cavadas and colleagues also identified the biochemical pathways involved in NPY effect. This, however, is not the whole story, as it still does not explain why in some species, like wild mice, calorie restriction has no effect

But by adding a new piece to the puzzle that is ageing, Cavadas and her group's research is an important step to one day help delay the the body deterioration signs, allowing individuals to have healthier lives until the end, in particular when it concerns the brain. Age-related neurodegenerative diseases seem to be unstoppable at the moment, and are not only an economical but also a huge social burden as patients became totally dependent on their family or the state.

In fact in the US more than 5 million people already suffer from Alzheimer's (1 million have Parkinson's), while in the UK this number is reaching 1 million. Just in the care of dementia patients, the UK health system is spending every year more than £26 billion English pounds (the equivalent to 38 billion dollars or 36 billion euros). Age-related neurodegenerative diseases are already the 4th highest disease burden in the western world. And growing.

It will be interesting now to further understand the long-debated mystery of the mechanism behind calorie restriction, and if it works on humans as some believe (it does not work, for example, on wild mice). In fact, during World War II in Europe, when food was short, there was a sharp decrease of heart diseases (which are age-related) that rapidly disappeared once the war ended. The same reduction is observed in Okinawa island in Japan, where people eat on average less 30% of calories than the rest of the country. Either a coincidence or not, it should be interesting to know if calorie restriction can work on humans, and even more interesting, if it does, what that that mean in our "junk-food" society.