26 Jan 2015

The secret for a longer life? Kill your unfit cells

If you had the choice, would you like to live until you’re 130 years old? New research in fruit flies shows that manipulating a single gene can extend their lifespan up to 60%, suggesting that living well into your hundreds might become a reality in the foreseeable future.

Dying of old age is a strange thing. Why does our health decline just because we’re old? Although the answer might at first seem obvious or simple, it really isn’t. There are countless theories of ageing, a few popular even outside the scientific community. Take ‘superfoods’, for example. The miracle properties credited to these antioxidant-rich foods stem from the free radical theory of ageing—older cells produce more of a toxic form of oxygen that gradually poisons them. Antioxidants like vitamin C or D counteract this deleterious effect and prevent ageing (and the appearance of wrinkles), superfood advocates claim.

A common denominator in these theories is that we age—and ultimately die—because our cells deteriorate with time (for whatever reason). As tissues and organs mount up more and more of these damaged cells, they begin to malfunction and eventually stop working. This raises an interesting assumption. What if we could get rid of these unfit cells and keep only the healthy ones? Would we live longer?

Jeanne Louise Calment had the longest confirmed human lifespan
on record (122 years and 164 days).

It’s well known that sick cells such as cancerous cells, are eliminated by our bodies, either by immune cells or by committing suicide. However, our ‘old’ unfit cells are still healthy enough to bypass this quality-control checkpoint. Or so it was thought. A few years ago, Eduardo Moreno and colleagues at the University of Bern, Switzerland, showed that healthy but less fit cells are also culled from tissues, by a mechanism they called “fitness fingerprints”. Each cell has a molecular fingerprint on its surface that tells its neighbours how healthy it is. When a given cell has a fingerprint that is worse than its neighbours', it kills itself. But the researchers didn’t know the importance of this cell elimination process for the organism. For example, would we age faster if those cells could not kill themselves?

To answer these questions, Moreno’s team genetically engineered fruit flies to control a newly found gene essential for marking unfit cells for culling. “If you put an extra copy of this gene you have better selection of the [unfit] cells, they are eliminated faster and therefore the animals can live longer”, says Moreno.

When the gene, which Moreno named azot, was removed from flies, they became sick and died prematurely. On the other hand, flies with an extra copy of the azot gene lived up to 60% longer.

Previously, only caloric restriction had been shown to prolong lifespan to such an extent in flies. In fact, reducing the amount of daily calorie input increases longevity in flies, nematodes, fish, mice and rats (data from studies with primates remain controversial). Could it be then, that starved flies with an extra copy of the azot gene live even longer? Indeed, these flies lived about 80% longer, Moreno’s team showed. In human time this would be equivalent to living up to 150 years!

The question remains whether these findings could be relevant for our species. Humans have the azot gene, in fact most organisms do, so potentially it should be possible to increase life expectancy in people by altering azot protein levels.

“You could start thinking of how to manipulate these mechanisms with drugs, for example, to treat ageing or diseases like neurodegeneration or myocardial infarction,” says Moreno, “I’m totally convinced it will be possible to delay aging and prolong lifespan in humans.”

Would we want to live longer though, if we spend most of our life old and sick? “Our long-term challenge will be to understand the biology of aging to address problems associated with steadily increasing life expectancy, such as metabolic disease and neurodegeneration”, says Martin Denzel, a researcher at the Max Planck Institute for Biology of Ageing in Cologne, Germany. With this in mind, Moreno’s team tested whether the long-living azot flies remained healthy as they aged. When the researchers looked in these flies’ brains, they found that their neurons accumulated fewer ageing cellular markers. Azot not only prolongs lifespan, but it also delays ageing.

In the future the team wants to understand what azot is actually doing. This gene encodes for a protein of unknown function, but the researchers know that when “the azot gene is activated, it triggers the normal cell death apoptosis pathway”, Moreno concludes. The team will also investigate the function of azot in mice, and collaborate with medical doctors to see if the azot-dependent cell elimination pathways are present in ageing-related diseases like Alzheimers.

“I have high hopes that eventually basic research into the aging process will yield treatments that extend the span of healthy living and that improve the quality of life in advanced age”, Denzel explains. “However, it will take a lot of additional work to investigate if this mechanism might be beneficial in mammals.”

Merino M., Jesus M. Lopez-Gay, David Buechel, Barbara Hauert & Eduardo Moreno (2015). Elimination of Unfit Cells Maintains Tissue Health and Prolongs Lifespan, Cell, DOI: http://dx.doi.org/10.1016/j.cell.2014.12.017

This article was published in Lab Times on the 23-01-2015. You can read it here

12 Jan 2015

Why do some people see ghosts?

For most people ghosts and spirits are part of the imaginary, but a few are truly convinced they can sometimes feel a strange presence near them. These individuals are not experiencing a paranormal phenomenon—they’re having an illusion. Schizophrenics, for instance, consistently report hearing voices or feeling someone—a ‘shadow’ or a ‘man’—close to them. Scientists have long known that illusions have a neurological cause, but they haven’t managed to pinpoint exactly how they are triggered by the brain.

Now, Olaf Blanke and colleagues have not only mapped the brain regions responsible for the ‘feeling of a presence’ illusion in neurological patients, but they have also developed a robot that tricks healthy people into sensing a ‘ghostly’ apparition. This work may shed light into what causes hallucinations in schizophrenia, and help design new therapeutic approaches to treat this psychosis.
Credit: Alain Herzog, EPFL.
In 2006, Blanke showed that he could induce the feeling of a presence in an epileptic patient by electrically stimulating a particular brain area—the temporoparietal junction. This region is involved in integrating body-related information from our senses and movements, and is often overactive in schizophrenic patients. But he found something even more interesting: the presence always mirrored the patient’s body position and movements; if the patient was sitting, the presence was also sitting and so on. “The presence was a duplicate of the patient, as if the patient’s body was recognised as another agent”, says Giulio Rognini, a collaborator at the Ecole Polytechnique Fédérale de Lausanne. “The body sensory information, which is not well integrated by the brain, is attributed to someone else.”

The researchers suspected that electrical stimulation of the temporoparietal region somehow disturbed integration of the patient’s sensory and motor information—her brain got confused and misplaced the bodily signals to the presence. To test this hypothesis, the team needed to be creative.

The patient studies show that when there is no appropriate integration of the body sensory signals, then the feeling of a presence can occur, so we tried to do the reverse process: we perturbed the sensory motor system to see whether we could induce the presence”, says Rognini. And what better way to do this than with… a robot.

In their new study, Blanke and colleagues asked 12 blindfolded healthy participants to stick their finger into a ‘master’ robot and then move it around. The ‘slave’ robot, which was touching the participants’ back, mimicked the movements of the master robot either simultaneously, or with a slight delay. In the first condition (simultaneous touch), the participants felt as though they were touching their own back. This is already a strange illusion, but what happened when the slave robot poked them with a slight delay relative to the master robot is even weirder. About a third of the participants felt like someone else was touching them. Not the robot, but just ‘someone’, a presence. This illusion was short lived, but according to the participants’ description, it was very vivid and also a bit creepy.

“30% [of the participants] reported without asking them that they had a feeling of a presence. This is already very strong because in this field of body illusions, it’s very rare to find somebody that reports the illusion without being asked” says Rognini, who is senior author in the study.

The team also mapped the brain regions that trigger the illusions in several neurological patients. As expected, electrical stimulation of the temporoparietal, but especially the frontoparietal brain regions, induced the illusion. And again, most patients reported that the presence mimicked their movements.
Lesion overlap analyses revealed three brain regions involved in the feeling of a presence illusion: temporo-parietal 
and fronto-parietal cortex (© Current Biology)

The feeling of a presence is mostly associated with epilepsy and schizophrenia, but healthy people can also feel ‘ghosts’, especially during periods of extreme stress or physical exhaustion. Many mountaineers report they sometimes feel someone climbing with them, even though there was no one around. “If you’re walking and doing repetitive movements over and over again, your brain loses control over your movements because they’re not informative anymore”, says Rognini. “Your actions and the consequences of your actions can be misinterpreted, and together with low oxygen conditions in high altitude, this could give rise to feeling of a presence. But this is completely speculative.” The researchers are planning to test this hypothesis by trying to exhaust people in treadmills, and then check whether they are more prone to experiencing the illusion. They are also developing an fMRI-compatible robot to induce the illusion while the participants are being scanned.

“The next steps are about understanding the brain mechanisms by putting the subjects in the scanner, and then try to investigate how this phenomenon is perceived in schizophrenic patients to try to set out a therapeutic strategy or a way to better understand this psychosis,” says Rognini.

Herta Flor, director of the Institute of Cognitive and Clinical Neuroscience of the University of Heidelberg (Germany) says “Disturbed body perception is a core feature in several mental disorders, such as schizophrenia or borderline-personality disorder. To be aware of the underlying neural mechanisms might not only help to understand clinically altered behaviour in patients, but may lead to innovative treatment approaches.”

Blanke O., Masayuki Hara, Lukas Heydrich, Andrea Serino, Akio Yamamoto, Toshiro Higuchi, Roy Salomon, Margitta Seeck, Theodor Landis & Shahar Arzy & (2014). Neurological and Robot-Controlled Induction of an Apparition, Current Biology, 24 (22) 2681-2686. DOI: http://dx.doi.org/10.1016/j.cub.2014.09.049

An edited version of this article was published in Lab Times on the 19-12-2014. You can red it here.