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.”

Reference:

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. 

Cancer research: fruit flies take it down a notch

You wouldn’t think that those pesky flies hovering around your fruit bowl could help scientists understand cancer. Flies don’t have cancer, and a fly is, well, just a fly. However, the fruit fly Drosophila melanogaster has been one of scientists' favourite animal models for over a century, and is nowadays used to study many human diseases. New research using fruit flies has now uncovered molecular details in tissue overgrowth that explain some long-standing questions in cancer research.

Why Drosophila? When compared to other lab animals like mice, for instance, flies have many advantages. They are tiny and hence you can grow them anywhere, they are cheap to maintain (in the old days they were fed with rotten bananas) and they breed in just 12 days while mice take 12 weeks. But the most important fact is that, even though flies and humans look very different, most of their genes are the same, or very similar. So while manipulating fly genes in the lab is quite easy, when scientists understand how a gene works in the fly, these discoveries can have significant implications for human medicine.

Fruit fly Drosophila melanogaster (Credit: therealbeast/everystockphoto)

To study a human disease in flies scientists begin by making them sick. They mutate, or disrupt, the same gene that is known (or suspected) to cause the human disease, and then they try to figure out why meddling with this particular gene causes the disease symptoms, which in flies are called phenotypes. And this is exactly what Sarah Bray’s team at the University of Cambridge did to understand the molecular details of tissue overgrowth that may lead to cancer.

In a study published in the January issue of EMBO Journal, the Cambridge scientists introduced in flies a modified version of the Notch gene that makes it overactive, or in other words, the gene is always turned on, and this set off massive tissue overgrowth in the larvae, mimicking what happens in cancer. Notch is a gene that is overactive in many cancers such as breast, lung and cervical cancers, but how Notch activation triggers cancer is not understood.

The Notch gene encodes for a protein involved in cell communication. When Notch receives a signal from a neighbouring cell, it becomes activated and instructs specific genes to switch on. Each of these genes does a different job in the cell, such as telling the cell to multiply. The problem is that, with the same signal, Notch can activate many genes, and it is difficult for scientists to predict what the combined effect of turning on all these genes will be for a cell or a tissue. To make matters worse, Notch activation can have opposite cellular outcomes. For instance, in some cases Notch causes tissue overgrowth and cancer, while in others Notch stops tissue growth. This paradox has been puzzling scientists for over a decade, and is a major factor hindering progress in Notch cancer research.

Magnified Drosophila larval tissue with fluorescent marker. Left: normal tissue, right: tissue with overactive Notch. (Credit: Bray lab, University of Cambridge)

To try and solve this problem, Bray's team used genomic approaches to search for genes activated by Notch in the overgrown tumour-like larval tissues. The researchers figured that knowing which genes are abnormally activated by Notch in their simplified ‘cancer’ fly model might explain the different cellular responses to Notch. And this is exactly what they found. “We found that in a same tissue, Notch activates genes that seem antagonistic” says Alexandre Djiane, leading author in the study. But when they had a closer look the team found that these opposing genes “are actually activated in different subsets of the tissue.” Notch activation produced a central region in the tissue where cells divided slowly, surrounded by cells that multiplied very quickly. How does Notch induce these different cellular responses? Djiane explains “this regionalisation of the response is at least in part a consequence of cross-regulation between the different Notch targets themselves”. Notch can not only activate different genes in the same tissue, but some genes can also interfere with one another, in a sort of battle between genes where the winner gets to tell the cell what to do.

But are these newly found genes involved in cancer? By comparing their results with cancer patients’ databases, the authors found that several of the genes abnormally activated by Notch in the fly overgrown tissue were overactive in human cancers. This is a good indication that the genes identified in the fly may be potential candidate cancer-promoting genes in humans. But the researchers went even further. They used genetic tricks that turned these genes up or down to test what they actually do in living flies, and found that about two thirds “play a role in tissue growth and mediate the effect of Notch,” says Djiane.

“The advantage of the fruit fly is, as demonstrated in this work, that several of these candidates can be rigorously tested via fast and efficient genetic testing to confirm the functional importance of each target gene” says Marcos Vidal, a cancer biologist at the Beatson Institute for Cancer Research in Glasgow who was not involved in this study. “This kind of research complements the one performed directly from clinical samples and cell lines.”

Current cancer drugs targeting Notch have side effects because Notch is critical for many biological processes. Vidal says “[…] direct inhibition of Notch appears to have undesired side effects and therefore may not be an ideal therapeutic target itself. On the other hand, the gene targets specifically regulated by Notch in tumorous growth identified in this study, could potentially be better therapeutic targets in Notch-driven cancers.”

Reference:

Djiane, A., Krejci, A., Bernard, F., Fexova, S., Millen, K., & Bray, S. (2013). Dissecting the mechanisms of Notch induced hyperplasia The EMBO Journal, 32 (1), 60-71 DOI: 10.1038/emboj.2012.326

This article was published in The Munich Eye on the 21-01-13. You can read it here.