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

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