Extending Healthy Life by Eliminating More Unfit Cells

An intriguing open access paper was published earlier this week in which the authors made significant headway in understanding the details of a mechanism by which flies eliminate less functional cells on an ongoing basis. The researchers then manipulated this mechanism via gene therapy so that a greater proportion of these less fit cells were destroyed, and as a result the genetically altered flies lived longer. The effect on median life span is a 50-60% increase, and for maximum life span a more modest 10-20% gain:

Prolonging lifespan: Researchers create 'Methuselah fly' by selecting best cells

"Our bodies are composed of several trillion cells, and during aging those cells accumulate random errors due to stress or external insults, like UV-light from the sun." But those errors do not affect all cells at the same time and with the same intensity: "Because some cells are more affected than others, we reasoned that selecting the less affected cells and eliminating the damaged ones could be a good strategy to maintain tissue health and therefore delay aging and prolong lifespan."

To test their hypothesis, the researchers used Drosophila melanogaster flies. The first challenge was to find out which cells within the organs of Drosophila were healthier. The team identified a gene which was activated in less healthy cells. They called the gene ahuizotl (azot) after a mythological Aztec creature selectively targeting fishing boats to protect the fish population of lakes, because the function of the gene was also to selectively target less healthy or less fit cells to protect the integrity and health of the organs like the brain or the gut.

Normally, there are two copies of this gene in each cell. By inserting a third copy, the researchers were able to select better cells more efficiently. The consequences of this improved cell quality control mechanism were that the flies appeared to maintain tissue health better, aged slower and had longer lifespans. However, the potential of the results goes beyond creating Methuselah flies, the researchers say: Because the gene azot is conserved in humans, this opens the possibility that selecting the healthier or fitter cells within organs could in the future be used as an anti aging mechanism. For example, it could prevent neuro- and tissue degeneration produced in our bodies over time.

Elimination of Unfit Cells Maintains Tissue Health and Prolongs Lifespan

Individual cells can suffer insults that affect their normal functioning, a situation often aggravated by exposure to external damaging agents. A fraction of damaged cells will critically lose their ability to live, but a different subset of cells may be more difficult to identify and eliminate: viable but suboptimal cells that, if unnoticed, may adversely affect the whole organism. What is the evidence that viable but damaged cells accumulate within tissues? The theory is supported by the experimental finding that clonal mosaicism occurs at unexpectedly high frequency in human tissues as a function of time. Does the high prevalence of mosaicism in our tissues mean that it is impossible to recognize and eliminate cells with subtle mutations and that suboptimal cells are bound to accumulate within organs? Or, on the contrary, can animal bodies identify and get rid of unfit viable cells?

In Drosophila, cells can compare their fitness using different isoforms of the transmembrane protein Flower. The "fitness fingerprints" are therefore defined as combinations of Flower isoforms present at the cell membrane that reveal optimal or reduced fitness. The isoforms that indicate reduced fitness have been called FlowerLose isoforms, because they are expressed in cells marked to be eliminated by apoptosis called "Loser cells". However, the presence of FlowerLose isoforms at the cell membrane of a particular cell does not imply that the cell will be culled, because at least two other parameters are taken into account: (1) the levels of FlowerLose isoforms in neighboring cells: if neighboring cells have similar levels of Lose isoforms, no cell will be killed; (2) the levels of a secreted protein called Sparc, the homolog of the Sparc/Osteonectin protein family, which counteracts the action of the Lose isoforms.

Here, we aimed to clarify how cells integrate fitness information in order to identify and eliminate suboptimal cells. We find Azot expression in a wide range of "less fit" cells, such as WT cells challenged by the presence of "supercompetitors," slow proliferating cells confronted with normal proliferating cells, cells with mutations in several signaling pathways, or photoreceptor neurons forming incomplete ommatidia. In order to be expressed specifically in "less fit" cells, the transcriptional regulation of azot integrates fitness information from at least three levels: (1) the cell's own levels of FlowerLose isoforms, (2) the levels of Sparc, and (3) the levels of Lose isoforms in neighboring cells. Therefore, Azot ON/OFF regulation acts as a cell-fitness checkpoint deciding which viable cells are eliminated. We propose that by implementing a cell-fitness checkpoint, multicellular communities became more robust and less sensitive to several mutations that create viable but potentially harmful cells. Moreover, azot is not involved in other types of apoptosis, suggesting a dedicated function, and - given the evolutionary conservation of Azot - pointing to the existence of central cell selection pathways in multicellular animals.

We show that active elimination of unfit cells is required to maintain tissue health during development and adulthood. We identify a gene (azot), whose expression is confined to suboptimal or misspecified but morphologically normal and viable cells. When tissues become scattered with suboptimal cells, lack of azot increases morphological malformations and susceptibility to random mutations and accelerates age-dependent tissue degeneration. On the contrary, experimental stimulation of azot function is beneficial for tissue health and extends lifespan.

The paper makes for an interesting read, as it is the first I've heard of this line of research and the details of this particular quality control mechanism. I look forward to seeing the results of further studies conducted in mammals whenever they might take place: is the process in fact similar in higher animals such as mammals, and similarly open to beneficial manipulation? The gain in maximum life span here is on a par with that seen in lower animals as a result of boosting the operation of other, better known quality control systems, such as autophagy. There is probably going to be a sizable grey area in the future between the undesirable approach of "messing with metabolism" and the desirable approach of repair of damage as the two distinct possible strategies when building treatments for degenerative aging, and this result is a good illustration of the midpoint of that grey area, I think.

One possibility that occurred to me is that this may be a path towards putting some numbers to the degree to which we should expect stochastic nuclear DNA damage to be a significant contributing cause of degenerative aging. As you might know the consensus is that yes of course the random accumulation of this damage leads to less well regulated cells, and thus should be relevant to aging - and not just in the matter of cancer, but in the more general dysfunction of tissues. This is not a consensus without debate, however, and at present there are no good studies providing evidence to quantify the degree to which nuclear DNA damage contributes to aging. That might fall out of further study of azot, though I see that the categories of less fit cells quoted above include a wide range of states and situations that probably have no direct relationship with nuclear DNA damage.