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.


How many cells do these flies have and how often do they divide? Is this another idea, like caloric restriction, that just isn't going to scale in larger animals?

Posted by: Michael-2 at January 17th, 2015 4:55 AM

From my layman's knowledge there are quality control mechanisms for senescent cells too, which for some reason become less effective with age, or are just perhaps imperfect and allow the slow buildup of senescent cells.

But a large question is - if the DNA damage theory of aging is correct, even to a degree, how the hell are all these bad cells going to be removed from the body? Doesn't this basic increase in entropy sink the SENS Foundation's goal of reversing aging?

Posted by: Jim at January 17th, 2015 10:03 AM

Jim: Not if the DNA damage is not present in freshly introduced cells. What we really need is digital read/write of DNA (which is in its infancy), straightforward digital "spot the differences" techniques to find the correct sequence, then re-introduction of stem cells with the correct sequence.

Posted by: Slicer at January 17th, 2015 10:51 AM

@Jim: Certainly, the clearest examples of "bad cells" in mammals are either senescent, which they can be ablated via recognition of cell surface proteins; or apoptotic, which can be replaced with cell therapy; or cancerous, which can be prevented and to some degree eliminated by denying potential cancer cells the ability to renew their telomeres.

Whether, indeed, low-level mutations accumulate in other cell types to a degree as to create "general cellular malaise" parallel to these "unfit" cells in mammals — and whether a sufficiently high percentage of such cells accumulate in a given tissue as to render real functional consequences with age — is something we'll just have to see. Even if it does, the question will be how much time in good youthful health will be bought simply by dealing with the clear-cut cases above before they become a serious cause of age-related ill health and we have to develop strategies to remove or reinforce them. Replacement, of course, can be effected with cell therapy.

Remember, fruit flies don't have to deal with the proliferative diseases that are so important in mammals, such as cancer and aspects of atherosclerosis, so the importance of mechanisms like this may in Drosophila not be at all representative of their threat to mammalian health with time. We are still in the early days of exploring this system even in flies, and Flower, the regulator of azot, has paradoxical effects in precancerous cells in mammals in the only system in which it's been studied.

I would watch but not yet worry about this line of research: in fact, I would look on it as a good sign that a backup approach likely exists to detect and deal with "unfit" cells suffering "general celluar malaise." Flower is itself a membrane protein, and it was already known from previous research that "unfit" cells can be distinguished through combinations of Flower isoforms at the membrane surface, so that's an obvious place to look for targets if we decide we need them after looking at their abundance in tissues cleared of senescent and cancerous cells and replenished with fresh ones as they otherwise atrophy.

(And if worse comes to worst, at least some tissues may be replaced wholesale, making the exact reasons for the dysfunction of the individual cells in the tissue moot).

Posted by: Michael at January 17th, 2015 12:33 PM

Thanks for the reply Michael. I don't know how you find the time!

Posted by: Jim at January 17th, 2015 1:08 PM

Michael: I noticed this on the site, in reference to turning somatic cells into pluripotent stem cells: "free of any defects that are present in the native cells (such as mutations or other aging damage)." For this to be possible, you'd *have to* have some kind of error-correction mechanism for DNA, because otherwise, how would you remove the mutations; in fact, how would you even know they were there?

Posted by: Slicer at January 17th, 2015 2:25 PM

@Slicer:- It's a much easier problem to isolate a stem cell line in culture free of stochastic damage than to identify or repair stochastic damage on a cell-by-cell basis. You could achieve the former using "quality control" methods based on existing gene / transcriptome sequencing methods. The latter is something science fictional that would probably require molecular nanotechnology.

Posted by: José at January 17th, 2015 2:56 PM

José: We might be talking around each other. All that I believe is necessary is some way of guaranteeing the DNA of replenishment cells in vitro before they're added, not fixing all the existing body cells in vivo. If this kind of guarantee exists, great- it's a non-problem.

But that DNA better be totally guaranteed error-free, otherwise changes would accumulate with repeated therapies and you'd have gradual genetic drift inside a single human being. It's also possible for a "good" cell to have horribly bad errors. For example, let's say you took a bone marrow cell that had an X-ray strike a peptide in the DNA that codes for neuron development. In its natural state, who cares? It's not growing neurons, and it never would. But you take that cell, turn it into a pluripotent cell, and start replenishing someone's neurons with it... more or less, you'd be giving an adult birth defects.

At the very least, without an absolute guarantee that the DNA's error-free, I'd want new pluripotent cells to be derived from a source that rarely divides and is not likely to be damaged, whether that was inside my body or in a frozen bank somewhere.

Posted by: Slicer at January 17th, 2015 3:40 PM

@Slicer:- What I'm saying is that if you just want to establish a genetic-damage-free cell line you could just start with a single transformed pluripotent cell, multiply it in culture, then sequence the genome from some of those cultured cells and check exhaustively for errors. If the sequenced cells are free from errors, then probably the other cells in the same culture and derived from the same source are free from errors. If the sequenced cells are not free from errors, try again a different culture. There could be some error that arose in vitro when the stem cell population was expanded, an error that occurred in the non-sequenced cells but not the sequenced ones, but this probability is low and does not depend on the age of the patient. It can be improved with better culturing methods. Therefore the only barrier to quality control for stem cells is the price of genome sequencing, which is coming down dramatically.

I was confused because although helpful and necessary this technology would not seem to offer a solution to the (unproven but possible) problem of generalized cellular malaise due to sporadic genetic damage being discussed here. One could perhaps ameliorate the problem by increasing the turnover of cells through apoptosis and then providing error-free stem cells to take their place?

Posted by: José at January 17th, 2015 4:15 PM

"One could perhaps ameliorate the problem by increasing the turnover of cells through apoptosis and then providing error-free stem cells to take their place?" - Yes, this would be necessary and appropriate. I think I was confused too.

Posted by: Slicer at January 17th, 2015 4:20 PM

Perhaps of interest -

"Nanoparticles against cellular aging"

Excerpt -
“The nanoparticles open, releasing their contents to remove senescent cells, or even prevent deterioration and reactivate the cells for rejuvenation”

Posted by: Lou Pagnucco at January 19th, 2015 9:57 AM

Very interesting reading about the ahuizotl (azot) gene. I was particularly interested in knowing this gene is already found in a smaller percentage of humans (although could be as high as 20%).

Some older people do not look old! Even without makeup :) They also seem to be fit and healthy even though they may not exercise regularly, and tend to live much longer even if they smoke!! If this gene is the sole reason for that (?) then everyone would want to be mutated with it.

I suspect that within the next century (or even decade as science advances keep escalating in health and technology) that most alive will own this gene, the dead would have obviously been too poor to participate. Well I'm out, but there's still hope for my kids (or their kids) ;)

Posted by: kimsland at June 10th, 2015 4:29 AM
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