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Category: Breaking Research (page 2 of 2)

Breaking Research: Fruit flies provide insights into metabolism and how we age

Why do we age? It’s more than just a philosophical question; it’s a puzzle that has frustrated scientists for decades. Currently, the most accepted hypothesis is that aging is the result of accumulated damage to our cells during our lifetime. “Accumulated damage” encompasses a variety of things that can go wrong, including DNA mutations, problems in the way molecules such as proteins are built, or abnormal interactions between molecules. Over time, the damage interferes with the body’s ability to maintain itself the way it used to, and the process we call “aging” occurs.

Damage by free radicalsClick on the picture for a bigger version. Multiple external and internal factors can lead to the formation of free radicals and cell damage, which accelerates aging.

It sounds like a great hypothesis, but how can we prove it, and how can we measure accumulated damage? Damage can be caused by a number of factors, and the types of damage that can occur varies wildly between species and even between individuals of the same species. To make matters worse, exposure to certain environmental influences or toxins can accelerate aging. For example, overexposure to UV light from the sun can increase signs of aging in skin cells, and studies have shown that smoking can also accelerate aging. How can scientists study something with so much variability and uncertainty? A recent fruit fly paper published in eLife by the Gladyshev lab describes a new way to study damage accumulation. Instead of measuring the damage itself, they measure the byproducts of cellular metabolism as a proxy.

You see, even if we were able to reduce exposure to environmental toxins, we’d still get older. That’s because unfortunately, even our bodies are working against us. Our cells have metabolic processes, which are the life-sustaining chemical reactions that are needed to keep them alive and reproducing.  The small molecules that are produced by these reactions (called metabolites) are usually important for the cells; they could be fuel for energy, signals for growth or reproduction, or even necessary for defenses and interactions with the environment. Unfortunately, these processes also create toxic byproducts such as reactive oxygen species (also known as free radicals). These byproducts cause damage and have often been associated with many age-related diseases such as cancer, heart disease, and Alzheimer’s disease.

To test the idea that accumulating metabolic byproducts can lead to aging, the authors of this study used a new method called “metabolite profiling” to measure the amount of metabolites in flies as they aged. (If you’re interested, the technique they used is called liquid chromatography mass spectrometry). They first found that the diversity of metabolites increases with age. This suggests that mistakes were being made during the metabolic reactions, causing new types of byproducts to appear that can damage cells. Additionally, a subset of metabolites accumulated with age, which may indicate that these byproducts are not being sufficiently cleaned up by maintenance processes in the cells. The authors found that many of these had previously been identified as damaging, directly confirming that accumulating toxic byproducts is correlated with aging.

Finally, the authors also used a calorie-restricted diet to extend the lifespan of a group of flies (although it’s not yet understood why, a severely restrictive diet can increase lifespan in many model animals, including mice and rats. It’s not recommended for humans, however, because there are unpleasant side-effects). Most interestingly, when the authors compared metabolite accumulation in normal flies versus the lifespan-extended flies, they showed that the metabolite accumulation was slower in the longer-lived flies, corresponding with the slower progression of aging.

So how can these findings help us? This paper supports the hypothesis that accumulation of damage leads to aging by showing that metabolites accumulate at a rate that corresponds with relative age in fruit flies. Because most species share the same cellular metabolic processes, these results are relevant to mammals. The next step will be to identify particular types of metabolites and determine how they contribute to aging in flies and mammalian models. The authors of this paper already did some of the legwork. They found that many of the metabolites that differed between the lifespan-extended group and the normal group of flies were associated with processes for using and storing energy from fats and proteins (not surprising considering the flies were on a strict diet). The authors suggest that changing these metabolic processes through diet may have compensated somehow for the accumulation of toxic byproducts. Future research may be able to expand upon these findings, and perhaps even figure out a way to interfere with these processes to slow or alter aging.  I just hope I live long enough to see it!


  • Avanesov A.S., Kerry A Pierce, Sun Hee Yim, Byung Cheon Lee, Clary B Clish & Vadim N Gladyshev (2014). Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation, eLife, 3 DOI:

General references:

Breaking research: A recent study in fruit flies suggests that sleep loss during childhood could lead to abnormal brain development

Discussions about whether schools for children should start later have been making headlines recently, highlighting the importance of getting enough sleep at night. We all know how important sleep is for day-to-day performance—you’ve likely experienced firsthand how hard it can be to think and focus after a bad night’s sleep. Luckily, these effects are reversible: just get enough sleep for the next couple of nights and you’ll feel refreshed again. But can sleep deprivation have long-term, irreversible consequences in children?

Table of sleep needs by ageTable 1. Human children require more sleep than adults. Data obtained from the National Sleep Foundation

Across multiple species, young animals need more sleep than adults. Although the purpose of sleep is not fully understood, researchers believe that the brain may use this time to repair itself, store new memories, and modify itself to stay current with recently learned skills or adapt to changes in the environment (a process known as plasticity). The brains of young animals are very plastic and are undergoing a lot of changes as they develop, and scientists have always suspected that increased sleep is necessary for normal brain development. In humans, the majority of brain growth occurs before the age of two, which is also the period of life with the highest amount of sleep. In a recent paper published in Science, the Sehgal lab studied the link between sleep and brain development using Drosophila melanogaster and found that loss of sleep in immature flies led to abnormal development in a fast-growing area of the brain and consequent behavioral problems in adult flies.

Just like humans and other mammals, fruit flies need a good night’s sleep to function normally during the day. The authors began their study by confirming that in flies, young animals also sleep more than adults. They then sleep deprived a group of flies by placing them in a shaking machine for two nights and measured their behavior three days later (a long time for a humble fruit fly!). Fly researchers prefer to study innate behaviors because they are instinctual instead of learned, suggesting that their underlying brain structure develops genetically rather than from experience (in these cases, it is thought that the “nature versus nurture scale” is tipped toward nature.) In this case, the authors studied “courtship behavior”, a measure of how well male flies can solicit female flies and successfully pass on his genes (so to speak). They found that flies that were sleep deprived when they were younger didn’t perform as well as flies that had gotten enough sleep. The authors showed that this behavioral abnormality was specifically caused by loss of sleep in young flies, because flies that were sleep deprived as adults performed normally three days later.

Table of sleep needs by ageFigure 1. Sleep is required in young flies for normal development of fast-growing brain regions. Sleep deprivation during youth causes lack of growth in the VA1v, an important region for courtship behavior. Image modified from Murakami and Keene, 2014.

What happened in the brains of young sleep-deprived flies that led to their courtship inadequacy as adults? Previous research had already located the brain regions responsible for this innate behavior, so the authors knew where to start looking. They found that one of the regions (a structure called the VA1v) had not grown as much in flies that had been sleep-deprived when they were young. The VA1v is a very fast-growing region during development, and the authors showed that loss of sleep irreversibly slowed its growth. On the other hand, structures that do not undergo fast growth during development were normal. The authors concluded that sleep deprivation in young animals impairs brain development in fast-growing areas, resulting in irreversible behavioral abnormalities.

These results demonstrate just how important it can be to get enough sleep, especially as children. Research with human children already indicate that loss of sleep can have long-term effects on behavior, and the findings from this paper suggest that the consequences may not always be reversible if developing regions of the brain are affected. But what if children have a developmental or genetic disorder—such as a pediatric sleep disorder—that causes loss of sleep during this critical time period?

The authors also figured out the difference in young fly brains that caused them to sleep more than adults. Using the impressive set of genetic tools that Drosophila are famous for, they identified a small set of dopaminergic (DA) cells that behaved differently in young versus adult flies. Dopamine is a chemical in the brain that some neurons use to communicate with each other, and is already known to be important for the “be awake!” signal in several mammalian species and humans. The authors found that this particular set of DA neurons was less active in young flies than adults, while other DA neurons had the same activity level regardless of age. The neurons communicated with a sleep-related structure known as the dorsal fan-shaped body (dFSB). The authors found that in young flies, reduced activity in these DA neurons allowed the dFSB to be more active, causing the flies to sleep more. When the authors artificially activated the DA neurons, they found that young flies were unable to sleep and had behavioral problems three days later, while adult flies did not experience any long-term effects. This result matched the one they obtained when they sleep deprived young flies by shaking them, confirming that reduced activity in these neurons was responsible for the extra sleep in young flies.

How can knowing the circuit responsible for extra sleep in young flies help us humans? Dopamine plays the same role in causing wakefulness in mammals as it does in flies, and the dFSB is similar to known mammalian sleep-related structures (such as the VLPO). Researchers can use these findings as a starting point for identifying similar DA neurons in mammals. Eventually, scientists may be able to develop a treatment that acts on these neurons in children with sleep disorders, allowing them to get more sleep and ensure normal brain development during this critical period.

Circuit underlying extra sleep in young fliesFigure 2. The circuit responsible for extra sleep in young flies. In young flies, a set of dopaminergic (DA) neurons is less active, allowing a sleep-related structure known as the dFSB to be more active and promote extra sleep. In adult flies, the DA neurons are more active and suppress dFSB activity, leading to relatively less sleep.

Original reference:

  • Kayser M.S., Yue Z. & A. Sehgal (2014). A Critical Period of Sleep for Development of Courtship Circuitry and Behavior in Drosophila, Science, 344 (6181) 269-274. DOI:

General references:

Breaking research: A study in fruit flies finds a possible drug target to compensate for symptoms of Parkinson’s disease

Parkinson’s disease is caused by the progressive death of neurons important for movement and results in symptoms such as shaking or rigidity in the limbs, slow movements, and difficulty walking. The primary treatment is a drug called L-Dopa, which compensates for the neuron loss but eventually becomes less effective as more and more neurons die off. Uncovering the cause of neuron death is necessary before treatments can be developed to stop it, and research in fruit flies has already begun to advance our understanding of the disease. A new study published in the open-access journal eLife by the Guo lab expands upon this previous work and uncovers a possible treatment option.

Although most cases of Parkinson’s disease have an unknown cause, about 10-15% are genetic. Two of the implicated genes, PINK1 and Parkin, have been well-studied in Drosophila melanogaster. Just as in humans, a mutation in these genes in fruit flies leads to neuron death and the loss of motor skills. But how? Fruit fly research has shown that PINK1 and Parkin maintain mitochondria, the structures inside cells that provide energy (think of them as little power plants). A single cell can have hundreds or even thousands of mitochondria, depending on its energy needs. Over time, mitochondria can become damaged and begin functioning abnormally.  These rogue mitochondria must be broken down and replaced with healthy ones before their dysfunctional behavior can cause damage to the cell. This is where the proteins created by the PINK1/Parkin genes come in.

Cartoon of mitochondrial maintainanceFigure 1. Pink1 latches onto mitochondria to determine whether or not they are healthy. If the mitochondrion is healthy, Pink1 is quickly removed. Otherwise, Pink1 binds to a passing parkin protein, triggering the destruction of the unhealthy mitochondrion. Image modified from Diedrich et al, 2011

PINK1’s job is to latch on to the surface of mitochondria and detect whether or not they are functioning normally. If the mitochondrion is fine, PINK1 gets removed and nothing else happens. On the other hand, if the mitochondrion has been damaged, PINK1 stays put and binds to a passing Parkin protein, which triggers the destruction of the offending mitochondrion. As you’ve probably guessed, a mutation in either the PINK1 or Parkin gene results in an accumulation of dysfunctional mitochondria and leads to cell death. This provides some explanation for why neurons are dying in patients in Parkinson’s disease.

PINK1/Parkin also maintain mitochondria in another way. Mitochondria regularly join with each other and then divide again to replenish their numbers. PINK1/Parkin helps to prevent damaged mitochondria from joining with healthy ones by breaking down a protein called mitofusin, which is responsible for joining mitochondria together. Cells with mutations in PINK1/Parkin have too much mitofusin, which means that damaged mitochondria can hurt the healthy ones by joining with them. To make matters worse, the ratio of joins to divisions is tightly controlled, so when the balance is tipped in favor of joining, big clumps of joined mitochondria begin to form.

The researchers in the Guo lab investigated other proteins involved in mitochondrial maintenance, searching for one that could compensate for mutations in PINK1/Parkin by preventing damaged mitochondria from joining with others and restoring the balance between joins and divisions. They turned their attention on MUL1, a protein that had previously been shown to interact with mitofusin. The authors discovered that adding extra MUL1 proteins into cells with a PINK1/Parkin mutation fixed the mitochondrial problems caused by the mutations!  Drosophila neurons with a mutation in PINK1/Parkin have clumps of mitochondria, while normal cells show mitochondria evenly spread out. Incredibly, mutant cells with extra MUL1 protein showed a normal spread of mitochondria. Adding extra MUL1 into mutant cells somehow compensated for the PINK1/Parkin mutations and returned the balance between joins and divisions to normal.

How was the extra MUL1 able to reverse the over-joining of mitochondria? The authors answered this question by manipulating and measuring MUL1 and mitofusin levels in a variety of situations. They found that cells with a non-functional mutation in the MUL1 gene had clumps of mitochondria and too much mitofusin, just like in PINK1/Parkin mutants. On the other hand, normal cells with extra MUL1 protein actually had too little mitofusin and mitochondria that were small and fragmented, suggesting that the balance in these cells had shifted toward too much division. With further investigation, the authors realized that MUL1 protein was actually breaking down mitofusin just like Parkin.

So the addition of extra MUL1 protein can compensate for PINK1/Parkin mutations by breaking down the extra mitofusin, thus returning mitofusin levels back to normal and rebalancing the ratio of mitochondrial joins to divisions. But this research was in fruit flies, so how do we know this will be useful for humans? The authors took their research a step further by demonstrating that MUL1 has the same function in mouse neurons and HeLa cells (human cells), and that extra MUL1 in these models still compensates for PINK1/Parkin mutations.

This is a fantastic finding, but unfortunately it doesn’t mean we’re ready to give MUL1 pills to Parkinson’s patients and cure the disease. The authors introduced extra MUL1 proteins genetically using a method called gene overexpression (check out this Wikipedia article on gene expression for more information). Basically, the authors made the cells produce their own extra MUL1, but a possible treatment would require developing and testing a drug that either forces cells to start making more MUL1 or adds MUL1 directly. Second, MUL1 doesn’t play a role in targeting and destroying damaged mitochondria. This means that while extra MUL1 could help to prevent clumps of mitochondria (which would have spread the damage from unhealthy ones faster), it can’t actually remove damaged mitochondria. So this treatment would not be able to completely stop the accumulation of dysfunctional mitochondria. But there is still hope! This option will be better than our current treatments because it could slow the progression of cell death instead of simply compensating for the loss. And in the future, research in this area will build upon these findings to develop an even better drug.

Cartoon of balance between PINK1/Parkin and MUL1Figure 2.  An increase in MUL1 levels can compensate for loss of PINK1/Parkin and maintain normal mitofusin (mfn) levels (A). A loss of either MUL1 (B) or PINK1/Parkin (C) alone causes an increase in mfn levels. Cells with a loss in both PINK1/Parkin and MUL1 show an even greater increase in mfn levels (D). Image modified from Yun et al, 2014







For more information on Parkinson’s disease research in fruit flies, check out the Parkinson’s Translational Findings post.


  • Yun J., Huan Yang, Michael A Lizzio, Chunlai Wu, Zu-Hang Sheng & Ming Guo (2014). MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin, eLife, 3 DOI:
  • Diedrich M., Grit Nebrich, Andrea Koppelstaetter, Jie Shen, Claus Zabel, Joachim Klose & Lei Mao (2011). Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson’s disease, Proteome Science, 9 (1) 59. DOI:

Breaking research: A new technique for uncovering cell-specific differences in the Drosophila “interactome”

You’ve probably heard the term “genome” before, which refers to the set of genes in an organism.  Biology has a lot of buzzwords for describing what’s going on inside cells, and one of the recent ones is “interactome”. The word “interactome” refers to all of the interactions that are occurring between proteins, the large molecules that do most of the work inside your cells. Proteins are built from their corresponding gene’s instructions, and they drive cellular processes by interacting with each other. For example, when a receptor protein on the cell membrane is triggered—such as by recognizing an invading virus—it temporarily binds to another type of protein, which interacts with yet another protein and so on, until the cell’s immune response is fully activated and self-defense proteins are released to deal with the invaders.  This series of protein interactions is called a “signaling cascade”.

As you might have guessed, if one of the proteins in a signaling cascade isn’t interacting properly, it leads to problems which can be the basis of diseases, such as Alzheimer’s disease, ALS, or cancer. As a result, it is very important to understand how proteins interact, especially when mutations can lead to human diseases. Unfortunately, a single protein can have dozens or even hundreds of binding partners. To make matters worse, it is thought that proteins have cell-specific interactions, which means that a given protein may interact with one set of proteins in one type of cell, and a different set of proteins in another cell type. However, current techniques for studying a protein’s binding partners use whole brains or brain structures consisting of many different types of cells and cannot distinguish among them.

A recent paper1 published in the Griffith lab addresses this problem by taking advantage of the genetics tools developed in Drosophila melanogaster. They created a fly line with a mutation in the gene for the protein of interest, and then used a binary expression system (UAS/GAL4) to reintroduce normal versions of the protein into specific subsets of cells. The authors then followed up with current techniques for studying the protein’s interactions, but they knew that the binding partners were specific to the cells they were interested in.

To demonstrate their new technique, the authors studied a protein called CASK. In mammals, CASK is important for signaling between neurons and is implicated in two human developmental disorders. In flies, CASK is present in almost all neurons, and CASK mutants have problems with locomotion and learning. Researchers already knew that different types of neurons were responsible for each of these behaviors, and thought that CASK may have different interactions based on the type of cell. To test this hypothesis, the authors used a fly line with a non-functioning mutation in the CASK gene, and then reintroduced normal versions of the protein in three different types of neurons.  They were then able to use current identification techniques (check out this link on mass spectrometry, if you’re interested) to determine which proteins had bound to CASK in each of the three lines and compare them to each other (as well as to a fly line where they had reintroduced CASK in all neurons). They found that while there were many proteins that interacted with CASK in all of the neuron subtypes, each group also had a set of unique interactions.

So what’s the bottom line?  How can the findings in this paper help us? Because abnormal protein interactions are the basis of many human diseases, the only way to treat them is to determine which proteins are involved and understand their function. Only then we would know how to fix the problem. Unfortunately, while many of those interactions are specific to certain types of cells, current techniques require researchers to investigate the protein’s binding partners from many cell types.  This creates unnecessary complexity because only specific populations of neurons are affected in some diseases. For example, in Parkinson’s disease, a type of cell known as dopaminergic neurons are most seriously affected. Researchers are studying proteins known to be involved in the disease, but may benefit from being able to limit the interactions to those that occur within dopaminergic neurons. Using fruit flies, the Griffith lab developed a technique for uncovering cell-specific differences in a protein’s interactions. In the future, researchers will be able to use Drosophila as a model organism for studying cell-specific protein interactions involved in human disease, and this technique may even be modified for use in mammalian systems.

  1. Mukherjee K., Bethany L. Christmann & Leslie C. Griffith (2014). Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry, Frontiers in Molecular Neuroscience, 7 DOI:
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