The study, published today in eLife, reveals why killifish accumulate harmful mutations that cause age-related conditions such as cancer or neurodegenerative diseases that shorten lifespan. This may help scientists better understand how lifespan evolves among populations and may lead to new insights on human aging.

The very short lives of turquoise killifish — between three and nine months — make them an ideal model for studying aging. Killifish live in temporary ponds in Africa that dry up for part of the year, meaning they must hatch, mature and reproduce before this happens. Their eggs survive the dry periods in a hibernation-like state and hatch when rains fill the pond again, starting a new generation.

“Different wild turquoise killifish populations have varying lifespans, and we wanted to explore the reasons behind this,” explains lead author David Willemsen, Postdoctoral Research Fellow at the Max Planck Institute for Biology of Ageing, Cologne, Germany.

For their study, Willemsen and senior author Dario Riccardo Valenzano carried out field work in savanna pools in Zimbabwe to catch and collect genome samples from the killifish for sequencing and analysing in the lab. The team then compared the genomes of killifish living in the driest environments, which have the shortest lives, with the genomes of killifish from wetter environments, which live for months longer.

The short-lived killifish have very small, often isolated populations, leading to so-called population bottlenecks which, the team found, result in harmful mutations accumulating in their populations. By contrast, the longer-lived killifish have larger populations and new fish with new genetic material frequently join their populations. Over time, these larger populations make it more efficient for natural selection to remove harmful mutations.

“Limited population sizes caused by habitat fragmentation and repeated population bottlenecks increase the chance for harmful mutations to accumulate in the population,” Willemsen says. “Our work may help answer a key question about aging by suggesting that population dynamics, rather than evolutionary selection for or against specific genes, contribute to this accumulation of harmful mutations that result in aging and shorter life.”

The results support a model where, given the brief rainy seasons, killifish are under strong selective constraints to survive in the absence of water as dormant embryos and to rapidly reach sexual maturation and reproduce before the water completely evaporates. However, the team believes that killifish are not selected to be short-lived. Instead, harmful mutations that affect late-life survival and reproduction (together causing aging in the killifish) accumulate over generations without being constrained by selection.

“Harmful mutations passively accumulate in killifish populations, and this is even more prominent in smaller populations which happen to live in drier environments,” says senior author Dario Riccardo Valenzano, Group Leader at the Max Planck Institute for Biology and Ageing, and Principle Investigator at CECAD, the Cluster of Excellence for Ageing Research at the University of Cologne, Germany. “Our findings highlight the role of demographic constraints in shaping lifespan within species and could potentially be expanded to provide new insights on aging within other animal and human populations.”

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‘We wanted to find out how antibiotics that inhibit protein synthesis in bacteria work when combined with each other, and predict these effects as far as possible, using mathematical models,’ Bollenbach explained. As head of the research group ‘Biological Physics and Systems Biology’ at the University of Cologne, he explores how cells respond to drug combinations and other signals.

Bacterial ribosomes can gradually translate the DNA sequence of genes into the amino acid sequence of proteins (translation). Many antibiotics target this process and inhibit translation. Different antibiotics specifically block different steps of the translation cycle. The scientists found out that the interactions between the antibiotics are often caused by bottlenecks in the translation cycle. For example, antibiotics that inhibit the beginning and middle of the translation cycle have much weaker effects when combined.

In order to clarify the underlying mechanisms of drug interactions, the scientists created artificial translation bottlenecks that genetically mimic the effect of specific antibiotics. If such a bottleneck is located in the middle of the translation cycle, a traffic jam of ribosomes forms, which dissolves upon introducing another bottleneck at the beginning of the translation cycle. Using a combination of theoretical models from statistical physics and experiments, the scientists showed that this effect explains the drug interaction between antibiotics that block these translation steps.

Tobias Bollenbach concluded: ‘A quantitative understanding of the effect of individual antibiotics allows us to predict the effect of antibiotic combinations without having to test all possible combinations by trial and error. This finding is important because the same approach can be applied to other drugs, enabling the development of new, particularly effective drug combinations in the long term.’

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“Quantum critical points are a very hot issue and interesting for many problems,” says Wei-Sheng Lee, a staff scientist at the Department of Energy’s SLAC National Accelerator Laboratory and investigator with the Stanford Institute for Materials and Energy Sciences (SIMES). “Some suggest that they’re even analogous to black holes in the sense that they are singularities — point-like intersections between different states of matter in a quantum material — where you can get all sorts of very strange electron behavior as you approach them.”

Lee and his collaborators reported in Nature Physics today that they have found strong evidence that QCPs and their associated fluctuations exist. They used a technique called resonant inelastic X-ray scattering (RIXS) to probe the electronic behavior of a copper oxide material, or cuprate, that conducts electricity with perfect efficiency at relatively high temperatures.

These so-called high-temperature superconductors are a bustling field of research because they could give rise to zero-waste transmission of energy, energy-efficient transportation systems and other futuristic technologies, although no one knows the underlying microscopic mechanism behind high-temperature superconductivity yet. Whether QCPs exist in cuprates is also a hotly debated issue.

In experiments at the UK’s Diamond Light Source, the team chilled the cuprate to temperatures below 90 kelvins (minus 183 degrees Celsius), where it became superconducting. They focused their attention on what’s known as charge order — alternating stripes in the material where electrons and their negative charges are denser or more sparse.

The scientists excited the cuprate with X-rays and measured the X-ray light that scattered into the RIXS detector. This allowed them to map out how the excitations propagated through the material in the form of subtle vibrations, or phonons, in the material’s atomic lattice, which are hard to measure and require very high-resolution tools.

At the same time, the X-rays and the phonons can excite electrons in the charge order stripes, causing the stripes to fluctuate. Since the data obtained by RIXS reflects the coupling between the behavior of the charge stripes and the behavior of the phonons, observing the phonons allowed the researchers to measure the behavior of the charge order stripes, too.

What the scientists expected to see is that when the charge order stripes grew weaker, their excitations would also fade away. “But what we observed was very strange,” Lee said. “We saw that when charge order became weaker in the superconducting state, the charge order excitations became stronger. This is a paradox because they should go hand in hand, and that’s what people find in other charge order systems.”

He added, “To my knowledge this is the first experiment about charge order that has shown this behavior. Some have suggested that this is what happens when a system is near a quantum critical point, where quantum fluctuations become so strong that they melt the charge order, much like heating ice increases thermal vibrations in its rigid atomic lattice and melts it into water. The difference is that quantum melting, in principle, occurs at zero temperature.” In this case, Lee said, the unexpectedly strong charge order excitations seen with RIXS were manifestations of those quantum fluctuations.

Lee said the team is now studying these phenomena at a wider range of temperatures and at different levels of doping — where compounds are added to change the density of freely moving electrons in the material — to see if they can nail down exactly where the quantum critical point could be in this material.

Thomas Devereaux, a theorist at SIMES and senior author of the report, noted that many phases of matter can be intertwined in cuprates and other quantum materials.

“Superconducting and magnetic states, charge order stripes and so on are so entangled that you can be in all of them at the same time,” he said. “But we’re stuck in our classical way of thinking that they have to be either one way or another.”

Here, he said, “We have an effect, and Wei-Sheng is trying to measure it in detail, trying to see what’s going on.”