New drug-like molecule extends lifespan, ameliorates pathology in worms and boosts function in mammalian muscle cells

Having healthy mitochondria, the organelles that produce energy in all our cells, usually portends a long healthy life whether in humans or in C. elegans, a tiny, short-lived nematode worm often used to study the aging process. Researchers at the Buck Institute have identified a new drug-like molecule that keeps mitochondria healthy via mitophagy, a process that removes and recycles damaged mitochondria in multicellular organisms. The compound, dubbed MIC, is a natural compound that extended lifespan in C. elegans, ameliorated pathology in neurodegenerative disease models of C. elegans, and improved mitochondrial function in mouse muscle cells. Results are published in the November 13, 2023, edition of Nature Aging.

The impact of mitochondrial dysfunction in age-related disease

Defective mitophagy is implicated in many age-related diseases. It's tied to neurodegenerative disorders such as Parkinson's and Alzheimer's; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field.

What's MIC?

MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance.

A new mechanism of action in mitophagy

The project started in a mouse model of Parkinson's disease where researchers in the laboratory of Julie Andersen, PhD, a senior author of the paper, were looking at known enhancers of mitophagy, including rapamycin. "Co-author Shankar Chinta, PhD, started screening natural compounds in neuronal cells and MIC came up as a major hit," she said. "Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB."

In an effort spearheaded by Andersen and research scientist Manish Chamoli, PhD, lead author of the study, researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells.

"This paper helps support the overall notion of TFEB being a key autophagy regulator that extends lifespan, "said Buck professor and Chief Scientific Officer Malene Hansen, PhD, who collaborated on the paper. She added, "Mitophagy is a selective and very significant form of autophagy. The field has recognized TFEB as a player when it comes to quality control in mitochondria. This study provides a possible translational route to induce mitophagy in a TFEB-dependent fashion."

A link to the brain/gut connection

Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. This provided Andersen with the clue needed to piece together MIC's potential mechanism of action in the latter. "This study provides another piece of the puzzle when it comes to understanding the brain/gut connection in terms of health and disease," said Andersen.

FXR is regulated by bile salts which are formed in the gut microbiome. "The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome," said Chamoli. "If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration," he said, noting that experiments are underway to explore neuronal FXR as a therapeutic target for Alzheimer's disease as part of a jointly funded grant shared by the Andersen and Lithgow labs.

MIC as a general geroprotective therapeutic

"There's a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we don't have enough molecules in the pipeline," said Gordon Lithgow, PhD, Buck Professor and Vice President of Academic Affairs and senior co-author. "MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule."

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Life on Earth didn't arise as described in textbooks

No, oxygen didn't catalyze the swift blossoming of Earth's first multicellular organisms. The result defies a 70-year-old assumption about what caused an explosion of oceanic fauna hundreds of millions of years ago.

Between 685 and 800 million years ago, multicellular organisms began to appear in all of Earth's oceans during what's known as the Avalon explosion, a forerunner era of the more famed Cambrian explosion. During this era, sea sponges and other bizarre multicellular organisms replaced small single-celled amoeba, algae and bacteria, which until then, had had run of the planet for more than 2 billion years.

Up until now, it was believed that increased oxygen levels triggered the evolutionary arrival of more advanced marine organisms. This is being disproved by University of Copenhagen researchers working together with colleagues from Woods Hole Oceanographic Institute, the University of Southern Denmark and Lund University, among others.

By studying the chemical composition of ancient rock samples from an Omani mountain range, the researchers have been able to "measure" oxygen concentrations in the world's oceans from when these multicellular organisms appeared. Defying expectations, the result shows that Earth's oxygen concentrations had not increased. Indeed, levels remained 5-10 times lower than today, which is roughly how much oxygen there is at twice the height of Mount Everest.

"Our measurements provide a good picture of what average oxygen concentrations were in the world's oceans at the time. And it's apparent to us that there was no major increase in the amount of oxygen when more advanced fauna began to evolve and dominate Earth. In fact, there was somewhat of a slight decrease," says Associate Professor Christian J. Bjerrum, who has been quantifying the conditions surrounding the origin of life for the past 20 years.

Revises our understanding of life's origins

The new result puts to rest a 70-year research story that advances the centrality of higher oxygen concentrations in the development of more advanced life on our planet.

"The fact that we now know, with a high degree of certainty, that oxygen didn't control the development of life on Earth provides us with an entirely new story about how life arose and what factors controlled this success," says the researcher, adding:

"Specifically, it means that we need to rethink a lot of the things that we believed to be true from our childhood learning. And textbooks need to be revised and rewritten."

There remains much that the researchers don't know, as well as and a plethora of controversy. Therefore, Bjerrum hopes that the new result can spur other researchers around the world to reconsider their previous results and data in a new light.

"There are many research sections around the world, including in the United States and China, that have done lots of research on this topic, whose earlier results may shed important new details if interpreted on the basis that oxygen didn't drive the development of life," says the researcher.

Absence of oxygen may have aided development

So, if not extra oxygen, what triggered the era's explosion of life? Perhaps the exact opposite, explains the researcher:

"It's interesting that the explosion of multicellular organisms occurs at a time with low concentrations of atmospheric and oceanic oxygen. That indicates that organisms benefited from lower levels of oxygen and were able to develop in peace, as the water chemistry protected their stem cells naturally," says Christian J. Bjerrum.

According to the researcher, the same phenomenon has been studied in cancer research, in the stem cells of humans and other animals. Here, colleagues at Lund University observed that low oxygen levels are crucial for keeping stem cells under control until an organism decides that the cell ought to develop into a specific type of cell, such as a muscle cell.

"We know that animals and humans must be able to maintain low concentrations of oxygen in order to control their stem cells, and in so doing, develop slowly and sustainably. With too much oxygen, the cells will develop, and in the worst case, mutate wildly and perish. It is far from inconceivable that this mechanism applied back then," concludes Christian J. Bjerrum.

Fossils from Oman

In the new study, the researchers analysed rock samples from, among other places, the Oman Mountains in northern Oman. While quite high and very dry today, the mountains were on the seabed during the Avalon explosion's rapid blossoming of organism diversity.

The researchers have had their findings confirmed in fossils from three different mountain ranges around the world: the Oman Mountains (Oman), Mackenzie Mountains (NW Canada) and the Yangtze Gorges area of South China.

Over time, clay and sand from land are washed into the sea, where they settle into layers on the seabed. By going down through these layers and examining their chemical composition, researchers can get a picture of ocean chemistry at a particular geologic time.

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Sponges 'sneeze' to dispose of waste

Sneezing out mucus may be one of the oldest ways for organisms to get rid of unwanted waste. A group of researchers found that sponges, one of the oldest multicellular organisms in existence, "sneeze" to unclog their internal filter systems that they use to capture nutrients from the water. Additionally, authors find that other animals who live with the sponges use their mucus as food. Their findings are publishing August 10 in the journal Current Biology.

"Our data suggest that sneezing is an adaptation that sponges evolved to keep themselves clean," says Jasper de Goeij, a marine biologist at the University of Amsterdam and the senior author of the paper.

While the field has known about this behavior for years, the authors of this paper show that these sneezes get rid of materials the sponges cannot use. "Let's be clear: sponges don't sneeze like humans do. A sponge sneeze takes about half an hour to complete. But both sponge and human sneezes exist as a waste disposal mechanism," says de Goeij.

Sponges gather food for themselves by filtering out organic matter from the water. They draw in and eject water from different openings, and sometimes the sponges will suck in particles that are too big. "These are sponges; they can't just walk to somewhere else when the water around them gets too dirty for them to handle," says de Goeij. This is when the "sneezing" mechanism comes in handy.

In videos that the authors included in the paper, you can see the water inlets slowly release mucus, and the mucus will accumulate at the surface of the sponge. Occasionally, sponge tissue will contract and push the waste-containing mucus into the surrounding water.

While the mucus may be waste to sponges, the fishes who live around them think otherwise. "We also observed fish and other animals feeding off of the sponge mucus as food," says Niklas Kornder, the first author of the study and a doctoral researcher in de Goeij's research group. "Some organic matter exists in the water surrounding the coral reef, but most of it is not concentrated enough for other animals to eat. Sponges transform this material into eatable mucus," says Kornder.

The paper recorded "sneezing" behavior in two species of sponges, the Caribbean tube sponge Aplysina archeri and another Indo-Pacific species of the genus Chelonaplysilla. "We actually think that most, if not all, sponges sneeze. I've seen mucus accumulate on different sponges while diving and in pictures taken by other scientists for other purposes," says Kornder.

"Our findings highlight opportunities to better understand material cycling in some of the most ancient Metazoans," say the authors in the paper.

There are still many aspects about sponge "sneezes" that remain open questions. "In the videos, you can see that the mucus moves along defined paths on the surface of the sponge before accumulating. I have some hypotheses, but more analysis is needed to find out what is happening," says Kornder.

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How multi-celled animals developed

Microscopic life.

Scientists at The University of Queensland have upended biologists' century-old understanding of the evolutionary history of animals.

Using new technology to investigate how multi-celled animals developed, their findings revealed a surprising truth.

Professor Bernie Degnan said the results contradicted years of tradition.

"We've found that the first multicellular animals probably weren't like the modern-day sponge cells, but were more like a collection of convertible cells," Professor Degnan said.

"The great-great-great-grandmother of all cells in the animal kingdom, so to speak, was probably quite similar to a stem cell.

"This is somewhat intuitive as, compared to plants and fungi, animals have many more cell types, used in very different ways -- from neurons to muscles -- and cell-flexibility has been critical to animal evolution from the start."

The findings disprove a long-standing idea: that multi-celled animals evolved from a single-celled ancestor resembling a modern sponge cell known as a choanocyte.

"Scattered throughout the history of evolution are major transitions, including the leap from a world of microscopic single-cells to a world of multi-celled animals," Professor Degnan said.

"With multicellularity came incredible complexity, creating the animal, plant, fungi and algae kingdoms we see today.

"These large organisms differ from the other more-than-99-per-cent of biodiversity that can only be seen under a microscope."

The team mapped individual cells, sequencing all of the genes expressed, allowing the researchers to compare similar types of cells over time.

Fellow senior author Associate Professor Sandie Degnan said this meant they could tease out the evolutionary history of individual cell types, by searching for the 'signatures' of each type.

"Biologists for decades believed the existing theory was a no-brainer, as sponge choanocytes look so much like single-celled choanoflagellates -- the organism considered to be the closest living relatives of the animals," she said.

"But their transcriptome signatures simply don't match, meaning that these aren't the core building blocks of animal life that we originally thought they were.

"This technology has been used only for the last few years, but it's helped us finally address an age-old question, discovering something completely contrary to what anyone had ever proposed."

"We're taking a core theory of evolutionary biology and turning it on its head," she said.

"Now we have an opportunity to re-imagine the steps that gave rise to the first animals, the underlying rules that turned single cells into multicellular animal life."

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Discovery of the oldest evidence of mobility on Earth

Previously, the oldest traces of this kind found dated to approximately 600 million years ago: the Ediacaran period, also characterized by a peak in dioxygen and a proliferation in biodiversity. Scale bar: 1 cm.

An international and multi-disciplinary team coordinated by Abderrazak El Albani at the Institut de chimie des milieux et matériaux de Poitiers (CNRS/Université de Poitiers) has uncovered the oldest fossilised traces of motility. Whereas previous remnants were dated to 570 million years ago, this new evidence is 2.1 billion years old. They were discovered in a fossil deposit in Gabon, where the oldest multicellular organisms have already been found. These results appear in the 11 February 2019 edition of PNAS.

A few years ago, geologist Abderrazak El Albani and his team at the Institut de chimie des milieux et matériaux de Poitiers (CNRS/Université de Poitiers) discovered the oldest existing fossils of multicellular organisms in a deposit in Gabon. Located in the Franceville Basin, the deposit allowed scientists to re-date the appearance of multicellular life on Earth to 2.1 billion years -- approximately 1.5 billion years earlier than previously thought (600 million). At the time, researchers showed that this rich biodiversity co-occurred with a peak in dioxygenation of the atmosphere, and developed in a calm and shallow marine environment.

In this same geological deposit, the team has now uncovered the existence of fossilised traces of motility. This shows that certain multicellular organisms in this primitive marine ecosystem were sophisticated enough to move through its mud, rich in organic matter.

The traces were analysed and reconstructed in 3D using X-ray computed micro-tomography, a non-destructive imaging technique. The more or less sinuous structures are tubular, of a generally consistent diameter of a few millimetres, and run through fine layers of sedimentary rock. Geometrical and chemical analysis reveals that they are biological in origin and appeared at the same time the sediment was deposited.

The traces are located next to fossilised microbial biofilms, which formed carpets between the superficial sedimentary layers. It is plausible that the organisms behind this phenomenon moved in search of nutritive elements and the dioxygen, both produced by cyanobacteria.

What did these living elements look like? Though difficult to know for certain, they may have been similar to colonial amoebae, which cluster together when resources become scarce, forming a type of slug, which moves in search of a more favourable environment.

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