For many, the idea of living forever is unappealing. Even if good health is thrown into the bargain, interest in immortality remains ambivalent. But what if we could stay healthy right up until a timely death? Recent work from the Houseley lab suggests that, at least in budding yeast, healthspan can be extended without also extending lifespan. In a 2023 paper, they showed that a galactose diet suppresses senescence (i.e., loss of fitness) in aging yeast without extending their lifespan. In a recent preprint, they claim to achieve the same effect in yeast on a normal (glucose-rich) diet by activating AMPK while simultaneously preventing AMPK-mediated repression of fatty acid synthesis.

Here’s an intriguing sentence from the discussion (that, however, might benefit from being split into two sentences): “It is not too surprising that issues arise when AMPK is ectopically activated on high glucose given that AMPK is a central energy regulator that evolved to manage metabolism under low nutrient conditions, and it is perhaps more surprising that a single point mutation largely corrects these issues, providing optimism that the benefits of AMPK activation could also be maximised in higher eukaryotes.”

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Re-engineering of acetyl coenzyme A metabolism prevents senescence in budding yeast
bioRxiv, March 2025
From the lab of Jon Houseley.

Snippet by Katrina Woolcock.

Image credit: Figure 5 from Hadj-Moussa et al. linked above (CC-BY).

Some scientific articles are must-reads because of what the scientists accomplished or developed. Some scientific articles are must-reads because of what the scientists discovered. And then some scientific articles are must-reads for both reasons. Here’s an example from a few weeks ago. A group of scientific teams in China worked for years to develop a vehicle that could carry researchers to Hell and back, so they could bring back dirt and animals from Hell. Then they went to Hell, brought back soil, and extensively analyzed the microbial communities in Hell. They discovered that these communities are dramatically distinct from communities in the nearby ocean, and thereby illuminated surprising evolutionary trajectories of the microbial organisms that inhabit Hell.

I’m overdramatizing. The scientists didn’t visit Hell. They visited Hades, which is mythologically different. Okay fine, their inspiring and successful mission went to the hadal zone of the ocean (named, aptly, after the dark underworld of Hades), specifically to the mysterious famous chasms of the Mariana Trench that are nearly 11,000 meters (about 6.8 miles) deep. Somehow, amazingly, microbes can live and reproduce and evolve at that depth. Maybe they’re even happy.

Here is the abstract from their Cell paper. I think it’s a bit too understated, but it is inspiring nonetheless, and we can all use some inspiration right now.

Systematic exploration of the hadal zone, Earth’s deepest oceanic realm, has historically faced technical limitations. Here, we collected 1,648 sediment samples at 6–11 km in the Mariana Trench, Yap Trench, and Philippine Basin for the Mariana Trench Environment and Ecology Research (MEER) project. Metagenomic and 16S rRNA gene amplicon sequencing generated the 92-Tbp MEER dataset, comprising 7,564 species (89.4% unreported), indicating high taxonomic novelty. Unlike in reported environments, neutral drift played a minimal role, while homogeneous selection (HoS, 50.5%) and dispersal limitation (DL, 43.8%) emerged as dominant ecological drivers. HoS favored streamlined genomes with key functions for hadal adaptation, e.g., aromatic compound utilization (oligotrophic adaptation) and antioxidation (high-pressure adaptation). Conversely, DL promoted versatile metabolism with larger genomes. These findings indicated that environmental factors drive the high taxonomic novelty in the hadal zone, advancing our understanding of the ecological mechanisms governing microbial ecosystems in such an extreme oceanic environment.

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Microbial ecosystems and ecological driving forces in the deepest ocean sediments

In Cell, 6 March 2025 (this issue of Cell includes three papers and a Commentary piece on the hadal ocean research)
From the groups of Xiang Xiao, Weishu Zhao, Wei-Jia Zhang, Mo Han, Xun Xu, and Shanshan Liu

Snippet by Stephen Matheson

Image credit: graphical abstract from Xiao et al. linked above (CC-BY)

Can you name a neglected tropical disease (NTD)? I would guess that most biologists can, or can at least make some accurate guesses. But by definition, these are maladies that don’t get adequate attention and resources, and so it is likely that many scientists are unaware of the current roster of NTDs. A new and exciting paper at Nature taught me that snakebite (envenoming, to be precise) is in fact a devastating NTD, with a heartbreaking death toll due in large part to the lack of effective and affordable* treatments. More importantly, the paper reports on how the authors discovered some simple and effective therapeutics with significant potential to make a difference. Their abstract is, to me, a tour de force of scientific writing that is straightforward and inspiring. (My favorite sentence suggests that we can “democratize therapeutic discovery.”) Here it is with references removed for readability:

Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity. At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs. Here we used deep learning methods to de novo design proteins to bind short-chain and long-chain α-neurotoxins and cytotoxins from the 3FTx family. With limited experimental screening, we obtained protein designs with remarkable thermal stability, high binding affinity and near-atomic-level agreement with the computational models. The designed proteins effectively neutralized all three 3FTx subfamilies in vitro and protected mice from a lethal neurotoxin challenge. Such potent, stable and readily manufacturable toxin-neutralizing proteins could provide the basis for safer, cost-effective and widely accessible next-generation antivenom therapeutics. Beyond snakebite, our results highlight how computational design could help democratize therapeutic discovery, particularly in resource-limited settings, by substantially reducing costs and resource requirements for the development of therapies for neglected tropical diseases.

*In a world in which a corrupt oligarch can buy the executive branch of the US government using less than 1% of his wealth, let’s not pretend that the main problem is “affordability.” The authors describe several other reasons why current approaches are badly inadequate.

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De novo designed proteins neutralize lethal snake venom toxins
In Nature, 15 January 2025
From the groups of Timothy P. Jenkins and David Baker.

Snippet by Stephen Matheson

Image credit: Figure 1 from Vázquez Torres et al. linked above (CC-BY-NC-ND).

Viruses and other parasites are famously adept at trickery and manipulation. Think of your favorite creepy example of that, then consider a new paper about a virus so devious that it might become your new favorite (if you’re into that sort of thing). The article in Science Advances reveals the strategic brilliance of the tomato yellow leaf curl virus (TYLCV), which infects tomato plants with the help of its vector, a whitefly. Step 1 of the evil plan: the virus induces the plant to make a protein that attracts the whitefly. Nice move, but now there’s a new problem, which is that flies are attracted to already-infected plants. Our scheming virus wants the flies to carry it to uninfected plants. So, step 2: the virus inhibits the fly’s olfactory receptor that makes it home in on that attractive signal. At first this might seem like the virus is undoing its work, but think about it: now only uninfected flies will be attracted to the infected plants. That means more infected flies, which now no longer prefer the infected plants! [virus voice] MWAAAHAHAHAHA.

Here the authors nicely summarize the evil plan, using vivid language that highlights the strategic brilliance of this devastating pathogen:

These results reveal a unique two-tiered pull-push strategy in which TYLCV maximizes transmission by modulating terpene release from host plants as well as the olfactory system of its vector.

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A plant virus manipulates both its host plant and the insect that facilitates its transmission
In Science Advances, 28 February 2025
From the groups of Ted Turlings, Wen Xie, and Youjun Zhang.

Snippet by Stephen Matheson

Image credit: Figure 6 from Liang et al. linked above (CC-BY-NC-ND).