Colder Temperatures May Help Clear Alzheimer’s-Linked Misfolded Proteins

Lower temperatures have been known to increase longevity for over half a century, but the mechanisms underpinning this increased longevity have remained unclear.

Now, scientists have unraveled a mechanism that underpins increased longevity in worms, and shown it to have an effect on human cells.

Published in Nature Aging, a study by researchers based in Cologne, Germany has shown that at lower temperatures activity of a molecule responsible for breaking down protein aggregates is increased.

This activity could play a role in reducing the prevalence of harmful misfolded proteins, which are thought to play a role in the development of a number of conditions associated with aging, such as Alzheimer’s disease.

A few decades ago it was believed that aging was due to the accumulation of toxins from oxidation. 

This changed in the 90s, when it was discovered that a genetic model organism, C. elegans—a type of worm—had increased longevity at lower temperatures, explained lead author of the study Professor David Vilchez, principal investigator at the CECAD Research Center, University of Cologne.

“We decided to focus on cold temperature because it was actually discovered over 50 years ago, even more, that cold temperature can prolong longevity […] So, that was discovered in flies, Drosophila, demonstrated in C. elegans, also fish, and most recently was also demonstrated in mice. So, it actually is one of the most effective mechanisms to prolong longevity across many different species,” he said.

It wasn’t until it was discovered that the process was genetically regulated, in 2012 in a paper published in Cell, that the potential for this discovery to shed light on the mechanisms behind aging became apparent.

To investigate the effect of cold temperatures on worms, researchers bred worms at 25ºC and then moved them to environments set at 15ºC, 20ºC, and 25ºC. They observed that at the lower temperatures, there was a significant increase in the activity of the molecule responsible for clearing misfolded proteins in the cell.

In order to investigate this further, researchers used worms that had their genomes altered to replicate key features of two human diseases associated with aging, Huntington’s disease and amyotrophic lateral sclerosis (ALS). 

It was possible to create these models easily as both are caused by changes in a single gene, unlike conditions such as Alzheimer’s disease which are multifactorial.

They found that the same mechanism was induced at low temperatures and prevented aggregation of misfolded proteins in worm models of Huntington’s disease and ALS.

People with Huntington’s disease have too many repeats in a part of their Huntingtin gene, which codes for a specific amino acid, which is the building block of proteins.

In addition to finding that cold temperatures promote the clearance of misfolded proteins in worms, researchers also found reducing the temperature of human cells to 36ºC, resulted in the same cell mechanism being induced.

However, the reverse was found at 35ºC, suggesting that moderate cold temperatures are optimal to induce this mechanism in human cells. 

Overexpression of the genes controlling this mechanism was also found to induce this pathway, which promoted an increase in the molecules that clear misfolded proteins in the cell.

While it is a long way off, Prof. Vilchez said that identifying a molecule in the pathway that could be used as a drug target could mean the findings from this study could help to guide future research into treating neurodegenerative disorders caused by protein misfolding.

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Sources:

Lee, H.J., Alirzayeva, H., Koyuncu, S. et al. Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes. Nat Aging (2023). https://doi.org/10.1038/s43587-023-00383-4

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