Cold activates a signaling chain that extends lifespan in worms

Moderately cold temperatures extend lifespan across multiple species, but the precise mechanisms remained unclear. The researchers worked with the nematode worm Caenorhabditis elegans and identified a chain of molecular signals activated by cold.

BH2 as a transport molecule between tissues

Cold temperature increases the activity of an enzyme called CAT-4, which produces a molecule called BH2. BH2 is made in muscle tissue and then transported to other tissues, including the gut and nerve cells. There it is converted into an active form called BH4, a helper molecule for an enzyme that makes tyrosine, an amino acid essential for many cellular functions.

The researchers found that this process extends lifespan and also prevents proteins from clumping together in nerve cells. Protein clumping in nerve cells is associated with conditions such as Huntington's disease and ALS. In human cells in the lab, adding BH2 or tyrosine reduced the clumping of proteins linked to those diseases.

Hormesis: mild stress, large effect

This mechanism is an example of hormesis, where a mild stressor, here cold, prompts cells to activate repair and protection processes. Notably, increasing BH2 production specifically in muscle was sufficient to extend lifespan and reduce protein clumping in distant tissues, even at normal temperature.

The researchers emphasize differences between cold hormesis and other forms such as calorie restriction. Different stressors activate partly different biological routes, which makes it difficult to translate a therapy mimicking one type of hormesis into another.

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