Cold extends lifespan in C. elegans partly through muscle-derived BH2: overproducing an enzyme for its synthesis only in muscle also extended lifespan at 20 and 25 °C

Cold extends lifespan in C. elegans partly through muscle-derived BH2: overproducing an enzyme for its synthesis only in muscle also extended lifespan at 20 and 25 °C

On 21 October, David Vilchez's group at the University of Cologne published a study in Nature. The authors conclude that, in the cold, worm muscles produce dihydrobiopterin (BH2) and release it for use by other tissues. Those tissues convert it into BH4, an enzyme cofactor needed to synthesize the amino acid tyrosine. In human cells, BH2 reduced the aggregation of mutant proteins associated with two neurological diseases.

Adult C. elegans live longer at 15 °C than at 20 °C: across experiments, mean adult lifespan was 35–76 % longer. Slower metabolism has been used to explain this effect, but the worm also responds actively to cold. In 2023, Vilchez's group showed that cold increases the activity of proteasomes, complexes that break down damaged proteins.

The signal coordinating this response across tissues remained to be identified. The authors proposed that it was a small molecule that could spread rapidly and whose effects could be reproduced without cold exposure. In two experiments, levels of 45 substances increased at 15 °C compared with 20 and 25 °C, and BH2 showed one of the largest increases. Among proteins, CAT-4, the enzyme that initiates BH2 synthesis, also increased. The body transports the unstable molecule BH4 between tissues as BH2, an inactive but stable form.

When the authors suppressed CAT-4 production in adult worms, the lifespan extension from cold exposure decreased, while lifespan at 20 and 25 °C was unchanged. CAT-4 is normally produced mainly in the intestine, but cold also induces its production in muscle. Suppressing CAT-4 only in muscle reduced the lifespan extension from cold exposure; suppressing it in the intestine, neurons, skin or germ cells had no such effect. Suppressing the enzyme that converts BH2 into BH4 reduced this extension when targeted to neurons, the intestine or germ cells, but not muscle. Vilchez explained to ORF Wissen:

The muscles themselves do not use BH2 at all. They produce and release it, and the intestine or nerve cells then take it up.

Worms take up BH2 poorly when it is added to their growth medium. It slightly extended lifespan at 15 °C but had no effect at 20 °C. The authors therefore increased BH2 synthesis genetically: worms that overproduced CAT-4 only in muscle lived longer at 15, 20 and 25 °C. Of the worm's four BH4-dependent enzymes, only suppression of PAH-1, which converts phenylalanine into tyrosine, reduced the lifespan extension from cold exposure. Adding tyrosine to the growth medium extended lifespan at 15 and 20 °C and restored the extension in worms with suppressed CAT-4.

As worms age, the intestinal protein IFB-2 aggregates, the intestinal wall weakens, and bacteria penetrate it. Cold prevents this aggregation. Overproducing CAT-4 only in muscle had the same effect at 20 °C and reduced bacterial penetration, while suppressing PAH-1 caused aggregation to return.

In worms used to model Huntington's disease, overproducing CAT-4 in muscle reduced mutant protein aggregation in neurons. This protection was lost without the chaperonin TRiC/CCT, a complex that helps proteins fold correctly, and weakened without PSME-3, a proteasome activator. Without PAH-1, cold induced smaller increases in the production of PSME-3 and one component of the TRiC/CCT complex.

In human kidney cells, BH2 reduced the aggregation of mutant huntingtin, the protein associated with Huntington's disease, and mutant TDP-43 and FUS, proteins associated with amyotrophic lateral sclerosis. In motor neurons derived from human stem cells carrying a FUS mutation, BH2 and tyrosine reduced the proportion of dying cells.

Vilchez told Earth.com that BH4 is already given to some patients with phenylketonuria, who have impaired PAH enzyme function. PAH is the human counterpart of the worm's PAH-1.