Moderate cold increases BH2 levels in the muscle of the nematode C. elegans. The muscle is an important source of BH2 and acts as a metabolic hub.
Image Credit: © David Vilchez / CECAD
Scientific Frontline: Extended "At a Glance" Summary: Cold Temperatures, BH2, and Longevity
The Core Concept: Moderately cold temperatures activate a metabolic pathway involving the metabolite dihydrobiopterin (BH2), which delays aging and protects against age-related neurodegenerative diseases by preserving protein homeostasis.
Key Distinction/Mechanism: Muscle tissue acts as a central hub, synthesizing and releasing BH2, which is transported to other tissues to induce the production of the amino acid tyrosine, strengthening the cellular machinery responsible for maintaining functional proteins.
Major Frameworks/Components:
- Caenorhabditis elegans utilized as the primary in vivo model organism.
- Human cell models of Huntington's disease and amyotrophic lateral sclerosis (ALS) used for validation.
- Proteostasis (protein homeostasis) identified as the primary protective mechanism against protein misfolding.
- Supplementation of BH2 and tyrosine demonstrated protective effects independently of temperature changes.
Branch of Science: Molecular Biology, Gerontology, Metabolic Biochemistry
Future Application: The development of targeted therapies or supplements (such as BH2 or tyrosine) that mimic the life-extending and disease-preventing benefits of cold exposure without requiring actual changes in body temperature.
Why It Matters: This pathway offers a novel, organism-wide therapeutic target for treating age-associated neurodegenerative diseases characterized by the accumulation of misfolded or damaged proteins.
Scientists at the University of Cologne have identified a key metabolic pathway linking cold temperatures to longevity. The metabolite dihydrobiopterin (BH2) and muscle tissue play a central role in the beneficial effects of cold temperatures on longevity and protein homeostasis. This finding could help prevent certain age-related diseases in the future.
Moderately cold temperatures have proven to effectively extend lifespan and delay age-related decline in animals. However, how cold temperatures trigger these beneficial effects at the molecular level has remained largely unclear. In their study, the research team led by Professor David Vilchez at the CECAD Cologne Cluster of Excellence on Aging and Aging-Associated Diseases, the Center for Molecular Medicine Cologne (CMMC) at the University of Cologne, and University Hospital Cologne was able to decipher a signaling system that is regulated across different tissues by metabolites. Using Caenorhabditis elegans as a model organism, they demonstrated a link between cold temperatures, increased lifespan, and proteostasis—the maintenance of protein homeostasis. They found that muscle acts as a “central factory,” producing the metabolite dihydrobiopterin (BH2). BH2 is then transported to other tissues, where it is used to induce the production of the amino acid tyrosine. This metabolic pathway helps strengthen the cellular machinery responsible for maintaining functional proteins and preserving protein homeostasis. The study, “Cold activates a BH2 metabolic network promoting longevity and proteostasis,” has been published in the journal Nature.
As part of their study, the scientists used the nematode C. elegans as a model organism and further validated their findings in human cell models of Huntington’s disease and amyotrophic lateral sclerosis (ALS). Both are age-associated neurodegenerative diseases in which the accumulation of misfolded or damaged proteins is a major feature.
“We are excited to show that mildly cold temperatures trigger significant production of a specific metabolite, BH2, which is synthesized, stored, and subsequently released by muscle tissue. BH2 then goes to other parts of the body, where it helps to maintain protein homeostasis and contributes to tissue health during aging,” explains principal investigator David Vilchez. “These findings suggest that specifically targeting a single tissue, such as muscle, could provide organism-wide protection. This opens up new avenues for therapeutic approaches.”
Building on previous studies of cold temperatures, the researchers also asked whether the beneficial effects of cold temperatures could be reproduced by supplementing the metabolites identified in their study. Remarkably, administration of both BH2 and tyrosine was sufficient to produce a protective effect in C. elegans, as well as in the cell cultures, suggesting that these metabolites can reproduce some of the beneficial effects of cold.
“We were genuinely surprised to find that the supplementation significantly extended lifespan, even at standard and warmer temperatures. Further experiments on human cells encourage us to look for treatments that mimic the beneficial effects of cold without requiring changes in body temperature.”
It is still far too early, at the current state of research, to develop a “pill” that replicates the longevity-promoting effects of cold temperatures. However, the results of the study do provide a good starting point for further research into metabolite-based treatment options for conditions such as Huntington’s disease and ALS. The project was carried out in collaboration with the laboratories of Professor Thorsten Hoppe and Professor Christian Frezza at the CECAD Cluster of Excellence.
Published in journal: Nature
Title: Cold activates a BH2 metabolic network promoting longevity and proteostasis
Authors: Hyun Ju Lee, Cansu Doğan, Seda Koyuncu, Markus Wehrmann, Murat Artan, Dunja Petrovic, Rute Loureiro, Amit Kumar Sahu, Joana Schnubel, Pavel Grobushkin, Dimitrios Prymidis, Theodoros Georgomanolis, Agnieszka Sokol, Ming Yang, Thorsten Hoppe, Christian Frezza, and David Vilchez
Source/Credit: University of Cologne
Edited by: Scientific Frontline
Reference Number: mbio102226_01