Defining the role of GTP cyclohydrolase 1/dihydrobiopterin in cold-induced longevity

• Applicant: Professor Dr. David Vilchez
• Subject Area: Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540723900

Aging is associated with alterations in numerous cellular pathways, leading to a loss of tissue integrity. The gradual deterioration of somatic tissues such as the intestine, muscle, and nervous system contributes to distinct metabolic and neurodegenerative disorders. Aging also decreases germline function, reducing fertility across species from invertebrates to mammals. Growing evidence demonstrates that aging is a regulated process that can be delayed through mechanisms conserved in evolution. Thus, defining longevity pathways to slow down aging can greatly benefit our ever-aging society. To this end, here we will focus on moderate cold temperature, which is one of the most effective interventions to prolong lifespan. In previous work, we demonstrated that cold temperature not only extends lifespan, but also prolongs fertility and delays disease-related protein aggregation. Thus, a better understanding of cold-induced changes can lead to potential targets that may be manipulated at normal temperature, thereby improving the quality of life during aging and preventing diseases. It is worth noting that overexpression of cold-induced proteins, such as the proteasome activator PSME3, has beneficial effects at normal temperature. While our previous findings have important implications for understanding aging, the need to overexpress these proteins to achieve beneficial effects at normal temperatures might limit their therapeutic potential. To overcome this limitation, here we will focus on cold-induced metabolites. These small molecules can have various functions, such as fuel provision, structural support, and enzyme modulation. In fact, some metabolites act as cofactors required for enzyme activity. In addition, they can serve as signaling molecules within cells and for intercellular communication. We hypothesize that identifying cold-induced metabolites can lead to the discovery of small molecules that extend longevity, prolong fertility and prevent diseases. Consequently, exogenous application of these metabolites may produce similar beneficial effects at normal temperatures. In our preliminary work, we integrated metabolomics with proteomics to define cold-induced pathways. Notably, we identified the metabolite dihydrobiopterin (BH2) and its rate-limiting enzyme GTP cyclohydrolase 1 (CAT-4/GCH1) as potential mechanisms of cold-induced longevity. In this proposal, we will determine the impact of the CAT-4/BH2 pathway on cold-induced longevity and whether exogenous application of BH2 delays aging at normal temperature (Aim 1). Then, we will define the mechanisms by which the CAT-4/BH2 pathway regulates cold-induced effects on organismal aging (Aim 2). Finally, we will assess whether application of exogenous BH2 can delay disease-related protein aggregation at normal and warmer temperatures in C. elegans and human cell models (Aim 3).

• DFG Programme: Research Grants