David Vilchez

Faculty of Medicine

Prof. Dr. David Vilchez

Principal Investigator
Head of Research Area 1

+49 221 478 84172

dvilchez[at]uni-koeln.de

Website

TheVilchezLab

Curriculum Vitae

Research Areas

Proteostasis of Aging and Stem Cells

By 2050, the global population over the age of 80 will triple. Thus, research for improving the quality of life at an older age can be of enormous benefit for our society. To address this challenge, we propose a series of innovative approaches based on a combination of stem cell research, genetic experiments in C. elegans, and state-of-the-art proteomics.

Research Focus

Human neurons from iPS cells derived from ALS patients: neurons (in green, marked is MAP2 = microtubule associated protein), dying cells (in red), cell nuclei (blue). Right picture: 37 degrees Celsius, Left picture: 36 degrees Celsius

In our laboratory, we aim to investigate the intricate relationships between proteostasis, cell non-autonomous responses, and environmental/organismal interactions in stem cell function, aging, and age-related diseases. Our goal is to uncover mechanisms that can extend healthspan and prevent multiple age-related diseases. To this end, we use an innovative approach that integrates cutting-edge proteomics, iPSC-based disease modeling, genetic studies in the model organism C. elegans, and plant research.

Our research has many potential outcomes and our findings can have a big impact in several fields such as proteostasis, stem cell research, cell reprogramming, cell therapy, aging and age-related diseases.

Our Goals

On top: mitochondria in healthy muscle of C. elegans. Bottom: fragmented mitochondria in the muscle after induction of aggregation of proteins in the germline.

Prof. Vilchez and his coworkers aim to define the mechanisms that maintain proteostasis in stem cells and organisms. Their final goal is to apply this knowledge for the discovery of pharmaceutical targets to ameliorate Alzheimer’s, Parkinson’s or Huntington’s disease.

In previous work, the laboratory made important discoveries to understand stem cell function, proteostasis and aging:

The immortal stem cell versus neuron approach to prevent disease: Since human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) are considered to be immortal in culture, we hypothesized that these cells can provide a novel paradigm to study the regulation of proteostasis and its failure during aging. In our previous work, we demonstrated that hESCs/iPSCs have unique proteostasis mechanisms that can be applied in somatic cells to delay aging and neurodegenerative diseases such as Huntington’s disease.
Delaying aging and disease through ubiquitin modifications: We have discovered a remodeling of the ubiquitinated proteome during aging, which was ameliorated by longevity paradigms such as dietary restriction and reduced insulin We discovered that regulatory proteins that escape proteasomal degradation with aging contribute to the development of age-related disorders that involve protein aggregation.

The germline regulates aging and proteostasis of neurons and muscle cells: In previous work, we discovered that removalof the germline enhances proteostasis in somatic tissues, a process that extends lifespan. More recently, we found that accumulation of protein aggregates in the germline triggers long-range Wnt signals that promotes somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington’s and ALS. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.
Defining cold-induced changes to prevent aging: Moderate cold temperature is one of the most effective interventions to prolong lifespan. Our previous work revealed that cold temperature not only prolongs lifespan but also maintenance of germline stem cells and subsequent fertility. More recently, we demonstrated that cold temperature also prevents disease-related protein aggregation in C. elegans and human iPSC-derived neurons.
Defining plant proteostasis to prevent human age-related diseases: Plants exhibit a remarkable ability to withstand stress and many species display considerable longevity. Despite facing adverse environmental conditions such as heat stress, plants manage to grow and survive without the ability to move. In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington’s disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. We found that chloroplast proteostasis components prevent aggregation of human polyQ-expanded huntingtin expressed in plants. Indeed, ectopic expression of the chloroplast stromal processing peptidase (SPP) in C. elegans and human cell models of Huntington’s disease prevents pathological aggregation and subsequent neuronal deficits.

During the next years, the laboratory will continue working on these research areas to define novel regulators of aging and proteostasis, with the aim to delay age-related diseases.

Key Publications

Lee, H.J., Alirzayeva, H., Koyuncu, S., Khodakarami, A., Noormohammadi, A., and Vilchez, D.(2023).Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes. Nature Aging 3: 545-566. DOI: 10.1038/s43587-023-00383-4
Llamas, E., Koyuncu, S., Lee, H.J., Wehrmann, M., Gutierrez-Garcia, R., Dunken, N., Charura, N., Torres-Montilla, S., Schlimgen, E., Mandel, A.M., Boelen-Theile, E., Grossbach, J., Wagle, P., Schermer, B., Benzing, T., Beyer, A., Pulido, P., Rodriguez-Concepcion, M., Zuccaro, A., and Vilchez, D. (2023).In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation. Nature Aging 3: 1345-1357 (cover). DOI: 10.1038/s43587-023-00502-1
Koyuncu, S., Loureiro, R., Lee, H.J., Wagle, P., Krueger, M., and Vilchez, D. (2021). Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature 596, 285-290. DOI: 10.1038/s41586-021-03781-z
Calculli, G., Lee, H.J., Shen, K., Pham, U., Herholz, M., Trifunovic, A., Dillin, A., and Vilchez, D.(2021). Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans. Science Advances 7, eabg3012. DOI: 10.1126/sciadv.abg3012
Lee, H.J., Noormohammadi, A., Koyuncu, S., Calculli, G., Simic, M.S., Herholz, M., Trifunovic, A., and Vilchez, D. (2019). Prostaglandin signals from adult germline stem cells delay somatic ageing of Caenorhabditis elegans. Nature Metabolism 1, 790-810 (cover). DOI: 10.1038/s42255-019-0097-9.