Projects Offered
Dorothee Dormann René Ketting Anton Khmelinskii/Jan Padeken Edward Lemke Katja Luck_Comp Katja Luck_BAF Johannes Mayer_Activate Johannes Mayer_DCTraining Sandra Schick_Cond Sandra Schick_BAF1 Vincent ten Cate Ari Waisman/Ilgiz Mufazalov Andreas Walther Eva Wolf Shuqing XuMaintaining Proteostasis in Aging
1 PhD project offered in the IPP winter call 2026/2027
Scientific Background
The progressive deterioration of protein homeostasis (proteostasis) is a primary hallmark of aging. As organisms age, the functionality of the proteostasis network, comprised of molecular chaperones, the ubiquitin-proteasome system and autophagy, declines, leading to the accumulation of misfolded and aggregated proteins that compromise cellular viability. Proteostatic decline is not merely a consequence of aging but an early, causal event whereby loss of proteostasis precedes and predicts organismal decline, and its onset is sufficient to accelerate aging. Conversely, genetic or pharmacological enhancement of proteostasis network capacity can extend lifespan and suppresses age-related disease associated with protein misfolding across multiple model systems. These observations raise fundamental questions: what endogenous small molecules sustain proteostasis during aging, can their supplementation prevent neurodegenerative (and other protein folding diseases) and slow the aging process?
PhD project: Therapeutic applications of small molecule modulators of proteostasis
Organisms across all domains of life employ the accumulation of small organic osmolytes, which include molecules such as betaine and taurine, to mitigate proteotoxic stress. Recent work has also demonstrated anti-aging properties of this molecules, through yet unclear mechanisms. This project aims at dissecting the mode of action of different osmolytes using human cellular model systems and C. elegans as a model of organismal aging. We would like to address the following questions:
1. How do osmolytes affect cellular and organismal physiology?
2. Which types of stresses can be mitigated with exogenous osmolytes?
3. What types of protein misfolding pathologies (e.g., neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimers's, Parkinson's, Huntington's) can be ameliorated with exogenous osmolytes?
The project is part of an ongoing collaboration between the Khmelinskii and Padeken groups, which gives you the opportunity to become an expert in a wide range of methods and experimental approaches. This includes transcriptomics, proteomics, cell and molecular biology, fluorescence microscopy and advanced high-throughput mutagenesis screening.
If you are interested in this project, please select Khmelinskii/Padeken as your group preference in the IPP application platform.
Publications relevant to the project
Singh P et al. (2023) Taurine deficiency as a driver of aging. Science. 80(6649):eabn9257 Link
Geng L et al. (2025) Systematic profiling reveals betaine as an exercise mimetic for geroprotection. Cell. 188(19):5426-5428 Link
