1. Research Background:

DNA damage contributes to cancer development and aging. Defects in the nucleotide excision repair (NER) pathway lead to distinct human disorders that are characterized by cancer susceptibility, developmental impairments and premature aging. It remains particularly challenging to understand the mechanisms through which genome instability impacts the pathobiology of aging. We have established the C. elegans system to investigate how DNA damage impacts tissue aging and how multicellular organisms respond to increasing levels of genome instability with aging. We have uncovered a novel function of the innate immune system to mediate systemic adjustments to tissue specific DNA damage. Moreover, we have uncovered mechanisms through which longevity assurance pathways respond to DNA damage accumulation and antagonize the detrimental consequences of increasing levels of DNA damage with aging. In addition, we are interested in understanding how germline genomes are maintained to allow the indefinite perpetuation of germ cells throughout the generation. Our long-term goals are gaining a deeper understanding of genome maintenance and longevity assurance pathways and to develop novel intervention strategies to combat aging-associated diseases and genetic predispositions to accelerated aging and cancer development.

2. Research questions addressed by the group:

We are interested in understanding the fundamental mechanisms through which the gradual accumulation of DNA damage leads to aging of cells and the organism and how, in contrast, germ cells can be immortal. Understanding the root causes of aging will allow developing future therapies that target the aging process in order to extend health span and prevent age-related diseases. The main focus of our work is to explore how the organism responds to the presence of DNA damage. We wish to better understand how genetic mechanisms of longevity assurance respond to genome instability and promote the functional integrity of cells and tissues. To investigate how beyond cell-autonomous DNA damage responses the organism adapts to genome instability, we are investigating systemic response mechanisms that impinge on the central maintenance pathways including DNA repair, autophagy, proteostasis, and gene expression programs. 

3. Possible projects:

Our project range from molecular biology, genetics and biochemistry to computational biology and bioinformatics. The causal contribution of DNA damage not only to cancer development but evenly to the aging process has been demonstrated by progeroid (premature aging-like) syndromes that are caused by mutations in DNA repair genes. We have established the nematode C. elegans as metazoan model to investigate the consequences of DNA repair defects that in humans cause either cancer predisposition or developmental retardation and premature aging. There are several possibilities for a research project:

1. How is somatic maintenance adapted to the requirements of the germline?
   We discovered germline DNA damage induced systemic stress resistance (GDISR) that elevates somatic endurance when offspring generation is compromised by genome instability in germ cells. We postulate that by elevating somatic endurance, GDISR extends reproductive lifespan to allow germ cells to repair their genomes and resume offspring generation later in life. Vice versa, we uncovered somatic stress responses that regulate the genome quality control of germ cells and determines the degree of aneuploidy in the offspring. We aim to better understand how reproductive lifespan is regulated and how the somatic aging process impacts the health and genetic composition of the offspring.

2. Which processes determine somatic maintenance and thus control aging?
   DNA damage accumulation in somatic tissues is thought to cause the functional deterioration during aging. We determined that the insulin-like growth factor signalling (IIS) effector DAF-16 responds to DNA damage in somatic tissues. DAF-16 and MPK-1 activity alleviates growth arrest and enhances DNA damage resistance in somatic tissues even in the absence of DNA repair. We propose that IIS and MAPK signalling mediates the DNA damage response (DDR) in somatic tissues and promotes maintenance of differentiated tissues through enhanced tolerance of DNA damage that accumulates with aging. An integrated proteomics, phosphoproteomics and lipidomics analysis of the in vivo response to persistent UV-induced DNA lesions revealed a comprehensive picture of the organism’s DDR. Our data provide new insights into the organism’s response program to DNA damage during development and aging and suggest new intervention targets for triggering stress responses to antagonize the detrimental consequences of genome instability. In this project we wish to gain better understanding of the interactions between signalling circuits and the physiological adaptations to DNA damage accumulation during aging.

3. What are the underlying mechanisms for germ cell immortality?
   Genome integrity in germ cells is a prerequisite for inheritance and germline immortality. We are investigating DDR in primordial and adult germ cells. Here, we focus on investigating DNA damage checkpoints and the C. elegans p53-like CEP-1 regulates the DDR in germ cells. In addition, we determined that specific neurons control the stability of germline genomes and impact the occurrence of de novo germline mutations. We are interested in better understanding of the soma confers environmental influences to the genome quality control of germ cells. Here, we hypothesize that environmental sensing could influence the course of evolution by regulating genome inheritance. We are dissecting impacts of regulatory mechanisms in somatic and germline tissues that influence the stability of heritable genomes. 

4. Which mechanisms regulate the pace of aging and rejuvenation?
   We have developed transcriptomic aging clocks and showed that the accumulation of stochastic variation alone is sufficient for building age predictors. We determined that stochastic aging clocks can detect age acceleration and deceleration in mice and humans as well as age reversal for instance upon cellular reprogramming. We employ a combination of machine learning algorithm and genetic methodologies to explore the regulatory mechanism that determine the loss of regulatory tightness that characterizes the aging process. We are employing the genetic model of C. elegans with its tremendous plasticity of longevity as well as human induced pluripotent stem cells and other systems to identify the regulatory mechanisms that determine the loss of maintenance during aging and it reversal during rejuvenation

4. Applied Methods and model organisms:

Methods: Genetics, Cell Biology, Bioinformatics, Systems Biology, Biochemistry, in vivo imaging, proteomics, genomics, transcriptomics

Model organism: C. elegans, mouse, human cell culture

5. Desirable skills and qualifications:

We are seeking highly motivated and dedicated candidates. Desired qualifications range from genetics, biochemistry, and molecular biology to bioinformatics and computational biology. Both wet lab and dry lab projects are available depending on the candidate.

6. References and key publications:

Gallrein C, Meyer DH, Woitzat Y, Ramirez-Ramirez V, Vuong-Bender T, Kirstein Y, Schumacher B. Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions. Nat Aging. 2026. https://doi.org/10.1038/s43587-026-01067-5

Meyer DH, Schumacher B. Aging clocks based on accumulating stochastic variation. Nat Aging. 2024 May;4(6):871–885. https://doi.org/10.1038/s43587-024-00619-x

Bujarrabal-Dueso A, Sendtner G, Meyer DH, Chatzinikolaou G, Stratigi G, Garinis G, Schumacher B. The DREAM complex functions as conserved master regulator of somatic DNA repair capacities. Nat Struct Mol Biol. 2023 Apr;30(4):475–488. https://doi.org/10.1038/s41594-023-00942-8 

Wang S, Meyer D, Schumacher B. Inheritance of paternal DNA damage by linker histone-mediated repair restriction. Nature. 2023Jan;613(7943):365-374. https://doi.org/10.1038/s41586-022-05544-w 

Soltanmohammadi N, Wang S, Schumacher B. Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy. Nat Commun. 2022 Feb 4;13(1):701. https://doi.org/10.1038/s41467-022-28225-8 

Schumacher B, Pothof J, Vijg J, Hoeijmakers JHJ. The central role of DNA damage in the ageing process. Nature. 2021 Apr;592(7856):695-703. https://doi.org/10.1038/s41586-021-03307-7 

Mueller M, Castells-Roca L, Babu V, Ermolaeva MA, Müller RU, Frommolt P, Williams AB, Greiss S, Schneider JI, Benzing T, Schermer B, Schumacher B. DAF-16/FoxO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat Cell Biol. 2014 Nov 24:16(12):1168–1179. https://doi.org/10.1038/ncb3071 

Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermöhlen O, Hoppe T, Schumacher B. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature. 2013 Sep 19;501(7467):416-20. https://doi.org/10.1038/nature12452