Deciphering Age-Related Decline in Neurogenesis

What have your Ph.D. studies focused on?

“Throughout my Ph.D., I have been exploring how inflammation contributes to the age-related decline of neurogenesis in the brain's neurogenic regions: the subventricular zone (SVZ) and the dentate gyrus (DG). These areas house neural stem cells responsible for generating new neurons through a process called neurogenesis. Neurogenesis in these areas supports memory and learning, but inflammation, both systemic and local, disrupts this process with age and is linked to cognitive decline and neurodegenerative disease risk.

The central question driving my research was, “How do inflammatory changes affect neurogenesis during aging?” Answering this is important because neurogenesis is closely tied to cognition, particularly in the hippocampus. With age, the decline of this process contributes to cognitive challenges, even in the absence of disease. In neurodegenerative conditions, both neurogenesis and immune activity are often disrupted. By understanding how inflammation influences these changes, we can better grasp the mechanisms behind cognitive decline and identify potential therapeutic targets to preserve brain health as we age.

To answer this question, I focused on three main projects. Using single-cell RNA sequencing, immunohistochemistry, and bioinformatics, I explored several immune pathways like CXCR5/CXCL13 and CX3CR1/CX3CL1. In the first, we used an animal model to investigate the role of CXCR5, a gene expressed on immune cells outside the brain. This showed specific indirect effects on neuroblast function, emphasizing its role in neurogenic processes. 

The second project turned inward, examining microglia—immune cells within the brain. We found that microglia in the neurogenic regions not only change with age but do so uniquely compared to other brain regions. Notably, we discovered that the gene CX3CR1, downregulated in aged microglia, played a surprising role as its reduced expression actually improved neurogenesis, suggesting that while inflammation is often considered detrimental, some aspects of microglial changes might actually counterbalance harmful effects.

In the third project, we looked at the aging intermediate progenitors themselves. Here our research revealed that a subset of aged SVZ progenitors adopt an immune-reactive transcriptional profile, potentially as an adaptive response to the aging environment.

This shift, along with the accelerated decline of excitatory neuron progenitors compared to inhibitory ones, highlights immune pathways such as Usp18 and Lgals9 as promising therapeutic targets.

Through this journey, I have come to view inflammation as a complex player in the aging brain—sometimes detrimental, sometimes supportive. Overall, inflammation impacts neurogenesis variably across brain regions and cell types, underscoring the importance of age- and region-specific approaches for interventions aimed at preserving cognitive health in aging,” explains Jonas Fritze.

Can you tell us more about the cover of your thesis?

“With the cover, I have tried to create an image that captures what I have been studying in my thesis. In the center, you find a newly formed neuron with aged features, emerging from a neurogenic niche, while surrounded by immune cells that influence its growth and migration. This image artistically represents the delicate balance between the supportive and inhibitory effects of inflammation on neurogenesis in aging, which is central to my research.

While it was designed with the help of AI tools, I had to make a few adjustments myself. For instance, I manually added details like the neuron stepping outside the niche and "holding" a cane,” notes Jonas.

How did you end up doing a Ph.D. at Lund Stem Cell Center?

“I am from a small village outside of Lund, called Lomma, and I did all of my studies here in Lund. During my master's in the biotechnology program at Lund University, I became interested in aging and understanding its role in age-related diseases. Initially, my curiosity was not specifically about the brain—rather, it was more broadly aimed at understanding the processes that change with aging and contribute to different types of functional decline and diseases throughout the body.

When it came time for my one-year master's project, I started to look around for projects that focused on aging and ended up in Henrik Ahlenius’ lab. The projects there and the environment were a perfect fit, and when an opportunity arose to continue with research, I decided to take it, even though it was not part of my original plan.

I spent quite a lot of time thinking about whether I wanted to do a Ph.D. I knew it would take a lot of commitment compared to a more “normal” type of work. In the end, it was science that I found interesting and fun, and I figured that if you spend a lot of time doing something you enjoy, it does not feel like work in the same way,” highlights Jonas.

What have you found the most enjoyable during your Ph.D. studies?

“That is simple; it is the research itself. It was something that I wanted to do from the start and that I found interesting, and it kept being interesting along the way. Of course, that fluctuated a bit with different projects and overtime, but the general basic concept I always found interesting. It has also been fun to interact with open-minded and insightful people,” adds Jonas.

What has been the most challenging aspect?

“For me, it has been the balance between wrapping up existing projects and diving into new, exciting ones. It is easy to get distracted by new ideas or projects, but finishing ongoing work is important before moving forward.

Then on a more personal level, becoming a parent during my Ph.D. was a big adjustment. Before that, I often worked long and odd hours in the lab. Then, suddenly you have to change everything. You notice a difference in how you manage to keep up with what you did before and have to prioritize much more. While the transition was initially tricky, after time I found a good balance,” Jonas shares.

What are your plans following your Ph.D. defense?

“I will continue in Henrik’s lab, building on a project we initiated but did not have room for in this thesis. So, we will continue with that, which will be very fun and exciting as this builds on the experimental science from the thesis toward a therapeutic approach aimed at rejuvenating neural stem- and immune cells to improve cognition in age-related dementia,” says Jonas.

Any tips or advice for future Ph.D. students?

“Take it easy. Relax. Have fun. Every Ph.D. journey is unique, so there is no one-size-fits-all advice. For me, being more structured would have helped, but that is not everyone’s challenge. Focus on what works for you and find joy in the science—it will make the journey much more rewarding,” Jonas concludes.