Aging Cell Paper and The Antibuddies Podcast
I am now 2 years removed from my postdoctoral training time, but through hard work by my previous lab, as well as some editing and revision I conducted remotely, my last study from the University of Texas was published earlier this summer in Aging Cell.
I was disappointed that I had been unable to complete this research while I was still a postdoc at The University of Texas, but I had already pushed off my faculty start date several months and I was also eager to start my new path. I managed to train an incoming postdoc to complete the experiments, and it was because of her diligent work with very technical experiments, as well as some amazing data generated by graduate students, that this work is complete.
I was recently interviewed for a podcast on the contents of the paper, and it is a wonderful companion to the work. Shortly after the paper was published and I was able to promote it on social media, I received a message from Antibuddies inviting me to talk about the paper. I had done a few brief media blurbs for Mayo Clinic when I first started my faculty position, but this was my first longer format conversation. I invite you to listen to the podcast as the hosts did an excellent job analyzing the paper.
Before the conversation, my usual pre-talk nerves were kicking in, but It was quite fun and exciting to record audio to later be spliced into the podcast conversation. (Antibuddies use the Audacity program, which was nifty).
Young (red) and middle-aged (blue) developing T cells, or thymocytes, migrate in the young thymus (green). Supplementary movie 1. Lancaster, et. al. Aging Cell. 2022, 21(6):e13624
Here is the paper’s backstory and how it set the stage for my faculty career. Starting around 2014, my postdoctoral mentor enlisted me to pilot some 2-photon microscopy experiments using thymus tissues obtained from middle-aged (12-month-old) mice. She was developing a grant with other investigators and wanted to start getting data to support the project. The group project was focused on the biological phenomenon of thymus involution, where the thymus– an organ dedicated to the maturation of T cells– naturally shrinks with age, which has ramifications on the number of new T cells it can produce.
The thymus is one of the first organs to develop the signs of aging, so early in life it starts involute and change. In older humans, the thymus dwindles to nothing, and thus it took a long time for modern medicine to suspect that it actually did anything important at all.
Revisiting my early data from that time, it is interesting to see just how important perseverance is and the underrated role it played in my career development. I did some experiments comparing live-cell imaging on 9-month-old tissues versus (early adult) 1-month-old mouse tissues and it looked like there was a difference. But it took many experiments spaced out over the course of a year before I could get any data from 12-month-old tissues. Like many aged organs, the tissues were both weirdly tough yet extremely fragile, often frustratingly yielding no usable tissue. I swore to my mentor that our techniques were NOT going to work for that age point, but she would calmly ask me to try again next time we had a mouse that was old enough. Strangely, the microscopy started to work, and I was able to start work in earnest. To my knowledge, my experiments are the only 2-photon microscopy experiments to use live lymphoid tissues from aged mice.
Young (red) and middle-aged (blue) thymocytes migrate in the middle-aged thymus (green). Thymocytes can still access the medulla, or interior, like in the young thymus, but are also stuck out in the cortex, or exterior compartment. As red and blue cells were pipetted onto the tissue and allowed to migrate in, the cells that didn’t make it into the tissue appear to ‘float’ outside in the medium. Supplementary Movie 2. Lancaster, et. al. Aging Cell. 2022, 21(6):e13624
After the grant was funded, I was able to continue my postdoctoral research. The multi-institutional nature of the grant also allowed me to interact regularly with some of the leaders of thymus research. Somewhere around 2018, I was getting antsy (or perhaps, having an existential senior-postdoc crisis) and was thinking about my next steps. Thanks to encouragement from my mentor and some of the project collaborators, I started thinking about what my lab would do if I were to find a faculty job.
As much as we would love to have genius eureka moments, those moments are actually more incremental than we would think. Certainly, science is so complex that even paradigm-shifting work is built from generations of previous efforts. Every scientist stands on the shoulders of the scientists that came before them. Inspired from what I was learning about immune aging, and thinking that I had developed a unique skill by being able to handle the delicate aged tissues, I wrote up my Research Interests for my faculty job application packet based on the ramifications of my studies. Thus, this work—which investigates what happens to T cells educated by the aging thymus—bridges my initial article on self-tolerance in the thymus and my first faculty publication, where we look at what the aged tissue environment looks like after these T cells leave the involuting thymus.
In 2021, I received word from my postdoc lab that the experiments were completed. The paper’s co-author was on maternity leave, so my mentor and I set to editing and preparing the publication. Given the long timeline for the paper experiments, we were overjoyed when minimal criticisms came up during peer review and we were able to prepare the final version for publication. It felt good to know that the study was so thorough that the reviewers did not see any large omissions to the work.
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Aging gets a bad rap. We perceive that we are getting weaker, feebler, sadder, and uglier. Indeed, we are on average living much longer now than at any other point in human history, and so the older individual must now live with the result of decades of lifestyle and environmental influences. As far as the immune system goes, it is all about trade-offs. The older human no longer has the primordial burden of reproducing and raising young, and so can afford to expend less energy. Less energy expended needs means less demands on physicality.
The prime directive of the immune system is to maintain homeostasis. Older humans from ancient times likely did not move around as much or interact with as many new environments, and so could perhaps let some infectious immune defenses go. Instead, the likelihood of cancer is increasing with time. As cancer is derived from the host’s own tissues, and so T cells from the older host need to be more vigilant for threats from within.
The way we interact with the world is very different, thanks to advancements in civic infrastructure and medicine. Also, a lifetime of fulfilling immediate desires (delicious foods, convenient transport, sedentary habits) catch up to us in older age, making immune homeostasis harder to achieve. It is now easy to tip into chaos, whether we develop autoimmune diseases (too much immune response) or succumb to new pathogens or cancer (too little immune response). Furthermore, we can articulate the desire to retain our health even when intrinsic biological mechanisms are winding us down. I think this is the true pursuit of aging research: we are not looking for a fountain of youth, but trying to dampen the built-in shutdown mechanisms that no longer serve our way of life, because more of us are alive and getting older and it is too great of a burden to expect the next generation to take care of us.