What happens as we age?

After graduating from college, I was awarded a one-year appointment as a Harrison Surgical Scholar at the University of Pennsylvania, where I carried out graduate-level research within the Department of Surgery. Although I mainly studied sepsis and hemorrhagic shock, I was asked to assist on a collaborative research project with a team from Princeton University. I am proud that the research we conducted was finally complete in September of this year and accepted for publication in Cell Systems. 

My lab at UPenn focused on aging and metabolism, and our research project was studying NAD+ concentrations with age. As the MSBS students know from biochemistry, NAD+ is an important biological molecule with huge implications in metabolic pathways such as glycolysis and oxidative phosphorylation. However, one of the consequences of aging is that NAD+ levels decrease, yet the question was still unknown if NAD+ precursors decline with age or if NAD+ levels decline due to an increase in its consumption. 

The main goal of our project was to use isotope-labeled NAD+ precursors, mass spectrometry, and quantitative modeling to determine NAD+ fluxes in aged mice. 

We know that NAD+ is made de novo from tryptophan, with the majority synthesized from the precursor nicotinamide (NAM). Labeling these precursors, we found that they don’t decline with age and their synthesis into NAD+ is also not hindered. What we were able to prove is that NAD+ decreases with age simply due to an increase in its consumption. As of now, most studies point to CD38 and PARP as the likely enzymatic consumers of NAD+. With aging, these two enzymes use up NAD+ in order to fight DNA damage and inflammation. 

For many years, people have been studying NAD+ precursors as a potential lifespan increasing therapeutic. Unfortunately, our study shows that no matter how much one tries to increase their NAD+ levels, its decline will still occur due to other processes. 

I am honored to have been a part of this research team and our results can allow future studies to occur with a new understanding of how NAD+ is metabolized with age. 

Reference:

McReynolds, M. R., Chellappa, K., Chiles, E., Jankowski, C., Shen, Y., Chen, L., Descamps, H. C., Mukherjee, S., Bhat, Y. R., Lingala, S. R., Chu, Q., Botolin, P., Hayat, F., Doke, T., Susztak, K., Thaiss, C. A., Lu, W., Migaud, M. E., Su, X., Rabinowitz, J. D., … Baur, J. A. (2021). NAD+ flux is maintained in aged mice despite lower tissue concentrations. Cell systems, S2405-4712(21)00338-0. Advance online publication. https://doi.org/10.1016/j.cels.2021.09.001