A recent study by Harvard Medical School scientists suggests that defective one-carbon metabolism and cellular respiration might contribute to age-related immunosenescence, the decline of immune function typically observed during aging .
T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.
T cells and immunosenescence
T cells play a central role in immune response; they are responsible for constantly patrolling the body and initiate attacks against any pathogens they come across. Naïve T cells are cells that haven’t yet encountered any threats, and when they do, they activate and quickly replicate in large numbers to stand up to the foreign invaders. Activated T cells may eventually differentiate into specialized memory T cells that “remember” the specific pathogen that caused their activation in the first place, allowing the body to more promptly mount an effective immune response, should the same threat present itself again.
If T cells are not working properly or scarce in numbers, the effectiveness of the immune system is compromised, as the body becomes less capable to face new threats or fails to appropriately respond to threats new and old. It has been known for a while that this is what happens with age, in no small measure because the thymus—an organ responsible for the production of T cells—shrinks and turns into fat with age, starting rather early on; to add to this, Harvard researchers have now observed that, in aged mice, T cells also exhibit defects in the metabolic pathway called one-carbon metabolism, as well as impaired cellular respiration, with ultimately results in a decrease in the T cells’ ability to get their job done.
One-carbon metabolism and cellular respiration
Cellular respiration is a process by which tiny organelles called mitochondria turn the biochemical energy of ingested nutrients into adenosine triphosphate (ATP), which is then used to power all sorts of cellular functions. One-carbon metabolism also takes place in the mitochondria, as well as in the intracellular fluid, and it consists of a series of chemical reactions that produce nucleotides and amino acids necessary to build proteins and DNA itself, without which cellular replication could simply not happen. The process owes its name to the fact that it involves the transfer of several chemical groups containing a single carbon atom.
In their research, the scientists started off by examining T cells extracted from aged and young mice. As expected, the T cell count was lower in elderly animals, but that was not all. When the researchers activated the T cells by simulating a pathogen attack, the response of aged T cells was rather lukewarm; compared to younger cells, they didn’t secrete as many immune-signaling molecules, grew slowly, and tended to die at a faster rate. On top of that, their oxygen consumption appeared to be lower, their mitochondria were smaller than in their younger counterparts, and their ability to break down sugars was impaired.
Proteomic analysis of the activated, aged T cells revealed that around 150 proteins within them were present at lower levels than normal, whereas about 40 exhibited higher than normal levels. In particular, proteins functioning as enzymes in one-carbon metabolism were a staggering 35% lower in aged cells compared to younger ones. These skewed values might impact not only the T cells’ ability to reproduce but also to fight off invaders.
The researchers decided to test what would happen if they replenished aged T cells with the very chemical products that their defective one-carbon metabolisms were no longer producing as necessary. Indeed, they supplied the cells with the two main products of the one-carbon pathway, formate and glycine, and observed that this enhanced their ability to reproduce and decreased their death rate.
These findings suggest that it might be possible to restore immune function in elderly individuals, either by enhancing one-carbon metabolism or by externally supplying immune cells with the chemicals they normally produce; however, it’s too early to say, as the effects that these scientists observed took place in cell cultures and not in vivo. Further experiments will be necessary to confirm their results, and even more studies will be needed to assess the possible benefits of this procedure in humans.
 Ron-Harel, N., Notarangelo, G., Ghergurovich, J. M., Paulo, J. A., Sage, P. T., Santos, D., … Haigis, M. C. (2018). Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice. Proceedings of the National Academy of Sciences, 201804149.