Examining Mitochondrial Dysfunction in Old T Cells

In older mice and humans, the immune system becomes dysfunctional. It is overactive, producing chronic inflammation that leads to harmful cellular behavior throughout the body, but at the same time it is much less capable when it comes to destroying pathogens and errant cells. In today's open access research, scientists investigate the incapacity of naive T cells in older mice. This population of T cells is necessary for a strong immune response, but their numbers decline due to the involution of the thymus. T cells begin life as thymocytes in the bone marrow, and then migrate to the thymus where they mature into T cells of various types. With advancing age the thymus atrophies, and the active tissue needed for T cell maturation is replaced with fat. The supply of new T cells diminishes, and thus so does the fraction of the overall immune cell population that is made up of naive T cells capable of meeting new threats.

In the research here, it is found that those naive T cells that do remain in old mice are dysfunctional, far less capable than their young counterparts. The mitochondria, the power plants of the cell, are altered and diminished. Many important mechanisms are thus likely compromised, or operating at levels far beneath what is minimally required for adequate cellular function. This mitochondrial malaise is observed in all tissues, but possibly best studied in the context of muscle and brain, both energy-hungry tissues that are greatly affected by a reduced supply of chemical energy store molecules packaged by mitochondria. Clearly similar problems exist in all cells.

Fixing this age-related alteration in mitochondrial structure and function is an interesting challenge. The problem is only peripherally related to the mitochondrial DNA damage of the SENS rejuvenation research program, and appears to be a downstream consequence of some combination of other molecular damage and altered signaling inside and outside cells. There is no clear view of which forms of repair would be most effective, as there is no solid link established between any of the known forms of molecular damage that lie at the root of aging and this general mitochondrial decline. Thus efforts to override specific mitochondrial mechanisms are further ahead as of the moment; providing additional NAD+ to cells, for example, perks up mitochondrial activity. That can be enough to provide incremental benefits to tissue function, as recently demonstrated in a small human trial. There are no doubt other similar possibilities. These are all limited in their upside by the fact that they don't address the underlying causes; there is a great need for more research and development focused on repair of those underlying causes.

The 'Graying' of T Cells

Researchers looked for overall differences between old and young T cells. They isolated T cells from the spleens of young and old mice and noticed that, in general, older mice had fewer T cells. Next, to gauge the cells' immune fitness, the researchers activated the T cells by mimicking signals normally turned on by pathogens during infection. The older T cells showed diminished activation and overall function in response to these alarm signals. Specifically, they grew more slowly, secreted fewer immune-signaling molecules and died at a much faster rate than young T cells. The researchers also observed that aged T cells had lower metabolism, consumed less oxygen and broke down sugars less efficiently. They also had smaller than normal mitochondria, the cells' power-generators that keep them alive

To pinpoint the metabolic pathways behind this malfunction, the scientists analyzed all the different proteins in the cells, including those that might be important for coaxing a T cell from dormancy into a fighting state. The team found that the levels of some 150 proteins were lower-than-normal upon activation of the aged T cells, compared with young T cells. About 40 proteins showed higher than normal levels in aged versus young T cells. Many of these proteins have unknown functions, but the researchers found that proteins involved a specific type of metabolism, called one-carbon metabolism, were reduced by nearly 35 percent in aged T cells.

One-carbon metabolism comprises a set of chemical reactions that take place in the cell's mitochondria and the cell cytosol to produce amino acids and nucleotides, the building blocks of proteins and DNA. This process is critical for cellular replication because it supplies the biologic material for building new cells. The team's previous work had shown that one-carbon metabolism plays a central role in supplying essential biological building blocks for the growing army of T cells during infection. So, the scientists wondered, could adding the products of this pathway to weakened T cells restore their fitness and function?

To test this hypothesis, the team added two molecules - formate and glycine, the main products of one-carbon metabolism - whose levels were markedly reduced in aged T cells. Indeed, adding the molecules boosted T cell proliferation and reduced cell death to normal levels. The researchers caution that while encouraging, the effects were observed solely in mouse cells in lab dishes rather than in animals and must be confirmed in further experiments.

Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice

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.

Comments

I agree thymus regeneration is urgently needed. Does anyone have an opinion reg. ProBoost - thymus protein a ? To help us tie over until a true regeneration therapy is available.
I have been taking it regularly, cross fingers, that it has an effect.

Posted by: Helga at December 16th, 2018 9:30 AM

@Helga: I'm of the opinion that nothing that is presently out there and available has a meaningful, reliable effect on thymic size and activity.

Recombinant KGF would be a plausible, albeit risky choice, given the growth of thymus and increased thymic activity observed in mice and non-human primates, except for the point that the one human trial showed exactly no effect in humans at the doses found safe enough to be approved for other uses:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216663/

The folk at Immune Intervene would disagree with me about whether or not any existing approaches work, but I'm not sold on their take on the challenge of thymic regeneration.

http://interveneimmune.com/

Posted by: Reason at December 16th, 2018 6:50 PM

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