How the immune cells ages, explained at the single cell level

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Our immune system is essential in keeping us healthy. But the immune system also changes profoundly as we age. Why is that? Could we prevent it? Let's see how #singlecell biology can help us better understand #immune #aging 🧵👇

First, some background. Everybody knows that the immune system is hugely complex. #singlecell sequencing has (arguably) done more for the immune system than for other health applications. Via #scRNAseq, we discovered & characterized crazily detailed immune cell phenotypes.

Such detailed phenotypes have been found in both healthy and diseased tissues. I wrote several threads about this topic and find it to be one of the most foundational & fascinating progresses that have happened in biomedicine in the past 10 years. twitter.com/simocristea/status/1580270605395324929?s=20&t=hMauXOdT5vETmcMaP3Puyg

Many such small, but important, discoveries are still under-appreciated. They are initially derived from animal experiments & observational clinical data. It often takes years until such findings are clinically implemented, even though the seed and knowledge had long existed. twitter.com/simocristea/status/1594736869211869187?s=20&t=hMauXOdT5vETmcMaP3Puyg

Now, how does this hugely complex entity, the immune system, change with age? Different immune populations shift in their own specific ways (no one-fits-all). This review paper is a great resource summarizing ~200 references on #singlecell immune aging. nature.com/articles/s41577-021-00646-4

Still, much more single cell data has been generated in mice 🐁 than in humans. Therefore, age-related immune changes are better characterized in the mouse #singlecell ecosystem. This table summarizes findings from multiple publications on mouse data (same reference as above).

By analyzing the two tables, we see that many immune age-related changes are shared among mice & humans. Still, some are different. Humans are constantly exposed to infections (unlike🐁), which may explain the more complex human age-related changes(e.g. in CD8 Tcells or Bcells)

Next, let's dive deeper into some of these immune age-related & age-induced changes, and also discuss the data resources based on which these conclusions were derived.

1. Inflammation: Unresolved systemic inflammation in the absence of active pathogen stimulation is one of the main features of immune aging. This is also called inflammageing, and is characterized by an unjustified increased production of pro-inflammatory factors.

A good paper to understand inflammation-specific age-related immune changes (such as via new gene signatures) is this 2020 @Nature article, which aggregates & analyzes data from multiple ages across the mouse lifespan. nature.com/articles/s41586-020-2499-y

2. Myeloid cell expansion As the activity of the thymus (where T cells are produced) decreases gradually with age, so does the number of T cells. In contrast, myeloid cells expand, and myeloid-biased hematopoietic stem cells (HSCs) accumulate in hematopoietic niches with age.

This 2019 @Nature paper characterizes the #singlecell transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast populations, both at homeostasis and under conditions of stress-induced hematopoiesis. nature.com/articles/s41586-019-1104-8

3. CD8+ T cells T cells are one of the most important immune system players, defending us from pathogens & tumors. They are also one of the populations suffering most from #aging: loss in naive CD8+, increase in memory Tcells & increase in clonality (i.e. decreased diversity). twitter.com/simocristea/status/1602745588709089281?s=20&t=yN6OGfNAamOxQexGAZ7Ibw

This comprehensive 2021 review article in @NatImmunol characterizes in detail the molecular features that define T cell aging. nature.com/articles/s41590-021-00927-z

Next, this 2020 @ImmunityCP paper comprehensively characterizes immune aging across four different mouse tissues (spleen, peritoneum, lungs and liver) by both #scRNAseq and #scTCRseq. cell.com/immunity/fulltext/S1074-7613(20)30492-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761320304921%3Fshowall%3Dtrue

It finds a specific age-associated T cell subpopulation (PD1+TOX+CD8+), which accumulates with age in all the tissues evaluated, making up to 60% of all CD8+ T cells in these tissues. This is interesting because this subpopulation seems to be systemic & not tissue-specific.

‼️ Next, a core reference paper for any #singlecell data analyst's portfolio of #DataScience resources: Tabula Muris Sensis 2020 @Nature paper: a #scRNAseq atlas across the mouse lifespan that includes data from 23 tissues and organs. nature.com/articles/s41586-020-2496-1

Among many interesting findings, this large analysis suggests that CD8+ T cells become progressively exhausted with age. Upon TCR stimulation, they produce pro-inflammatory molecules.

4. CD4+ T cells Similarly to CD8, the amount of naive CD4 T cells decreases with age, while memory CD4 T cells increase. Regulatory T cells increase, but not everywhere, rather only in some organs (s.a. spleen and lymph nodes), and not in others, (s.a. lungs or liver).

Interestingly, in supercentenarians, a specific population of cytotoxic CD4+ T cells are greatly expanded towards the end of life. pnas.org/doi/full/10.1073/pnas.1907883116

5. Stroma (non-immune) cells Fibroblasts are key players in multiple diseases, in particular cancer. A recent #scRNAseq paper characterizes in detail the stroma landscape across cancer types, noting the complex interaction among stroma & immune cells in driving tumor progression twitter.com/simocristea/status/1589669703731253249?s=20&t=yN6OGfNAamOxQexGAZ7Ibw

In general, aged stroma and endothelial cells become enriched in pathways related to cytokine signaling and inflammation. Such changes are potentially related to the increased prevalence of down-regulation & dys-regulation of immune responses in advanced age.

6. Senescent cells Senescence is the last stage of cell differentiation and means permanent withdrawal from the cell cycle. It often happens to damaged or stressed cells. Senescent cells secrete chemokines, cytokines & growth factors, leading to low-grade systemic inflammation.

Senescent cells are usually recognized & eliminated by immune cells. Multiple immune cell types interact with senescent cells: Tcells, NKs, neutrophils, macrophages. Immune-mediated senescent cell removal could contribute to extending healthy aging & is therapeutically explored

How can anti-aging therapies use this complex information? One promising route seems to be dietary interventions. A 2020 @CellCellPress showed that caloric restriction triggers reshaped transcriptional landscapes in old rats🐀, including immune changes. sciencedirect.com/science/article/pii/S0092867420301525

The link between metabolism & the immune system is very interesting. T cell metabolism undergoes heavy reprogramming with age. This recent paper discusses in detail the mechanisms of these transformations, with particular relevance to tumor development. cell.com/cell-metabolism/fulltext/S1550-4131(22)00496-X#%20

Bonus Tweets 1/2: The same publication I first referenced above (nature.com/articles/s41577-021-00646-4) also provides a comprehensive table with #singlecell #DataScience transcriptomic & epigenetic datasets of immune aging. A great starting point for #Bioinformatics analyses!

Bonus Tweet 2/2: Even more: they provide an interactive webpage to explore these (‼️preprocessed) datasets. Kudos to the authors for this effort and for facilitating data access to so many relevant datasets #OpenScience👏 Good times to be grateful🎄 artyomovlab.wustl.edu/immune-aging/explore.html