#1

https://www.nature.com/articles/s41586-024-07238-x

Abstract

Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.

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#2

There is an interesting point here which is if the myeloid HSCs are depleted then the proportion of lymphocytes goes up.

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#3

Fascinating study. I hope this can be start of a discussion on how to improve our crucial immunity when this is poor.

Unfortunately the optimized protocol of the study linked by John that achieved in depleting my-HSCs in mice cannot be used by us now. It achieved this by targeting the CD62p antigen using an anti-CD62p antibody of mouse lgG2a isotope in combination with NEO1 antigen using combined goat anti-mouse NE01 antisera with anti-CD47 and anti-KIT. Anyone care to ask the researchers to supply those substances with dosage recommendations :blush:

Another possible way to deplete my-HSC is by addressing changes in the bone marrow microenvironment, from a study focused on leukemia: . Hematopoietic stem cell aging and leukemia transformation | Blood | American Society of Hematology (ashpublications.org) In this study, a more complicated and much broader range of HSC deficiencies are described than just myeloid bias : “old HSCs have impaired hematopoiesis,[3] myeloid bias at the transcriptome and functional levels,[4]( dysfunctional mitochondria,[5]) decreased polarity of Cdc42,[6]increased reactive oxygen species (ROSs),[increased γH2.AX caused by ineffective H2.AX dephosphorylation rather than sustained DNA damage,[8]altered DNA methylation,[9](changes in histone modification patterns[10] (which are also observed in aged human hematopoietic stem and progenitor cells [HSPCs]),[11]and increased transformation to leukemia.

The most promising method I could find from this study is on fecal microbiota transplantation: “Fecal microbiota transplantation from young mice into old mice rejuvenated HSC function, mitigated inflammatory signaling, and restored lymphoid differentiation capacity of aging HSCs”… … “Autologous fecal microbiota transfer has been shown to be safe in patients with AML in a recent phase 2 clinical trial.[76] These observations supports alterations in gut microbiota and intestinal barrier damage during aging dysregulates HSC function and provides a therapeutic option for restoring HSC function and preventing hematologic malignancies”.

**Fecal transplants were covered in Can Fecal Transplants Help Reverse Aging? Taking resistant staches, sauerkraut and having a veggy-berry heavy diet, I´m not sure I would wind up winning from a fecal transplant and would have to make an analysis of my gut bacteria first.

Pharmacological inhibition of interleukin 1β (IL-1β) (reduces inflammation, probably not an issue for most on this forum) and senolytics are amongst the other potential methods described for reducing my-HSCs.

In my own case, most important is to increase lymphocytes, that are an abysmally low 0.6 (ref range 1.1-3.5) despite doing everything right in life-style factors (possibly a long-lasting result of radiation therapy over 3 years ago), rather than improving the neutrophil(myeloid)/lymphocyte ratio which at 3 is not good but not disastrous.

Searching, I find that lithium increases white blood cell count perhaps from action in the bone marrow. However the effect is dose-dependent and it was for bi-polar patients so with the low-lithium dose many of use it may not be relevant. The effects of lithium therapy on leukocytes: a 1-year follow-up study. - PMC (nih.gov)

Finally, there are pharmacological interventions e.g. Targeted Drug Delivery to Lymphocytes: A Route to Site-Specific Immunomodulation? | Molecular Pharmaceutics (acs.org) Fairly heavy stuff, have not checked it.

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#4

Given that my near-perfect diet for immunity and a higher lymphocyte count is not helpful (enough), I went on searching for pharmacological interventions. Neulasta and Neuprogen reliably increase total white blood cell count, but it mainly neutrophils that are raised; effect on lymphocytes is uncertain so they may actually worsen the myeloid (neutrophil)/lymphoid ratio. Side effects on top.

But there is a supplement, beta-glucans, with fairly strong evidence that it improves immunity and raises lymphocytes Effects of fungal beta-glucans on health – a systematic review of randomized controlled trials - Food & Function (RSC Publishing)

Effects of fungal beta-glucans on health – a systematic review of randomized controlled trials.

I am going for the brand with best results from comparative research, Transfer Point and its Beta 1.3D Glucan 300. Recent data indicates 100 - 250 mg daily is enough (with 100 mg giving 80% of the benefit of 250 mg). I believe it is yeast not fungal derived but it apparently beats its competitors.

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#5

The take of Physionic’s Nicolas Verhoeven on this study in some depth:

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