Thread by @__ice9

Reasonably thorough review article on aging and the immune system.

Relevant to severe COVID-19, but also of more general interest.

https://twitter.com/ArtirKel/status/1287122444046815241

Some of the better papers from related discussion or subsequent reading:

dev.biologists.org/content/141/8/…

biorxiv.org/content/10.110…

frontiersin.org/articles/10.33…

ncbi.nlm.nih.gov/pmc/articles/P…

ncbi.nlm.nih.gov/pmc/articles/P…

intechopen.com/books/gerontol…

Mostly on thymic regeneration.

Several methods have been proposed for doing so.

My impression is that targeting FOXN1 may be the most direct method-- perhaps using a fragment peptide binding to whichever relevant promoter region(s) are determined to be most important.

Needs more study.

Other routes have been proposed.

FOXN1 downregulates members of the protein kinase C family to suppress thymic epithelial cell apoptosis, but inhibiting PKCs affects other organ systems.

Rb1 inhibition boosts FOXN1 but likewise has effects elsewhere. Rb1 is a tumor suppressor.

Therefore targeting FOXN1 directly seems most likely to avoid off-target effects, except that it also promotes continued hair and nail health.

Nude mice are FOXN1 null.

It is interesting that there is a decline in both thymic and hair/nail integrity and function with age.

The binding sequences of FOX transcription factors are insufficient to confer the specificity with which they act.

pnas.org/content/110/30…

FoxN1 binds ACGC, the 'FHL motif,' but so does e.g. FoxN4.

Cofactors are involved. FoxN1 emulation per se may be an impractical approach.

Likewise, FOX transcription factors may also interact with one another in binding.

Example from FOXO3:
ncbi.nlm.nih.gov/pmc/articles/P…

Then again, this article does imply at least some degree of intrinsic specificity across the varying binding sequences of different FOX TFs.

More on the intrinsic specificity of the binding regions--

One might then wonder whether any experiments have compared isolated fragment binding regions from any Fox TF proteins, compared to the full proteins, and whether unconditional transcription of the same genes occurred.

Both the binding domain and transcriptional activation region are required for activity.

onlinelibrary.wiley.com/doi/epdf/10.11…

Note BMP proteins are upstream, e.g. BMPr1a knockout severely downregulates FoxN1.

Paper discusses routes around FoxN1 for hair, but this is tangential.

Transgenic exosomes obtained from thymic epithelial cells in culture were able to counteract thymic involution in mice.

frontiersin.org/articles/10.33…

Other notes:
- corticosteroids promote apoptosis in the thymus
- PPAR-gamma (fenofibrate, telmisartan) promotes thymic adiposity

Conversely, low levels of PPAR-gamma counteract thymic senescence, though this tends to have adverse metabolic effects.

ncbi.nlm.nih.gov/pmc/articles/P…

The adverse effects of corticosteroids on the thymus are suspected of arising from PPAR-gamma activity.

Continued results--

Low expression of PPAR-gamma mostly prevents decline in thymic function with age, in both humans and mice.

Vaccines still work in older people with deficient PPAR-gamma.

But again, PPAR-gamma deficiency promotes diabetes and lipodystrophy.

As another interesting trade-off, nude mice heal injuries without scars, though they are not quite fully able to regenerate lost digits.

sciencedirect.com/topics/neurosc…

miRNAs increasing FOXN1, siRNAs for miRNAs decreasing FOXN1 expression:
hindawi.com/journals/jir/2…

GH (ill-targeted):
journals.plos.org/plosone/articl…

Fibroblast growth factor receptor 3 (ill-targeted):
ncbi.nlm.nih.gov/pmc/articles/P…

Keratinocyte growth factor (likewise):
ncbi.nlm.nih.gov/pmc/articles/P…

An entire functioning thymus can be regrown by using FoxN1 to reprogram fibroblasts and then implanting resulting TECs.

This required a transgenic approach, though:
ncbi.nlm.nih.gov/pmc/articles/P…

Hypothetically could be done ex vivo, but costs would be high and approval unknown.

Fibroblast growth factor 7 regenerates thymus:
jimmunol.org/content/195/12…

Off target at skin/hair/lung:
en.wikipedia.org/wiki/FGF7

Protects in lung injury, but reversible epithelial barrier disruption if used 7-14 days:
tandfonline.com/doi/abs/10.108…

May limit to local use, difficult site.

FoxN1 itself could most likely also be made cell-permeable, given that Foxp3 can be (see below):

pubmed.ncbi.nlm.nih.gov/20937878/

However, it would turn anything it touches into a thymus.

Presumably would still require site use.

Fibroblast growth factor 21 (Fgf21) looks somewhat more promising than Fgf7.

Off-target effects are limited and possibly beneficial.

nature.com/articles/s4159….

Fgf21 apparently delays thymic involution and immunosenescence in mice.

ncbi.nlm.nih.gov/pmc/articles/P…

Then again, brief treatment (3 days) with Fgf7 did not produce any pulmonary adverse effects in this mouse study either, so perhaps useful:

ncbi.nlm.nih.gov/pmc/articles/P…

Mechanism is upstream of IL-7. Effects were larger in older mice, lasted a few months, and were quite repeatable.

Fgf21 also increased lifespan up to 40% in mice.

liebertpub.com/doi/pdf/10.108…

Fgf10 has off-target effects in many organ systems (anything with branching epithelial tissue).

Fgf10 may prevent pulmonary fibrosis after lung injury:
europepmc.org/article/pmc/pm…

I have not seen any thymus studies in vivo using it.

Synthetic agonists of fibroblast growth factor receptors have been developed:
nature.com/articles/nbt12…

Some also promote neurite outgrowth:
pubmed.ncbi.nlm.nih.gov/19634127/

Here is a short peptide that closely emulates Fgf21 (!):
sciencedirect.com/science/articl…
F91-8A07: LPGRTCREYPDLWWVRCY

The only analogue of Fgf7 I have seen so far is Palifermin, a slightly truncated version with improved stability, for use in preventing various chemotherapy side effects.

en.wikipedia.org/wiki/Palifermin

sciencedirect.com/topics/veterin…

It has an evident effect.

Sequence is still a bit long.

https://twitter.com/__ice9/status/1287807131627003904?s=19