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Intrinsic HSC aging
(reviewed by Zhou et al.157). A very interesting integrative study combining human and mice datasets from young and aged fibroblasts has revealed that NF-kB enforces the aging phenotype and it can be targeted, at least in mice, to revert the aged phenotype.158 Also, NF-kB signaling seems to be activated in aged tissues and it negatively reg- ulates autophagy (reviewed by Salminen et al.159).
hematopoietic system has been studied under inflamma- tion stimuli in mice showing that aged LT-HSC present with an altered myeloid-biased response to inflamma- tion.18
In another study, carried out in mice, aged HSC were shown to be failing in down-regulating NF-kB signaling when an acute inflammatory stimulus occurs,43,160 and that this is dependent on the levels of Rad21/cohesin.160
Figure 4. Interconnections between dif- ferent biological processes involved in intrinsic hematopoietic stem cell (HSC) aging. We have defined five biological processes affected during aging that cannot be compartmentalized from each other. They are interconnected and a change in one of the processes might affect the others, and all of them converge in the final outcome of intrin- sic aging. Specific documented inter- connections between different biologi- cal processes involved in intrinsic HSC aging are numbered (1 to 10).
Table 1. Details of documented connections between different biological processes involved in intrinsic hematopoietic stem cell aging.
More recently, NF-kB signaling activation in the
Connection
Process
Reference
(35)
(114) (53-56) (107) (72)
(12,44) (127,128)
(28)
(15,28) (39,45)
1 -Change in some metabolite levels affect to the activity of methylases on DNA methylation
2 -SIRT7 overexpression in aged HSC, preserves against mitochondrial stress
3 -Specific mutations in epigenetic regulators such as DNMT3, TET2 or ASXL2 tend to appear upon ageing
4 -Accumulation of ROS is related to augmented DNA damage
5 -Pot1 has a dual role inhibiting ATR-dependent DNA damage repair at telomeres at the same time that it controls the expression of genes involved in ROS reduction and mTOR signaling
6 -Wnt non-canonical pathway activates Cdc42 in young HSC inducing ageing-like phenotypes
7 -The UPS malfunctions in aged HSC which inhibits the correct degradation of histone modifying enzymes such as HDAC1 and DNMT1
8 -rRNA genes are hypomethylated in aged HSC which involves increased rRNA transcription, more ribosomal
10 -The UPS malfunctions in aged HSC which inhibits the correct degradation of Notch signaling-related factors
biogenesis and higher levels of protein translation
9 -TGF-β signaling-related genes are enriched in young HSC by ATAC-seq and Wnt signaling-related genes are enriched in old HSC by ATAC-seq
HSC: hematopoietic stem cell; ROS: reactive oxygen species; UPS: ubiquitin proteasome system.
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