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Intrinsic HSC aging
Atg1scKO mice, autophagy is deregulated and aged HSC present with reduced quiescence, an increased rate of dif- ferentiation biased toward the myeloid lineage, and an increment in OXPHOS rates. In HSC from conditional knockout Atg12 mice, changes in the methylome of essen- tial genes for the formation of autophagosomes have been reported. These changes could be explained by the alter- ations of metabolite levels caused by the loss of autophagy, such as reduction of S-adenylmethionine (SAM), methyl-donor co-substrate for methylases, and an increment in alpha-ketoglutrate (αKG), a co-factor for demethylases.35,116
Intriguingly, it was also reported that a fraction of aged HSC showing high levels of autophagy displayed higher resistance to exhaustion, as demonstrated by secondary transplants in mice. These data suggest that, although aged HSC are apparently phenotypically equal, there might be a subset that maintains the autophagy levels of young HSC and are consequently resilient to aging, pre- serving their stemness and regenerative potential.35
Nowadays, autophagy represents a target for therapeu- tic interventions in vitro and in vivo, with clinical trials ongoing for several aged-related hematopoietic disorders, such as AML.117,118 A number of these autophagy-targeting approaches are based on the use of different mTOR path- way inhibitors119 and could offer a potential therapeutic approach to improve healthy aging as well.
Proteostasis role in hematopoietic stem cell aging
Homeostasis of proteins, also called proteostasis, indi- cates a situation in which the proteome within the cell reaches an equilibrium by balancing the elimination of misfolded or damaged proteins while preserving at the same time the necessary levels of properly assembled proteins.36
Proteostasis relys in part on protein translation, that is, it is directly dependent on ribosomal levels and biogene- sis. Transcription of rRNA genes is regulated by the methylation state of the rRNA genes themselves. Interestingly, it has been shown that ribosomal biogene- sis is a target of aging with hypo-methylation of rRNA genes and higher levels of transcription in aged HSC.28
Cell polarity and aging
Cell polarity is a universal biological feature, and age seems to be a factor contributing to the loss of cell polar- ity regulation.120 Polarity can be defined as the asymmet- ric distribution of cellular components, biomolecules and structures within the cells. The number of genes linking polarity and aging is strikingly increasing and, conse- quently, the number of targets to be investigated in order to ameliorate aging is growing.121 For instance, in the baker yeast S. cerevisiae, it has been demonstrated that damaged and aggregated proteins are retained in the mother cell establishing an asymmetry that marks which of the cells is aged. The lysine deacetylase Sir2p is responsible for this, since it regulates the ultimate correct folding of actin in order to keep the protein aggregates in the mother (aged) cell.122 This mechanism is highly con- served among organisms, as is shown in Drosophila larval and adult stem cells (female germline and intestinal stem cells). Here, proteostasis seems to be, at least in part, reg-
ulated by asymmetric division: the shortest life-span daughter inherits the majority of damaged proteins leav- ing the stem cell daughter as damage-free as possible.123 This is particularly important in adult stem cells, since the accumulation of damaged or misfolded proteins can con- tribute to aging.36,124 Asymmetry has been described in HSCs for several proteins such as Cdc42, Dlg, Crumb3, Scribble, H4K16ac, LaminA/C. Polarity of these proteins is characteristic of young HSC and apolarity is more prominent in aged stem cells.14,15,29,44,125 CD71, the transfer- rin receptor, and CD53 and CD63, endosomal-associated proteins are also described to be polar and confer asym- metry during division of HSC, being characteristic of the most primitive population of HSC when they are togeth- er with the stem marker CD133.126
In summary, despite the wide experimental evidence linking loss of cell polarity and the proteostasis decay upon aging, only a few pharmacological approaches have been proposed so far. For example, CASIN was success- fully used to recover HSC cell polarity and rejuvenate function of aged stem cells in mice.14
Protein degradation systems and folding stress response
The ubiquitin proteasome system (UPS) is a complex of factors responsible for tagging proteins for signaling or for degradation, and is, therefore, implied in regulating pro- teostasis in eukaryotic cells.39 It has been shown that HSC function can be affected by the absence or malfunction of different UPS system factors, such as E3 ligases or deubiq- uitinases. This happens in an indirect way, affecting the accumulation of its protein targets, like STAT5, c-myc or Notch, and promoting exacerbated responses.39 Moreover, the UPS regulates the degradation of histone modifying enzymes such as HDAC1 and DNMT1.127 This means that the epigenetic changes observed might be a consequence of the proteasome decay occurring with aging.128
Another system controlling proteostasis is the unfolded protein response that occurs in the endoplasmic reticulum (UPRER). This system preferentially induces apoptosis under ER (endoplasmic reticulum) stress in HSPC com- pared to closely related progenitors. The biological rele- vance of this mechanism relys on the elimination by apoptosis of those HSC that are under ER stress due to accumulation of misfolded proteins.129 Intimately related with the UPRER, protein chaperones function by enhanc- ing the correct folding of proteins, and, in turn, protecting against UPR-induced apoptosis. For example, the overex- pression of the UPRER factor ATF4 and the co-chaperone ERFJ4 in HSC isolated from human cord blood samples confers greater repopulation capacity compared to non- modified HSC or progenitor cells.129
UPRER is up-regulated in intestinal stem cells (ISC) in Drosophila with aging and oxidative stress, which leads to age-related dysplasia and proliferation,130 although in other biological organisms, such as C. elegans, it promotes longevity.131 In mice, UPRER is transiently hyper-activated after fasting-re-feeding periods as has been observed by the overexpression of Xbp1, a transcription factor that activates the expression of the UPRER components. Furthermore, Xbp1 overexpression leads to hypo- glycemia due to an improvement in insulin sensitivity and triggers lipolysis in the liver.132 Adaptation to fasting is linked to the UPRER system through IRE1α, a protein
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