Table 1.
Attempts to rejuvenate aged HSCs.
| Intervention: | Methodology: | Result: | Reference: | |
|---|---|---|---|---|
| Systemic | Rapamycin treatment | 4mg/kg rapamycin injection every other day for 6 weeks in 22-month-old mice | More youthful HSC numbers and HSC cell cycling in vivo; improved engraftment and lymphoid output upon HSC transplantation; increased B cell progenitors and vaccine response in primary mice | Chen et al, 2009174 |
| Prolonged fasting | 8 cycles of 48 hour fasting in 18-month-old mice | Decreased frequency of myeloid-biased HSCs and increased peripheral blood lymphocytes in primary mice | Cheng et al, 2014183 | |
| Exposure to young bloodborne factors | Heterochronic parabiosis (1 month) or injection of young plasma (8x over 1 month) in 24-month-old mice | No effect on old HSC function (engraftment or myeloid bias upon HSC transplantation, division time in vitro) | Ho et al, 2021152 | |
| Exercise | 7-week long free access to running wheel in 18-month-old-mice | No effect on HSC function (engraftment or myeloid bias upon HSC transplantation) | Ho et al, 2021152 | |
| Calorie restriction | 30% calorie restriction for 9 months, analysis of 12-month-old mice | Decreased HSC number and decreased frequency of myeloid-biased HSCs in primary mice; improved engraftment and lymphoid output upon HSC transplantation | Tang et al, 2016184 | |
| 40% reduction in calorie intake in 3.5- to24-month-old mice | No effect on HSC function (engraftment or myeloid bias upon HSC transplantation) | Ho et al, 2021152 | ||
| Microenvironmental | Endothelial cell transplantation | Young endothelial cells infusion for 4 consecutive days in 24-month-old-mice followed by sublethal irradiation and whole BM transplantation 1 month later | Improved peripheral blood mature cell production following irradiation; improved engraftment and lymphoid output upon whole BM transplantation | Poulos et al, 2017155 |
| Small molecule mimetic of β3-adrenergic signaling | 12-week delivery with osmotic pumps in 20- to 24-month-old-mice | Improved engraftment and lymphoid output upon primary HSC transplantation and secondary BM transplantation | Maryanovich et al, 2018109 | |
| 8 weeks daily injection in progeroid mice | Decreased myeloid and increased lymphoid cells in peripheral blood | Ho et al, 2019118 | ||
| IGF1 stimulation | In vitro treatment of 14-month-old HSCs with 100ng/ml IGF1 | Rescue of γH2AX foci, Cdc42 polarization, mitochondrial membrane potential, and morphology | Young et al, 2021105 | |
| IL1R antagonism using Anakinra | 3 weeks daily injection in 24-month-old mice before HSC transplantation | Increased lymphoid output in HSC transplantation; no difference in engraftment | Kovtonyuk et al, 2022119 | |
| 2 weeks daily injection in 24-month-old mice before immunophenotyping and HSC transplantation | Decreased HSC numbers in primary mice; no effect on HSC function (engraftment or myeloid bias upon HSC transplantation) | Mitchell et al, 2023104 | ||
| 2 weeks daily injection starting 2 days prior to 5-FU myeloablation in 24-month-old mice | Improved regenerative response; Increased B cell and red blood cell recovery in peripheral blood; increased lymphoid-biased progenitors and erythroid progenitors in BM | Mitchell et al, 2023104 | ||
| Netrin-1 supplementation | 10 injections over 2-week period of 4 μg of recombinant murine Netrin-1 in 18-month-old mice | Improved engraftment and lymphoid output in primary mice | Ramalingam et al, 2023185 | |
| Microbiome modulation | 1-year-old germ-free mice or 8-week antibiotic treatment in 2-year-old mice | Improved lymphoid output upon HSC transplantation; no difference in engraftment | Kovtonyuk et al, 2022119 | |
| Oral gavage in 20- to 24-month mice with fecal slurry from 7- to 8-week-old mice | Improved B cell numbers in primary mice, improved chimerism and HSC engraftment in transplantation | Zeng et al., 2023160 | ||
| Epigenetic | Cdc42 inhibition | In vitro treatment with small molecule inhibitor (CASIN) in 20- to 26-month-old mice | Rescue of Cdc42 and H4K16 acetylation polarization; improved myeloid bias upon primary HSC transplantation; improved engraftment and myeloid bias upon secondary BM transplantation | Florian et al, 2012165 |
| Satb1 overexpression | Retroviral transduction of LSK cells from 2-year-old mice In vitro | Improved growth of T cells, B cells and NK cells in co-culture with lymphopoiesis supporting stromal cells | Satoh et al, 2013166 | |
| Yamanaka factor reprogramming | iPSC generation from HSC clones from 23-month-old mice followed by redifferentiation into HSCs (“iHSC”) | T cell chimerism following transplantation of iHSC derived from aged HSC clones which previously did not exhibit T cell output | Wahlestedt et al, 2017167 | |
| Metabolic/mitochondrial | Rapamycin treatment | 4 mg/kg every other day for 6 weeks in 22-month-old mice | Decreased HSC numbers; improved BrdU incorporation; decreased p16 and Arf expression; improved engraftment and lymphoid output upon HSC transplantation; improved vaccine response in vivo | Chen et al, 2009174 |
| Sirt2 overexpression | Lentiviral transduction of HSCs from 20- to 24-month-old mice in vitro | Decreased caspase-1 activation; improved engraftment and lymphoid output upon HSC transplantation | Luo et al, 2019139 | |
| Sirt3 overexpression | Lentiviral transduction of lineage-depleted BM cells from 18- 24-month-old mice in vitro | Improved engraftment upon HSC transplantation | Brown et al, 2013140 | |
| Sirt7 overexpression | Lentiviral transduction of murine HSCs in vitro | Reduced mitochondrial protein folding stress; improved engraftment and lymphoid output upon HSC transplantation | Mohrin et al, 2015141 | |
| NLRP3/Caspase-1 knockdown | Lentiviral shRNA knockdown of HSCs from 20- to 24-month-old mice in vitro | Improved engraftment and lymphoid output upon HSC transplantation | Luo et al, 2019139 | |
| Nicotinamide riboside supplementation | 3mg/mL in drinking water for 8 weeks in 20- to 24-month-old mice | Decreased HSC and GMP frequency and number in primary mice; more youthful HSC transcriptome; improved metabolic parameters; improved engraftment in HSC transplantation | Sun et al, 2021176 | |
Many groups have applied interventions to old HSCs, aimed at returning them to a more youthful state. These attempts span a wide range of techniques and biological mechanisms and have had mixed success. GMP, granulocyte-macrophage progenitor, iPSC: induced pluripotent stem cell, LSK: lineage−/Sca-1+/c-Kit+, shRNA: small hairpin RNA, 5-FU: 5-fluorouracil.