Table 1.

Interventions that contribute to HSC rejuvenation or prevent HSC aging

Rejuvenation Approach	Mechanism	Rejuvenation Phenotype	References
Pharmacological interventions
Nicotinamide riboside	NAD+	Elevates NAD+ levels through SIRT1 activation, Enhances mitochondrial function and proteostasis in aged HSC	[84]
Metformin	AMPK activator	Downregulates mTOR, Improves HSC numbers and competitive repopulation ability	[94]
Rapamycin	mTOR inhibitor	Reduces the number of HSC to normal (young) levels, Restores HSC self-renewal upon transplantation, Reduces the frequency of myeloid-biased HSC	[156]
Casin	Cdc42; H4K16 acetylation	Inhibits Cdc42 activity, Enhances competitive repopulation ability, Reduces the frequency of myeloid-biased HSC	[116]
Senolytic drug	Inhibitor of BCL- 2 and BCL-xL	Depletes senescent HSC from the bone marrow, Attenuates myeloid skewing, Improves reconstitution potential of HSC following serial transplantation	[19, 22]
NAC (N-acetyl L- cysteine)	ROS scavenger	Improves the replicative potential of HSC	[69, 65]
Nutrient sensing
Caloric restriction	IGF-1, mTOR, AMPK, FOXO, Sirtuins	Reduces the frequency of myeloid-biased HSC, Restores youthful HSC self-renewal ability and regenerative capacity upon serial transplantation	[157, 75]
Resveratrol	Caloric mimetic	Increases mitochondrial biogenesis of HSC through activation of SIRT1 and PGC1α, Increases the total number of functional HSC	[93]
Genetic modulator
Satb1 overexpression	Epigenetic modification	Overexpression enriches lymphoid progeny of aged HSC	[132]
Sirt3 overexpression	ROS, mitochondrial function	Restores long-term competitive repopulation ability during serial transplantation, Decreases ROS production	[158]
Sirt7 overexpression	Mitochondrial function	Overexpression reduces mitochondrial protein folding stress, Rescues myeloid-biased differentiation, Improves reconstitution potential of HSC	[102]