Hematopoietic stem cells are responsible for generating blood and immune cells. They are vital to the function of the immune system. With age their function alters in unfavorable ways, leading to the production of too great a proportion of myeloid cells versus lymphoid cells, but also declines in total. This is one of the contributing factors in the aging of the immune system, which is itself very influential of the progression of aging and age-related frailty. Thus potential ways to restore the hematopoietic stem cell population to a more youthful capacity to generate immune cells is an important part of the toolkit for human rejuvenation that lies somewhere ahead of us.
A key step in hematopoietic stem cell (HSC) aging research was achieved in 1996, revealing that HSCs from old mice were only one-quarter as efficient as those from young mice at homing to and engrafting the bone marrow (BM) of irradiated recipients. Aged HSCs are inferior to young HSCs and show incomplete reconstitution potential. This discovery established that the HSC aging process is accompanied by functional decline. Since then, differences between young and aged HSCs have been elucidated from multiple aspects, and the mechanisms of HSC aging have been gradually illustrated.
Different studies have explored the mechanisms by which aged HSC dysfunction occurs. Altered expression levels of multiple genes and mutation of some specific genes were shown to lead to HSC aging. In addition, inhibition of some signaling pathways, such as the mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways, was closely related to HSC aging. Furthermore, epigenetic perturbations also drove both cellular functional attenuation and other aging manifestations. Finally, some factors in the HSC niche, such as cytokines and enzymes, are also crucial during the aging process.
Currently, there is no doubt that HSCs show declining function during aging, but whether this dysfunction is reversible remains unclear. Notably, researchers showed that prolonged fasting can rejuvenate HSCs. Prolonged fasting reduces circulating IGF-1 levels and protein kinase A (PKA) activity in various cell populations and promotes stress resistance, self-renewal, and lineage-balanced regeneration. Further, HSC aging is accompanied by alterations in gene expression. Therefore, overexpressing knocking down the expression specific genes might be strategies to prevent HSC dysfunction. Reduced Satb1 expression was found in aged HSCs and associated with compromised lymphopoietic potential, and forced Satb1 overexpression partially restored that potential.
Aged mice exhibit increased mTOR signaling in HSCs, and mTOR inhibitor rapamycin can enhance the regenerative capacity of HSCs from aged mice, improve their immune response, and extend their life span. Cdc42 regulates diverse cellular functions, including cellular transformation, cell division, migration, enzyme activity, and cell polarity. Aged HSCs show elevated Cdc42 activity, and Cdc42 inhibition has been demonstrated to rejuvenate HSC functions. Further, inhibition of p38 MAPK reduces reactive oxygen species (ROS) levels and contributes to HSC rejuvenation. TN13, a cell-penetrating peptide-conjugated peptide, inhibited p38 activity and rejuvenated aged HSCs by reducing ROS.
One strategy to delay aging is to restore cell functions, while another is to clear senescent cells. Senescent cells accumulate with age and contribute to the development of aging-related diseases. Depletion of senescent cells mitigated irradiation-induced premature aging of the hematopoietic system and rejuvenated aged HSCs in normally aged mice.