Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

Abstract

Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.

Keywords: Cdc42; autophagy; calorie restriction; health span; lifespan; parabiosis; partial reprogramming; senolytic; stem cell aging; stem cell rejuvenation.

Fig. 1

Cartoon summarizing the effects of aging on several human somatic stem cells [5, 7, 17, 76, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100]. The strategy proposed in the cartoon suggests the use of rejuvenated stem cells as a therapeutic tool to improve the homeostasis of the entire tissue/organ by restoring the stem cell regenerative potential. For this reason, stem cell rejuvenation can represent a promising approach to simultaneously rejuvenate several organs and to globally improve organism health and lifespan in the elderly. Aging effects on stem cells are written in gray when they have been proven in mice, but not in human. Graphics created with Biorender.

Fig. 2

Cartoon depicting interventions to rejuvenate aged somatic stem cells. Several strategies to increase stem cell function and lifespan have been described so far. This cartoon summarizes the interventions proposed to rejuvenate aged somatic stem cells and their effect, specifying the stem cell type where the intervention has been experimentally applied, and highlighting when the described intervention had an effect in extending the organism lifespan. A question mark indicates cases with contradictory results. Graphics were created with Biorender.

Fig. 3

Cartoon summarizing the major findings described in Montserrat et al. [73]. Rejuvenation of skeletal muscle stem cells (MuSCs) and hematopoietic stem cells (HSCs) with a short treatment with CASIN (Cdc42 activity‐specific inhibitor) increases skeletal muscle function and restores the hematopoietic differentiation output. CASIN treatment restores HSC epipolarity, increases transcriptional network connectivity and restores HSC localization within the bone marrow to the same niches occupied by young HSCs. Importantly, the transplantation of CASIN‐rejuvenated HSCs is sufficient to increase heath and lifespan in immunocompromised aged recipients, directly linking stem cell rejuvenation with lifespan extension. Graphics were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/.