Autophagy in stem cell aging

Abstract

Aging is responsible for changes in mammalian tissues that result in an imbalance to tissue homeostasis and a decline in the regeneration capacity of organs due to stem cell exhaustion. Autophagy is a constitutive pathway necessary to degrade damaged organelles and protein aggregates. Autophagy is one of the hallmarks of aging, which involves a decline in the number and functionality of stem cells. Recent studies show that stem cells require autophagy to get rid of cellular waste produced during the quiescent stage. In particular, two independent studies in muscle and hematopoietic stem cells demonstrate the relevance of the autophagy impairment for stem cell exhaustion and aging. In this review, we summarize the main results of these works, which helped to elucidate the impact of autophagy in stem cell activity as well as in age-associated diseases.

Keywords: HSC; MSC; aging; autophagy; stem cell.

Figure 1

Autophagy in stem cell function. Under normal conditions, basal autophagy is high in quiescent stem cells (SCs), at least in MSCs and HSCs, and MA is necessary for the maintenance of quiescence state and self‐renewal activity. Under stress conditions such as aging, there is a decline in stem cell numbers and activity that impairs stem cell activation, lineage differentiation and consequently, there is a failure in regenerative capacity. These processes correlates with reduced MA as the levels of several autophagy machinery genes are decreased in aged SCs. Autophagic function, measured by different methods, is also impaired in aged SCs. Maintenance of self‐renewal, SC activation, differentiation ability, and regeneration capacity in muscle and hematopoietic system is mediated by MA genes such as Atg5, Atg7, or Atg12 (Garcia‐Prat et al., 2016; Ho et al., 2017).

Figure 2

Effect of aging in young and old stem cells in terms of autophagy activity. There is altered autophagy activity between young and old SCs, at least in MSCs and HSCs. Aged SCs present decreased autophagy activity (specially reduced MA) that correlates and promotes impaired self‐renewal, SC exhaustion and defective regeneration capacity. Mechanistically, decreased autophagy activity induces loss of proteostasis, increased mitochondrial activity, increased oxidative stress, and activated metabolic state in both MSCs and HSCs. However, there are also differences between MSCs and HSCs in terms of autophagy function with aging. Autophagy impairment causes MSC to undergo senescence whilst it alters HSCs metabolism and replication stress response. Pharmacological reactivation (with rapamycin and spermidine) or re‐establishment of MA (with genetic overexpression of Atg7) reverses SC function and restores regenerative capacity. Similarly, a proportion of high autophagy SCs maintains self‐renewal and preserves regenerative potential (Garcia‐Prat et al., 2016; Ho et al., 2017).