Autophagy is Protective Against Hematopoietic Stem Cell Aging
Hematopoietic stem cells in the bone marrow give rise to red blood cells and immune cells. Like all stem cell populations, they become increasingly dysfunctional with age, however. In part this is damage to the stem cells themselves, but a sizable portion of the problem results from age-related damage and change in the niche of supporting cells that is needed to maintain a stem cell population. It is hoped that restoring stem cell function in older individuals will go a long way towards producing slowed aging and improved health. At present the research community is progressing towards this goal one stem cell population at a time, but it seems plausible that some discoveries will be broadly applicable to all stem cells in the adult body.
Aging of the hematopoietic system promotes various blood, immune, and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction. Autophagy is central for the benefits associated with activation of longevity signaling programs, and for HSC function and response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional. However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown.
Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche. We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment.
Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.