Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

Abstract

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways.

Dietary Regulation of Adult Stem Cells

“…Although the effects of CR on physiology have been found to promote health, a recent study by Tang et al [24•] suggests that caloric restriction may exert both beneficial and adverse effects on hematopoiesis. It has been observed that during aging in C57BL/6 mice, HSCs expand in number but have reduced functionality, such as lowered self-renewal capability and skewing of differentiation towards the myeloid lineage, due to stress associated with active HSC cycling [25].…”

“…It has been observed that during aging in C57BL/6 mice, HSCs expand in number but have reduced functionality, such as lowered self-renewal capability and skewing of differentiation towards the myeloid lineage, due to stress associated with active HSC cycling [25]. Four to nine months of caloric restriction in mice increases HSC quiescence and prevents age-related increases in HSC numbers, suggesting that CR conditions are beneficial in reducing proliferation-associated stress [24•]. CR conditions also rescue HSC skewing towards the myeloid lineage, as the number of lymphoid-biased HSCs and myeloid-biased HSCs are similar.…”

“…The decrease in lymphoid progenitor numbers with CR in aged mice may hamper their ability to respond to infections [26]. Interestingly, treatment of aged CR mice with IGF-1 decreases the number of quiescent HSC numbers close to ad libitum levels and further increases myeloid numbers compared to CR mice [24•]. On the other hand, treatment with IL-7 and IL-6 (cytokines that promote lymphoid development) in aged mice restores lymphoid progenitor differentiation.…”

Short-Term Fasting Induces Cell Cycle Arrest in Immature Hematopoietic Cells and Increases the Number of Naïve T Cells in the Bone Marrow of Mice

“…The number of hematopoietic stem cells in BM was changed with aging and the function of repopulation as stem cells in vivo diminished when hematopoietic stem cells form aged mice were transplanted along with competitor cells. Diet restriction restored not only the number of stem cells but also the repopulation capacity [31, 32]. In this study, the number of colonies was not different between SF and NC mice in the first, secondary, and tertiary courses.…”

The epigenetic basis of hematopoietic stem cell aging

“…Although global changes to the epigenome occur during aging, it is more likely that the functional decline in aging HSCs is due to specific changes to key regulatory loci. Examining the molecular changes associated with other approaches of rejuvenating old HSCs such as transcription factor-based reprogramming to induced HSCs (iHSCs) 70,71 , calorie restriction 72 , or exposure to a young circulatory system through parabiosis 73 may identify epigenetic differences at critical loci which enforce the aging phenotype. Reversal of these specific modifications may provide a mechanism to restore self-renewal and lymphoid differentiation potential to old HSCs.…”