Common fasting methods. Different fasting regimens (Table 1) can affect metabolism, aging, disease and mortality in simple organisms and mammals. IF includes various eating patterns; water-only fasting or severely restricted (over 50%) calorie intake lasts between 12 and 48 hours, and in most cases is repeated in cycles occurring every day to once per week 25. There are several types of IF diets commonly adopted in rodents and human clinical studies: complete water-only fasting that occurs every other day (also called alternate-day fasting (ADF)) 26-28 ; 70% energy restriction every other day 27-29 ; the 5:2 diet, which provides between 500 and 700 calories for 2 days per week 30,31 ; and time-restricted feeding (TRF), in which food intake is in most cases restricted to 6-12 hours per day 32,33. Thus, IF regimens usually encompass a period in which only water is consumped or calorie intake is very low, which is followed by a normal feeding period that in most cases lasts between 12 and 48 hours.

We have found that panel A in Figure 5 (subpanel Old + C) is mistakenly a duplication of panel H in Figure 4 (subpanel Old + FL). According to our inspection of the original data sets, this is due to a mistake during the assembly of the panels. We show here the amended correct images for Figure 5, panel A (Old + C).The change does not affect the original conclusions presented. We apologize for this mistake. All authors approve of this correction. Old + Thr

BackgroundThe decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac.ResultsHere, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs.ConclusionsCollectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1557-3) contains supplementary material, which is available to authorized users.

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age‐related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long‐term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin‐cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma‐derived OPN for HSC aging and identify thrombin‐cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging.