Hematopoietic senescence is postponed and hematopoietic stem cell function is enhanced by dietary restriction

Objective. The aim of this study was to test dietary restriction (DR) as an intervention to alleviate senescence-associated functional defects in hematopoietic stem cells (HSCs). Materials and Methods. BALB/cByJ (BALB) mice were fed ad libitum (AL) or were diet restricted (DR) to 75% of the AL food intake after I month of age. Peripheral blood and bone marrow cell compositions were compared in 3- and 25-month-old AL (AL-3, AL-25) mice and in 25-month-old DR (DR-25) mice using fluorescence-activated cell staining. Relative HSC functions in vivo were compared using competitive repopulation, and were also tested in 6-month-old BALB mice to measure the effects of short-term DR. Results. Compared to AL-3, AL-25 blood had significantly lower levels of red blood cells and hemoglobin. AL-25 marrow contained less than half the concentration of Lin(-)CD34(-)Sca1(+) CD117(+) HSCs and showed only half the in vivo functional ability of AL-3 marrow. In vivo, AL-25 HSCs failed to produce the strong correlations over time that demonstrate clonal stability during competitive repopulation. These correlations were shown in AL-3 HSCs. DR for 24 months alleviated hematopoietic deficiencies in the blood, increased concentrations of bone marrow Lin(-)CD34(-)Sca1(+)CD117(+) HSCs and improved HSC functional abilities in DR-25 mice to values far greater than those in normally aged mice. Surprisingly, HSC function in 25-month-old DR mice was better than that in young adults. Degrees of recipient repopulation by HSCs from DR-25 mice also correlated well over time, demonstrating clonal stability. Shortterm DR for 5 months also improved HSC function, but to a much smaller degree. Conclusions. Aged BALB mice show hematopoietic and HSC senescence and clonal succession. Lifelong DR slows hematopoietic senescence and prevents HSC aging. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.