III. Diet restriction (DR) and HSC aging
Diet restriction (DR) is the "gold standard" of anti-aging interventions because it 1) consistently increases maximum life span in a wide range of laboratory animals, including long-lived genotypes, while 2) delaying or preventing senescence for a very wide range of markers of aging, and 3) delaying the expression of almost all age-related pathology. How DR retards aging is not known. Recently our group discovered that lifelong DR can reverse HSC aging, opening the door to the possibility that DR retards aging in general by altering patterns of stem cell aging.
Our control group was BALB/cByJ (BALB) mice fed ad lib. Starting at 1 month of age, our diet restricted BALB mice received 75% of the ad lib food intake. Bone marrow cells (BMCs) from 25-month-old, diet restricted donors repopulated nearly 3 times as well as BMCs from old controls, and about 1.7 times as well as those from young controls.
Importantly, DR appears to prevent HSC proliferative exhaustion with aging by protecting clonal stability in HSCs from old BALB mice (Chen et al., 2003). The proportion of erythrocytes and lymphocytes in each recipient that was generated by HSCs from old diet restricted donors correlated well between 5 and 8 months after transplantation, with r = 0.95, so values at 8 months account for 90% of the variance at 5 months. This demonstrates clonal stability, because to sustain a constant proportion of donor to competitor-differentiated cells in a given recipient, the same HSCs must be active. Clonal succession, the alternate, would produce no correlation over time.
Young BALB marrow also showed clonal stability, with r = 0.97, accounting for 94% of the variance. Clonal stability was far less in old BALB marrow without DR, with r = 0.48, accounting for only 23% of the variance. This is consistent with HSC exhaustion.
To test if benefits of DR are due to a short-term response to low food intake, independent of aging, we tested short-term DR in young BALB mice. DR for 5 months had far less effect than DR for 24 months. Short-term DR appeared to slightly improve HSC function, but differences were not significant. Thus, DR alters HSC aging, not a physiological set point, in the marrow stem cell compartment of BALB mice (Chen et al., 2003).
Because DR reduces levels of insulin-like growth factor (IGF), reduces thyroid hormone (TH) responses, and increases corticosterone, we are testing whether one of these changes alone affects stem cell aging. The dwarf mutation reduces both IGF and TH; the little mutation reduces just IGF, which doubled HSC function per million cells in young mice (Sharma et al., 2005). Because DR had little effect on BALB mice at young ages, these mutations may have little effect on HSC function in young mice; HSCs from old mutants will be tested when mice are available.
