There has been considerable interest in using hormone replacement therapy to rejuvenate the involuted thymus during aging.
GH and insulin-like growth factor-I (IGF-I), a mediator of GH actions, have been of particular interest because of their thymopoietic effects and the fact that their serum concentrations decline during aging.
However, treatment of aging rodents with either GH or IGF-I does not restore thymus cellularity to levels present in young animals, suggesting that additional defects might limit the magnitude of their effects.
In particular, deficiencies have been reported to accumulate in the bone marrow T cell precursor compartment during aging.
Aging in mammals is accompanied by a decline in immune responsiveness that results, in part, from defects accumulating in the T cell compartment.
Because reduced production of T cells in the thymus, as it undergoes involution, could significantly contribute to this phenomenon, there has been considerable interest in developing means to either restore T cell production in the involuted thymus or delay its rate of decline.
GH and insulin-like growth factor-I (IGF-I) have been of particular interest in this regard, because they have been shown to stimulate thymopoiesis in young animals.
Both thymus size and cellularity increase significantly after treatment of young rodents with these hormones, and IGF-I administration can increase thymic cellularity in mice after cyclosporine treatment or in diabetic rats.
The production of GH and IGF-I decline steadily with age, which in turn, could be a factor that contributes to the decline of thymopoiesis.
This possibility has formed the rationale for studies in which GH or IGF-I was administered to old individuals in an attempt to rejuvenate the involuted thymus.
Although thymus cellularity increases in aged rodents treated with either GH or IGF-I, a consistent finding was that cell production was not restored to levels present in young animals.
For example, whereas IGF-I treatment doubled the number of cells in the thymus of 9-month-old mice, the absolute number of thymocytes remained only 25% of that present in young animals.
Similarly, GH treatment increased thymic cellularity in aged animals by only 10-20 million thymocytes.
The similarity of GH and IGF-I effects is not surprising, because IGF-I is thought to mediate many GH actions.
Higher increases in thymic cellularity were observed after transplantation of GH-secreting GH3 tumor cells into 18- to 24-month-old rats, although the total thymocyte number remained below numbers in young rats.
Taken together, these findings suggest that there may be limits on the extent to which GH, IGF-I, or other thymopoietic hormones can stimulate thymopoiesis in old animals.
One reason for this is that additional defects develop during aging.
Deficiencies that have been reported in the bone marrow T cell precursor compartment of old animals would be particularly relevant to this hypothesis.
Sustained cell production in the thymus is thought to be dependent on the migration of T cell precursors from the marrow to thymus, and the frequency of bone marrow thymocyte precursors in old mice has been shown to be reduced by 40-fold.
In addition, these cells display a reduced potential to colonize the thymus in vitro and in vivo.
These observations raise the possibility that hematopoietic defects that accumulate during aging limit the degree to which hormones can rejuvenate the involuted thymus and suggest that treatment of aged mice with a combination of hormone therapy and young hematopoietic cells should be more effective at increasing thymus cellularity than administration of hormones alone.
In view of this, 18-month-old mice were administered either recombinant IGF-I, bone marrow cells from young mice, or a combination of IGF-I and young bone marrow cells.
Thymus cellularity in the latter group of mice was significantly higher than in animals treated with hormone or bone marrow transplantation alone, suggesting that optimal therapies for restoring thymus cellularity must address both endocrine and hematopoietic defects that accumulate during aging.
Results from in vitro studies using fetal thymic organ cultures suggest that IGF-I acts by potentiating thymic colonization by bone marrow T cell precursors and/or that the hormone affects some other event soon after thymus colonization.