Our previous work demonstrates that aging of the immune system is driven to a large extent by aging associated changes in the function of HSCs. HSCs isolated from young or aged HSCs reconstitute distinct T- and B cell subsets that mirror young or aged immune systems. Aging of HSCs is caused by the elevated activity of the small RhoGTPase Cdc42 within HSCs. Inhibition of Cdc42 activity in aged HSCs ex vivo with a small pharmacologic inhibitor termed CASIN resulted in a sustainable rejuvenation of the function of aged HSCs. Importantly, aged HSCs treated with CASIN in vitro generated a youthful immune system capable of mounting a significantly higher immune response to vaccination compared to an immune system originated form untreated old HSCs. Thus, these experiments provide a rationale for testing CASIN in vivo treatment of aged animals to restore immune functions.
The gut houses a large community of microorganisms and bacteria, which is referred to as microbiota. Changes in the gut microbiota have been linked to multiple types of diseases. The gut microbiota interacts with the host immune system and vice versa. The current paradigm holds that changes in the gut microbiota change the function of the immune system of the host. The composition of the gut microbiota changes upon aging. Also the function of the immune system changes with age. My preliminary data support a novel hypothesis in which aging-associated changes in the immune system cause the change in the composition of the microbiota upon aging. I will thus test the extent to which changes in the immune system upon aging control or alter the composition of the microbiota in the gut.
Aging negatively impacts on the T cell receptor repertoire. Since the strength of an immune response correlates directly with the proportion of different antigen-specific TCRs present in the naïve T cell pool, it is thus thought that the reduced TCR clonality contributes to the decline in immune function with age. In previous work, we could show that aging of the immune system is driven to a large extent by aging of HSCs: HSCs isolated from young or old donor mice regenerated distinct immune systems resembling the ones of young or aged mice phenotypically and functionally. Importantly, HSCs, which were rejuvenated in vitro by pharmacological means, regenerated a youthful immune system with a function similar to the one found in young animals. Based on this, we will determine the clonality of T cells via sequencing approaches as a measure of determination of clonality driven by HSCs.