Hematopoietic Stem Cell Ageing, Immunosenescence and Prospects for Rejuvenation

Progress in health care and general life standards has led to pronounced and continuous increases of the ageing population.

This poses severe challenges to our healthcare systems and emphasizes the need for intervention strategies that can promote a healthier ageing process.Immuno-senescence (IS) is used as a collective term for reduced immunity, and most often have an ageing-component.

Apart from underlying susceptibility to infectious diseases, IS leads to reduced efficacy of immune-cell based treatments.

We and other have shown that the reduced lymphopoiesis with age is strongly influenced by intrinsic alterations in hematopoetic stem cells (HSCs). However, several questions remain: 1) An emerging issue is that individual HSCs do not respond homogenously to ageing. Why and how some HSCs are more strongly affected by age remains unknown.

This includes the stability of the "ageing HSC-state", including the prospects for selective stimulation/expansion of those chronologically aged HSCs with more "youthful" properties. 2) What is the influence of the ageing environment on HSC function? 3) Is it possible to reduce/reverse features of HSC ageing by alterating metabolism, of which reduced NAD+ levels has emerged as a primary candidate for organismal ageing.In my proposal, I will approach these questions by leveraging on the mouse as a model system of IS and HSC ageing.

The will permit assessments of cellular and molecular changes at the highest possible (clonal) resolution.