Cell Biology

“Normal” aging itself is a complex degenerative process occurring in all individuals at the molecular, cellular and systemic level, while frailty is a state characterized by a more progressive decline in the physiological and adaptive capacity. Frailty results in morbidity, institutionalization and significantly decreases social participation and the life expectancy.

Since 20% of men and women older than 75 years show no sign of frailty, whereas also 20% of people with same age are highly frail, there is evidence for a wide variety in the degree of frailty among different elderly. The underlying reasons why elderly are differentially affected by frailty still remain elusive. Since adult stem cells, such as Mesenchymal Stromal Cells (MSCs), play a curial role in tissue maintenance & regeneration, it is reasonable to presume that some of these aging aspects reflect a decline of their regenerative potential. Indeed, our previous studies showed an age-related decline in bone repair, which could be tracked back to a decline in MSC’s regenerative function. Aging directly alters MSC’s function, but age-related alterations in the local and systemic environment (serum) additionally impair MSC survival & regeneration ability, thereby contributing to the age-related delay in regeneration. Whether the link between age-related serum changes, compromised MSC function, and tissue properties is also valid for the frailty status is our current focus. We aim to uncover how age-related changes at the molecular, cellular and systemic level contribute to the age-related pathophysiology of frailty. We hypothesize that human MSCs from frail elderly could be, at least partially, “rejuvenated” by specific molecular mediators in the serum of young, healthy donors. Specific aims are: a) to validate our findings using an existing human serum cohort, b) to identify the causative serum factor(s) using “omics” approaches, and c) to characterize the impact of an exercise intervention on the identified molecular alterations and MSC function using longitudinal serum samples of frail elderly.

We want to learn from the nature of the senescence phenotype to take therapeutic advantage of those parts which are positive for (bone) regeneration, but overcome the disadvantages compromising new tissue formation.

ASC (Adult Stem Cell) aging is characterized by a reduced response to environmental stimuli, which leads to increased cellular senescence and a progressive decline in regenerative capacity. However, recent evidence implies that cellular senescence can also play a positive role in tissue regeneration, possibly due to paracrine signaling. The interplay between mechanical stimulation and senescence of ASCs during bone regeneration is still poorly understood. Using 3D bioreactors, we currently investigate the intracellular signaling response to mechanical stimuli of young and aged human MSCs (Mesenchymal Stromal Cells) and analyze their secretion pattern. Concurrently, we explore the interaction of mechanical stimulation and cellular senescence and its relevance for fracture healing in vivo using mouse models with reduced and enhanced cellular senescence.