Aging of Mesenchymal Tissues

‘Aging seems to be the only available way to live a long life.’ (Daniel Francois Esprit Auber) Thus, the only remaining question is HOW do we successfully grow old but avoiding to become frail? We are trying to answer this question with our research.

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Fig. 1 MSC-associated changes in aged individuals might cause
a decrease in regeneration capacity. MSC numbers are reduced in the bone marrow of old individuals. Also, due to the lower migratory speed of old mesenchymal stem cells (oMSCs), fewer cells might be capable of homing to the site of injury, thereby further depleting their numbers in the hematoma. Reactive oxygen species, present especially in the early phases of healing, might affect oMSCs more dramatically than young mesenchymal stem cells, because of the age related reduction in antioxidant power. A higher susceptibility toward senescence in oMSCs might additionally contribute to a shortage of functional progenitor cells able to augment a fast and uneventful regeneration.
Fig. 2 Aging is a multifaceted process, which occurs at the molecular, cellular and systemic level. Thus, adult stem cell aging potentially is due to cell-autonomous (intrinsic) alterations and/or due to (extrinsic) changes in the local environment of the stem-cell niche, the surrounding tissue, the systemic milieu. In addition, alterations in adult stem cell function due to prolonged cultivation in vitro are described (in vitro aging).

“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.