Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells

Cells respond to stress by synthesizing chaperone proteins that seek to correct protein misfolding and maintain function. However, abrogation of protein homeostasis is a hallmark of aging, leading to loss of function and the formation of proteotoxic aggregates characteristic of pathology. Consequently, discovering the underlying molecular causes of this deterioration in proteostasis is key to designing effective interventions to disease or to maintaining cell health in regenerative medicine strategies. Here, we examined primary human mesenchymal stem cells, cultured to a point of replicative senescence and subjected to heat shock, as an in vitro model of the aging stress response. Multi -omics analysis showed how homeostasis components were reduced in senescent cells, caused by dysregulation of a functional network of chaperones, thereby limiting proteostatic competence. Time-resolved analysis of the primary response factors, including those regulating heat shock protein 70 kDa (HSPA1A), revealed that regulatory control is essentially translational. Senescent cells have a reduced capacity for chaperone protein translation and misfolded protein (MFP) turnover, driven by downregulation of ribosomal proteins and loss of the E3 ubiquitin ligase CHIP (C-terminus of HSP70 interacting protein) which marks MFPs for degradation. This limits the cell’s stress response and subsequent recovery. A kinetic model recapitulated these reduced capacities and predicted an accumulation of MFP, a hypothesis supported by evidence of systematic changes to the proteomic fold state. These results thus establish a specific loss of regulatory capacity at the protein, rather than transcript, level and uncover underlying systematic links between aging and loss of protein homeostasis.</jats:p

Loss of cytoskeletal proteostasis links dysregulation of cell size and mechanotransduction in mesenchymal stem cell senescence

ABSTRACT Tissues are maintained by homeostatic feedback mechanisms where cells respond to, but also modify, the chemical and mechanical properties of the surrounding extracellular matrix. Mesenchymal stem cells (MSCs) resident in the marrow niche experience a diverse mechanical environment, but ageing can affect the composition and quality of bone and marrow tissues. Here we quantified the effect of replication-induced senescence on MSC morphology and their ability to correctly respond to different substrate stiffnesses. The matrix proteome was found to be sensitive to substrate stiffness, but pharmacological inhibition of cellular contractility perturbed this response, decreasing levels of tenascin-C, fibulins and fibronectin. Similar decreases in these mechanosensitive proteins were observed in senescent cells, suggested a decoupling of mechanotransduction pathways. Intracellular proteomic and transcriptomic analyses confirmed a decrease in components of the cytoskeletal chaperone complex CCT/TRiC in senescent MSCs. Finally, pharmacological inhibition of CCT/TRiC was able to partially recapitulate senescence-associated morphological changes in non-senescent MSCs. These results demonstrate a senescence-mediated perturbation to cytoskeletal homeostasis, pathways of mechanotransduction and the secretion of matrix proteins required for tissue maintenance

Uncertain outcome presentations bias decisions: experimental evidence from Finland and Italy

Even in their everyday lives people are expected to make difficult decisions objectively and rationally, no matter how complex or uncertain the situation. In this research, we study how the format of presentation and the amount of presented information concerning risky events influence the decision-making process, and the propensity to take risk in decision makers. The results of an exploratory survey conducted in Finland and in Italy suggest that decision-making behavior changes according to the way the information is presented. We provide experimental evidence that different representations of expected outcomes create distinct cognitive biases and as a result affect the decisions made. This identified change in the perception of risk has, to the best of our knowledge, not been identified nor directly studied previously in the scientific literature. The paper thus presents novel insights into managerial decision-making that are potentially relevant for decision support theory, with implications to decision-makers and for information providers. Understanding the impact of various forms of presentation of risk is crucial in being able to convey information clearly and in a way that avoids misunderstandings. The implications of the results on being able to avoid opportunistic manipulation of decisions, are also of great concern in many application areas. Social networks are more and more frequently being used as a source of information and in this context it is crucial to acknowledge the effect that different ways of presenting and communicating risky outcomes may have on the behavior of the target group. Here presented results may, for example, be highly relevant for marketing and advertising that is conducted by using social media or social networks