A gerophysiology perspective on healthy ageing.

Improvements in public health and health care have resulted in significant increases in lifespan globally, but also in a significant increase in chronic disease prevalence. This has led to a focus on healthy ageing bringing a shift from a pathology-centered to an intrinsic capacity and function-centered view. In parallel, the emerging field of geroscience has promoted the exploration of the biomolecular drivers of ageing towards a transverse vision by proposing an integrated set of molecular hallmarks. In this review, we propose to take a step further in this direction, highlighting a gerophysiological perspective that considers the notion of homeostasis/allostasis relating to robustness/fragility respectively. While robustness is associated with homeostasis achieved by an optimal structure/function relationship in all organs, successive repair processes occurring after daily injuries and infections result in accumulation of scar healing leading to progressive tissue degeneration, allostasis and frailty. Considering biological ageing as the accumulation of scarring at the level of the whole organism emphasizes three transverse and shared elements in the body - mesenchymal stroma cells/immunity/metabolism (SIM). This SIM tryptich drives tissue and organ fate to regulate the age-related evolution of body functions. It provides the basis of a gerophysiology perspective, possibly representing a better way to decipher healthy ageing, not only by defining a composite biomarker(s) but also by developing new preventive/curative strategies.

Extra-cellular matrix rigidity may dictate the fate of injury outcome.

After injury, while regeneration can be observed in hydra, planaria and some vertebrates, regeneration is rare in mammals and particularly in humans. In this paper, we investigate the mechanisms by which biological tissues recover after injury. We explore this question on adipose tissue, using the mathematical framework recently developed in Peurichard et al., J. Theoret. Biol. 429 (2017), pp. 61-81. Our assumption is that simple mechanical cues between the Extra-Cellular Matrix (ECM) and differentiated cells can explain adipose tissue morphogenesis and that regeneration requires after injury the same mechanisms. We validate this hypothesis by means of a two-dimensional Individual Based Model (IBM) of interacting adipocytes and ECM fiber elements. The model successfully generates regeneration or scar formation as functions of few key parameters, and seems to indicate that the fate of injury outcome could be mainly due to ECM rigidity.

Identification of the ectoenzyme CD38 as a marker of committed preadipocytes.

BACKGROUND/OBJECTIVES: Characterisation of the adipocyte cellular lineage is required for a better understanding of white adipose tissue homoeostasis and expansion. Although several studies have focused on the phenotype of the most immature adipocyte progenitors, very few tools exist to identify committed cells. In haematopoiesis, the CD38 ectoenzyme is largely used to delineate various stages of stem cell lineage commitment. We hypothesise that this marker could be used to identify committed preadipocytes. METHODS: Complementary strategies including flow cytometry, cell-sorting approaches, immunohistochemistry and primary cultures of murine adipose progenitors isolated from different fat pads of control or high-fat diet exposed C57BL/6 J mice were used to determine the molecular expression profile, proliferative and differentiation potentials of adipose progenitors expressing the CD38 molecule. RESULTS: We demonstrate here that a subpopulation of CD45- CD31- CD34+ adipose progenitors express the cell surface protein CD38. Using a cell-sorting approach, we found that native CD45- CD31- CD34+ CD38+ (CD38+) adipose cells expressed lower CD34 mRNA and protein levels and higher levels of adipogenic genes such as Pparg, aP2, Lpl and Cd36 than did the CD45- CD31- CD34+ CD38- (CD38-) population. When cultivated, CD38+ cells displayed reduced proliferative potential, assessed by BrdU incorporation and colony-forming unit assays, and greater adipogenic potential. In vitro, both CD38 mRNA and protein levels were increased during adipogenesis and CD38- cells converted into CD38+ cells when committed to the adipogenic differentiation programme. We also found that obesity development was associated with an increase in the number of CD38+ adipose progenitors, this effect being more pronounced in intra-abdominal than in subcutaneous fat, suggesting a higher rate of adipocyte commitment in visceral depots. CONCLUSIONS: Together, these data demonstrate that CD38 represents a new marker that identifies committed preadipocytes as CD45- CD31- CD34low CD38+ cells.

Novel application assigned to toluquinol: inhibition of lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signalling pathway.

BACKGROUND AND PURPOSE: Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphoedema and other inflammatory disorders. The development of new drugs that block lymphangiogenesis has become a promising therapeutic strategy. In this study, we investigated the ability of toluquinol, a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004, to inhibit lymphangiogenesis in vitro, ex vivo and in vivo. EXPERIMENTAL APPROACH: We used human lymphatic endothelial cells (LECs) to analyse the effect of toluquinol in 2D and 3D in vitro cultures and in the ex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, mouse ear sponges and cornea models were used. Western blotting and apoptosis analyses were carried out to search for drug targets. KEY RESULTS: Toluquinol inhibited LEC proliferation, migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol induced apoptosis of LECs after 14 h of treatment in vitro, blocked the development of the thoracic duct in zebrafish and reduced the VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we demonstrated that this drug attenuates VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependent manner and suppresses the phosphorylation of Akt and ERK1/2. CONCLUSIONS AND IMPLICATIONS: Based on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment of lymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications in vascular ocular pathologies.

Immuno-metabolism and adipose tissue: The key role of hematopoietic stem cells.

The field of immunometabolism has come a long way in the past decade, leading to the emergence of a new role for white adipose tissue (WAT) that is now recognized to stand at the junction of immune and metabolic regulations. Interestingly, a crucial role of the abundant and heterogeneous immune population present in WAT has been proposed in the induction and development of metabolic diseases. Although a large body of data focused on mature immune cells, only few scattered studies are dedicated to leukocyte production, and the activity of hematopoietic stem cells (HSC) in these pathological states. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from their microenvironment, it thus seems worth to better understand the relationships between metabolism and HSC. This review discusses the alterations of hematopoietic process described in metabolic diseases and focused on the emerging data concerning HSC present in WAT.