Metabolic cell senescence promotes insulin resistance and CVD

Bakgrund:

Based on our recent results we postulate that the dysmetabolic state associated with human CVD is associated with, and driven by, metabolic cell senescence and we will use our SCAPIS cohort to examine this and also our other high-risk CVD groups. We will focus on the adipose tissue and its precursor/stem cells/ fully mature adipose cells, tissue endothelial cells and also human cardiac vascular cells (cMVEC).

Cell senescence is a consequence of ageing, the major risk factor for CVD, but also of other exogenous and genetic factors and we have found increased cell senescence in adipose tissue cells from individuals with high risk for CVD/T2D independent of age. We also found that tissue microvascular endothelial cells (aMVEC), which regulate lipid transport, and surprisingly also mature adipose cells, become senescent which inhibits normal regulation of lipid transport in/out of the tissue as well as other adipose tissue functions.

Målsättning:

Characterize phenotype and metabolic cell senescence in adipose tissue-derived cells from matched individuals in the Gothenburg SCAPIS cohort with or without angiographically verified atherosclerosis as well as in our existing cohorts with high risk for CVD. We will also characterize which cells drive tissue cell senescence, and thus are therapeutic targets. We will transplant senescent vs non-senescent human cells in mouse models to examine consequences in vivo.

Arbetsplan:

Characterize cell-cell cross talk to examine which cells are target cells and which cells are primary drivers of tissue cell senescence. Perform transplantation of senescent cells in susceptible mouse models to examine development of diabetes and atherosclerosis. We will examine the possibility that senolytic agents kill human senescent cells to restore normal tissue function and inhibit SASP secretion and, thus, may become future therapies for CVD and T2D.

Positive effects will lead to the development of a clinical trial in insulin-resistant FDR in collaboration with Jim Kirkland and Tamara Tchkonia, Mayo Clinic who have FDA-approvals for at least 3 wks trials with the senolytic agents. Betydelse:

Senescence and SASP secretion are novel concepts in CVD and associated risks and verifying this will allow us to identify mechanisms and senolytic agents as therapeutic targets.