Cellular Senescence is a damage and stress-response which locks up mitotically competent cells into an essentially irreversible form of growth arrest. Originally described in cultured cells, cellular senescence is also now known to occur in vivo, where it has been linked to the process of ageing and to the development of age-related diseases. In 2000, we described the presence of senescent vascular cells in the arterial wall and since then we have been investigating the mechanisms that control this phenomenon in endothelial cells^1-,5

The increase in life expectancy of Western Societies is having major socio-economic and public health impacts. One crucial aspect emanating from this scenario is the increase in the number of frail people. Frailty is an age-associated syndrome characterised by a decline in several physiological systems and a decrease in resistance to stress. Frailty places elderly adults at increased risk of disability, falls, hospitalisation and premature death.

             

 

Currently, assessment of frailty relies primarily on measuring functional parameters such as cognitive function, exhaustion, weight loss, walking speed and grip strength. However, it is now increasingly recognised that the clinical utility of such parameters in terms of risk prediction, diagnosis and prognosis, is limited. Hence, there is an urgent need to ameliorate this situation. To this end, we are participating in a major European project, the FRAILOMIC initiative, which is measuring the levels of candidate biomarkers in the blood and urine of elderly individuals across the World¹.

Working within this research programme we have demonstrated that the chemokine CCL11 (also known as Eotaxin-1) is associated with cognitive decline in rural dwellers². We have also shown that the vascular inflammation-related protein sRAGE predicts mortality in frail older adults³. Ongoing work in this area aims to validate our findings in additional cohorts of older adults.

1. Erusalimsky J.D., Grillari J., Grune T., Jansen-Duerr P. Lippi G., Sinclair A.J., Tegner J., Vina J., Durrance-Bagale A., Minambres R., Viegas M. and Rodriguez-Mañas L. (2016) In search of ‘omics’-based biomarkers to predict the risk of frailty and its consequences in older individuals: The FRAILOMIC initiative Gerontology 62, 182-190.

2. Butcher L., Pérès K., André P., Morris R.H., Walter S., Dartigues J-F., Rodriguez-Mañas L., Feart C. and Erusalimsky J.D. (2018) Association between plasma CCL11 (eotaxin-1) and cognitive status in older adults: Differences between rural and urban dwellers. Exp. Gerontol. 113, 173-179

3. Butcher L., Carnicero J.A., Gomez Cabrero D., Dartigues J-F., Pérès K., Garcia-Garcia F.J., Rodriguez-Mañas L. and Erusalimsky J.D. (2019) Increased levels of soluble Receptor for Advanced Glycation End-products (RAGE) are associated with a higher risk of mortality in frail older adults. Age and Ageing. 48, 696-702

Neurodegenerative diseases such as Parkinson's and Huntington's disease are characterised by focal cell loss in the central nervous system. Despite an increasing understanding of the pathophysiology behind these devastating diseases, as yet there is no known cure. 'Proof of principle' studies have shown that cell replacement therapy is a viable approach to treating these conditions. To overcome the limitations of this work, our current research is looking at adapting alternative cell sources as the donor tissue^1,2. Dr Claire Kelly, the lead investigator in this area, is a board member of The Network for European CNS Transplantation and Restoration (NECTAR), an organisation that brings together European groups who share the common goal of protecting, repairing and restoring the central nervous system damaged through degenerative disease or injury. For more information on Nectar, click here.

 

Left Image: Neural cells expanded in culture and stained for β-III tubulin (red) and glial fibrillary acidic protein (green).

MIddle and Right Images: Transplanted human foetal cells in an experimental model of Huntington's Disease differentiated into neurons (A) and more specifically into medium spiny neurons (B).

            

Of particular interest to our group is the role of inflammation in these diseases and how it contributes to their pathophysiology. Microglia cells are the resident immune cells of the brain that can acquire a pro- or anti-inflammatory character. There is a high abundance of these cells in the brain of diseased patients but their role and how they impact on the ability of transplanted cells to survive is unknown³.

Microglia cells stained positive for Iba1. The cells acquire different morphologies with the classical appearance being the ramified, scavenging cell (left). In the activated state these cells appear clumped (right).

1. Kelly C.M. and Caldwell M.A. (2018) Derivation of Neural Stem Cells from the Developing and Adult Human Brain. Results Probl Cell Differ. 66, 3-20.

2. Noakes Z., Keefe F., Tamburini C., Kelly C.M., Cruz Santos M., Dunnett S.B., Errington A.C. and Li M. (2019) Human Pluripotent Stem Cell-Derived Striatal Interneurons: Differentiation and Maturation In Vitro and in the Rat Brain. Stem Cell Reports.12, 191-200.

3. Kodosaki E. (2019) The development of a novel model for microglia-like cells, and an investigation of the proinflammatory potential and response of CNS cells in vitro. Ph.D. Thesis. Cardiff Metropolitan University Research Repository (https://repository.cardiffmet.ac.uk/)

A main drive of our laboratory is to understand the role of the different cell types in neuro-inflammation. Within this remit, we are examining the contribution of immune cells that can cross the blood brain barrier. We have developed a cell model of these cells and characterised their differentiation in a neural environment in vitro. Ongoing work is looking at their functions in response to inflammatory stimuli and the effects on other neural cells.