Identifying small molecules to remove or modify the phenotype of ageing cells

Cellular senescence is a tumour-suppressor mechanism that causes permanent cell cycle arrest both in vivo and in vitro. This arrest is driven by a variety of different stimuli that converge on over-expression of the cyclin dependent kinase inhibitors p21^waf1 and p16^ink4a. Senescence probably functions as a component of an in vivo tumour suppression system (allowing either permanent growth arrest, or arrest followed by NK-mediated immune clearance of senescent cells).

Although senescence in this context may result in health benefits, the progressive accumulation of senescent cells is now known to be a causal factor in physiological ageing and there are numerous lines of evidence that suggest that the altered physiology of senescent cells (notably their elevated secretion of pro-inflammatory cytokines, the so-called Senescent-Associated Secretory Phenotype (SASP) may produce a deleterious tissue microenvironment and contribute to elevated systemic risk of age-related inflammatory diseases, such as in the cardiovascular system.

The aim of the research project is to target a leading cause of human ageing (cell senescence) and to test promising potential interventions, in a single integrated programme.

Researchers demonstrated that a range of small molecules (including existing drugs) are able to block the Senescent-Associated Secretory Phenotype. In addition new compounds were synthesised by novel routes which showed desirable combinations of toxicity, growth promotion/suppression and blockade of deleterious features of the senescent cell phenotype.

Research caused the team to challenge traditional ideas concerning the relationship between ageing and age-related disease, which had important policy and ethical implications and potential impacts on health and welfare, public policy and services.

Outputs

Poster presented at the 43rd Annual Scientific Meeting of the American Aging Association in San Antonio, Texas, USA

Poster presented at the 44th Annual Scientific Meeting of the American Aging Association in San Antonio, Texas, USA

Poster presented at the 64th Annual Scientific Meeting of the British Society for Research on Ageing in Liverpool, England, UK.

Poster presented at the 65th Annual Scientific Meeting of the British Society for Research on Ageing in London, England, UK.

Lecture given at the "Molecular Basis of Aging and Disease" at Cold Spring Harbor Laboratory Asia September 2015.

Kenessary et al. (2013) Biomarkers, interventions and healthy ageing. N Biotechnol. 30(4):373-7

Burton DG, Faragher RG. (2015) Cellular senescence: from growth arrest to immunogenic conversion. Age (Dordr) 37(2):27

Birar VC, Sheerin AN, Milkovicova J, Faragher RG, Ostler EL. (2015) A facile, stereoselective, one-pot synthesis of resveratrol derivatives. Chem Cent J. ;9:26

Faragher RG. (2015) Should we treat aging as a disease? The consequences and dangers of miscategorisation. Front Genet. 6:171

Alimbetov et al (2015) Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology. [Epub ahead of print]