Understanding and ameliorating ageing through the characterization of novel effectors of senescence

Lead Research Organisation: University of Leicester
Department Name: Molecular and Cell Biology

Abstract

Evidence suggests that the increase with time of old cells plays a critical role in the deleterious effects that ageing has on organs and in the symptoms of many diseases, including cancer, fibrosis, diabetes and Alzheimer's. Eliminating old cells as they accumulate substantially improves fitness and longevity in mice, proving that such therapies could have a clinical impact. If a similar strategy could be applied to humans, it could potentially ameliorate the pathologies that have been linked to old cell accumulation, thus increasing the quality of life and even extending the lifespan.
We have characterized a panel of new markers that allow us to selectively identify old cells. We will use this to obtain more information about the mechanisms involved in the ageing of cells, so we can better understand why and how it happens. Moreover, we propose to use take advantage of this information to design therapies that specifically target and kill old cells without affecting the normal ones. One approach is to obtain antibodies against these markers and attach them to a toxic compound. Previous research indicates that when such modified antibodies recognize and bind to their targets, the chemical is released and the cell is selectively eliminated. Cancer therapies based on this idea are already being used to successfully treat patients and we propose to apply the same idea to old cells.
We will also test a similar approach using nanotechnology. The compounds generated through this novel technique would be cost-effective, economic and easier to prepare than the antibodies and would have similar abilities. They could be used to quantitate the number of senescent cells in a tissue and to find better ways to kill them. Finally we will use chemical inhibitors that block the cellular ageing process. Together, these approaches will allow us to better understand why cells age and to propose potential therapies that could eliminate old cells from the body and thus improve our health.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1791026 Studentship BB/M01116X/1 03/10/2016 31/03/2021 Marta Anna Poblocka
 
Description My project is focusing on the prevention of aging and age-related disorders by targeting senescent cells. Cellular senescence can be defined as cellular response for a variety of stressors, like DNA-damage or oncogene activation. The number of senescent cells increases with age in different organs and in age-related disorders. Because of these reasons, cellular senescence has been identified as one of the hallmarks of aging. It is known that genetic manipulations that resulted in the clearance of senescent cells from animals significantly improved their healthspan. However, the currently available methods of targeting and eliminating senescent cells are characterized by a lack of specificity and off-target effects. Our research proposed a more specific approach to the identification and elimination of senescent cells. The novelty of our approach is to directly target senescent cells through the markers expressed in their plasma membrane, called the senescent surfaceome, For that purpose, we designed Nano-particles and Antibody Drug Conjugates which recognize a marker specifically expressed on senescent cells but not in their proliferating counterparts. Our approach specifically recognizes and delivers the drug to the cells of interests based on the identification of the marker present on the surface of senescent cells.

Our approach of using the Nano-particles was already published:
Ekpenyong-Akiba, Akang E., et al. "Detecting and targeting senescent cells using molecularly imprinted nanoparticles." Nanoscale Horizons 4.3 (2019): 757-768.

The results of the second method, Antibody-Drug Conjugates designed to recognize senescent cells through surfaceome marker we are planning to publish until the end of the year.


The last approach that we are studying is focusing on the blockage of cellular senescence before it occurs. For that purpose, we are using the inhibitor of BTK, a protein that has been found that, when inhibited, the induction of cellular senescence is blocked. In my project, we were treating mice (a progeroid syndrome mouse model) with ibrutinib, a clinically available BTK inhibitor. The treatment resulted in an improvement of the healthspan and protection of a decline in brain performance. These data have been published:

EkpenyongAkiba, Akang E., et al. "Amelioration of agerelated brain function decline by Bruton's tyrosine kinase inhibition." Aging cell (2019): e13079
Exploitation Route Our results provide a proof-of-principle assessment of specific and safe nanotechnology-based approaches for senescent cell detection and clearance with potential clinical relevance. Also, our data suggest that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology