Regulation of DNA damage signaling by autophagy in senescence.

Cell senescence is a stable proliferation arrest of damaged cells that prevents the onset of cancer. Paradoxically, cell senescence can also contribute to tissue ageing, by preventing tissue renewal and causing tissue inflammation. Triggers of cell senescence include DNA damage and dysfunctional mitochondria (sites of cellular energy production). Appropriate healthy ageing (i.e. a healthy lifespan without cancer) depends on appropriate balance of the senescence program.

Autophagy is a cellular recycling process that degrades and eliminates damaged structures from the cell. Our preliminary data indicates that autophagy serves to suppress accumulation of DNA damage and dysfunctional mitochondria in the cell. Hence, we hypothesise that autophagy controls - and perhaps dampens - onset and/or maintenance of cell senescence, and so tissue and organismal ageing.

By exploiting the complementary strengths of Drs. Passos and Adams we will investigate this hypothesis in cell culture and mouse models.

Progress in these studies will facilitate development of biomarkers of interventions to promote healthy ageing.

This application investigates cellular and molecular mechanisms that control cell and tissue ageing. Cellular senescence is an important tumor suppression mechanism, but also contributes to tissue and organismal ageing. DNA damage signaling, dysfunctional mitochondria and reactive oxygen species (ROS) are established triggers and effectors of the senescence program.
Autophagy is a cellular recycling process, whereby double membrane vesicles, called autophagosomes, sequester cytoplasmic content and organelles and deliver it to lysosomes for degradation. Like senescence, autophagy is implicated in control of tumor suppression and ageing. In fact, recent studies have demonstrated a role for autophagy in control of cell senescence. However, the precise role played by autophagy and whether it serves as an activator or repressor of senescence is unclear. To understand the contribution of autophagy to tumor suppression and ageing, it is essential to understand its role in cell senescence.
Building on extensive preliminary data from the labs of Drs. Adams and Passos, we propose that autophagy antagonizes the senescence program in at least two ways. First, we hypothesize that autophagy suppresses accumulation of dysfunctional mitochondria, thereby suppressing accumulation of ROS and DNA damage. Second, we hypothesize that autophagy degrades fragments of DNA damage-containing chromatin that accumulate in the cytoplasm of senescent cells. By suppressing such DNA damage signals, autophagy antagonizes onset or maintenance of cell senescence and tissue aging. We will investigate these hypotheses through the following two Aims.

Aim 1. Investigate the role of autophagy in suppression of DDR via elimination of dysfunctional mitochondria and ROS.

Aim 2. Investigate the role of autophagy in degradation of senescence-inducing cytoplasmic chromatin fragments (CCF) containing damaged DNA.

------Who will benefit from this research?

The pharmaceutical and drug discovery industry; government policy makers; the wider general public.
The importance of research on ageing is recognised as a high strategic priority not only by BBSRC but also by other UK Research Councils, government departments and other agencies. There is a need for much deeper understanding of the biology of ageing, if society is to appreciate how to secure the best possible lifelong health and prepare for a world in which a much greater fraction of the population will be old.

------How will they benefit from this research?

Research needs to be done at many levels, ranging from fundamental mechanistic studies through to translation into healthspan and quality of life for older people, and economically important innovation in a broad range of business sectors. It is well accepted that ageing is an extremely complex process which involves the interaction of many gene products and biological process. The research programme presented in this application will allow the understanding of basic mechanisms of ageing and ultimately aims to identify potential targets for therapies to ameliorate the ageing process and age-related diseases.

The pharmaceutical and drug discovery industry will benefit from an improved understanding of the molecular basis of senescence-associated tissue ageing and tumour suppression. This will aid them in the rational selection of target molecules for drug discovery efforts. Possible opportunities for engagement with industrial partners and commercialisation will be explored with support from existing mechanisms at both Newcastle and Glasgow university (see pathways to impact).
Government policy makers will gain, indirectly, from an improved understanding of the fundamental mechanisms underpinning the ageing process. It is critical that future decisions can be traced back to a solid scientific literature particularly when society is facing an unprecedented demographic shift resulting in a remarkable increase in the fraction of older people.
The general public will benefit from an improved understanding of the molecular basis of cancer, ageing and age-associated disease, to help them make better lifestyle choices.