Activation of transcription factor nrf2 by isothiocyanates and prevention of cellular senescence in vitro
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
Growing old takes a continuing toll on our skin, tissues and general health. An understanding of the ageing process and appropriate drugs or nutritional supplements to slow the process down may help us be healthier in old age. Spontaneous damage to proteins and DNA accumulates in cells during their life and contributes to the ageing effects. This can probably be resisted by increasing the activity of enzymes that protect proteins and DNA from damage. One such enzyme is glyoxalase I (GLO1). GLO1 protects proteins and DNA directly against damage from reactive sugar-derived molecules and protects indirectly against oxidative damage and impairment of cell respiration. Increasing the amount of GLO1, by overexpression of the gene for GLO1 in experimental conditions, has recently been shown to produce a 40% increase in lifespan of a small worm (nematode) commonly used as an experimental model of ageing. I have recently found that GLO1 can also be increased by compounds absorbed from Brassica vegetables such as cabbage, broccoli and others. These compounds, isothiocyanates, activate processes that affect the regulation of the GLO1 gene. I think it highly likely that isothiocyanates may slow the ageing process by increasing GLO1 expression / with probably also other effects. To test this, in this project I will use a human cell culture model of ageing. I will test if overexpression of GLO1 achieved by genetic techniques prevents ageing of human cells / measuring the expected decrease in damage to protein and DNA. I will then see and if this can also be achieved by induction of GLO1 gene expression by isothiocyanates. A successful outcome will give the first suggestions that eating your greens may slow the ageing process.
Technical Summary
Proteins suffer spontaneous damage by glycation, oxidation and nitration leading to the formation of protein glycation, oxidation and nitration adducts. Nucleotides also suffer analogous damage. These adducts accumulate in the ageing process as a consequence of both increased formation and decreased removal and repair. Recent progress in experimental models of ageing has indicated that related functional impairment is key to the ageing process. A strategy to slow this process is to enhance the endogenous protection against cellular damage. Well-tolerated chemical interventions that achieve this may suppress the ageing process without long-term safety concerns. The possibility to achieve an anti-ageing effect with chemical intervention has arisen from the observations that dietary isothiocyanates (ITCs) induced antioxidant response element (ARE)-linked gene expression via the transcription factor nrf2. In this project, I will examine if the induction of ARE-linked gene expression by ITCs will prevent cellular senescence of human fibroblasts in vitro and show that in so doing damage to proteins and DNA is prevented. A successful outcome will show how simple chemical intervention with nrf2 activators can delay cell senescence.
Organisations
Publications
Morcos M
(2008)
Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans.
in Aging cell
Rabbani N
(2012)
Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome.
in Amino acids
Fleming T
(2008)
Preparation of nucleotide advanced glycation endproducts--imidazopurinone adducts formed by glycation of deoxyguanosine with glyoxal and methylglyoxal.
in Annals of the New York Academy of Sciences
Rabbani N
(2008)
The dicarbonyl proteome: proteins susceptible to dicarbonyl glycation at functional sites in health, aging, and disease.
in Annals of the New York Academy of Sciences
Rabbani N
(2015)
Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease.
in Biochemical and biophysical research communications
Thornalley PJ
(2014)
Assay of methylglyoxal and glyoxal and control of peroxidase interference.
in Biochemical Society transactions
Xue M
(2014)
Measurement of glyoxalase gene expression.
in Biochemical Society transactions
Rabbani N
(2014)
Glyoxalase Centennial conference: introduction, history of research on the glyoxalase system and future prospects.
in Biochemical Society transactions
Arai M
(2014)
Measurement of glyoxalase activities.
in Biochemical Society transactions
Shaheen F
(2014)
A fluorogenic assay for methylglyoxal.
in Biochemical Society transactions
Rabbani N
(2014)
Activity, regulation, copy number and function in the glyoxalase system.
in Biochemical Society transactions
Rabbani N
(2014)
Assay of methylglyoxal-derived protein and nucleotide AGEs.
in Biochemical Society transactions
Schlotterer A
(2009)
C. elegans as model for the study of high glucose- mediated life span reduction.
in Diabetes
Thornalley PJ
(2008)
Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems--role in ageing and disease.
in Drug metabolism and drug interactions
Fleming T
(2013)
Aging-Dependent Reduction in Glyoxalase 1 Delays Wound Healing
in Gerontology
Thornalley PJ
(2007)
Dietary AGEs and ALEs and risk to human health by their interaction with the receptor for advanced glycation endproducts (RAGE)--an introduction.
in Molecular nutrition & food research
Rabbani N
(2014)
Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples.
in Nature protocols
Thornalley PJ
(2010)
Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance.
in Nucleic acids research
Xue M
(2011)
Glyoxalase in ageing.
in Seminars in cell & developmental biology
Xue M
(2012)
Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation.
in The Biochemical journal
Xue M, Adaikalakoteswari A, Rabbani N, Thornalley PJ
(2009)
Redox metabolism and longevity relationships in animals and plants
Description | We discovered that certain dietary substances from fruits and vegetables delay ageing of human tissue cells in culture. |
Exploitation Route | The studies were taken forward on a BBSRC Industrial PhD studentship with Unilever where the mechanism of action was discovered. This has produced new methods to screen for dietary substances that may help us maintain good health for longer in later life. |
Sectors | Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology |
Description | The studies were used to build on in a BBSRC Industrial PhD studentship with Unilever where the mechanism of action was discovered. |
First Year Of Impact | 2010 |
Sector | Agriculture, Food and Drink |
Impact Types | Economic |
Description | Advanced Lecture Course |
Geographic Reach | Asia |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Used of improved analytical protocols. |
Description | Methods Workshop for Glyoxalase Research |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Use of improved analytical protocols. |
Description | 34th FEBS Congress |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Talk sparked questions and discussion International awareness of my research activity. |
Year(s) Of Engagement Activity | 2009 |
Description | Discussions for collaboration (Unilever) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Discussions on decisions for collaborative research Decisions made. |
Year(s) Of Engagement Activity | 2010 |
Description | Fifth Strategies for Engineered Negligible Senescence (SENS) Conference, Cambridge, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | Talk sparked questions and discussion Made new collaborations and increased awareness of research |
Year(s) Of Engagement Activity | 2011 |
Description | Hot Topic Event (Biochemical Society) - Nrf2 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | Talk sparked questions and discussion. Raised awareness of research and facilitated further interactions. |
Year(s) Of Engagement Activity | 2011 |
URL | http://www.youtube.com/watch?v=Lrnc6q0MVyI |
Description | Inaugural seminar at Warwick Medical School |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talk sparked discussion afterwards. Increased awareness of a life in scientific research. |
Year(s) Of Engagement Activity | 2008 |
Description | Media interest (broccoli bioactives) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The activity was filming for a video to go on-line "Don't boil broccoli" by Research TV Ltd. Further requests by media for comments on brassica vegetables and health benefits. |
Year(s) Of Engagement Activity | 2007 |
URL | http://www.research-tv.com/stories/health/boilbroccoli/bb/ |
Description | Presentation to British Growers Association |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk sparked questions and discussion. Further correspondence and interest in research, |
Year(s) Of Engagement Activity | 2008 |
Description | Presentation to British Growers Association II |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk sparked discussions. Maintained contacts and interest in research, |
Year(s) Of Engagement Activity | 2009 |