Common epigenetic pathways regulating ageing and circadian clocks: implications for therapeutic intervention
Lead Research Organisation:
University of Manchester
Department Name: Life Sciences
Abstract
One important feature of getting old is deteriorated sleep quality. Sleep is regulated by circadian clocks, the internal time pieces in various body organs, consisting of clock genes and proteins that are capable of generating ~24 hr rhythmic outputs. Age-associated sleep disorders are thought to be due to loss of proper circadian regulation, such as reduced amplitude, non-24 hour periodicity or inappropriate phase. Studying changes in circadian clocks with ageing will in the long run aid therapeutic drug design targeting sleep disorders in the elderly.
Expression and stability of the clock genes and proteins are controlled by modifications such as acetylation/deacetylation, describing the presence or absence of the acetyl group on target proteins. Many of these modification mechanisms have been found as hallmarks for ageing.
I will investigate changes of rhythms and acetylation/deacetylation activities with ageing process using animal models and skin cells isolated from biopsies of human subjects. Changes of modifications will be correlated with alterations in circadian rhythms. By filling in questionnaire, the chronotype and sleep pattern will be correlated to the rhythms in skin cells. I will also probe the possibility of altering the acetylation/deacetylation balance by drugs in order to restore the age-related rhythm changes.
Expression and stability of the clock genes and proteins are controlled by modifications such as acetylation/deacetylation, describing the presence or absence of the acetyl group on target proteins. Many of these modification mechanisms have been found as hallmarks for ageing.
I will investigate changes of rhythms and acetylation/deacetylation activities with ageing process using animal models and skin cells isolated from biopsies of human subjects. Changes of modifications will be correlated with alterations in circadian rhythms. By filling in questionnaire, the chronotype and sleep pattern will be correlated to the rhythms in skin cells. I will also probe the possibility of altering the acetylation/deacetylation balance by drugs in order to restore the age-related rhythm changes.
Technical Summary
Abstract
The rapid increase in the ageing population represents both a major biological and social challenge. Among these are changes in circadian rhythms, the endogenous 24 hour cycles governing nearly all aspects of mammalian physiology and behavior, including sleep-wake cycle. During ageing, one of the most common and troublesome events are sleep disorders, implying fundamental changes within the circadian pacemakers that gate sleep patterns. It is unclear how ageing impacts on the molecular clockworks and what the underpinning mechanisms are. Epigenetic modifications have recently been implicated in the regulation of circadian clocks. Epigenetic processes are also recognized as a hallmark of ageing. Remarkably, sirtuins are implicated in both processes through their actions on the interface between energy metabolism and cellular senescence. These findings implicate common epigenetic changes in ageing process and altered circadian pacemaker function.
The primary aims of the proposal are: 1) To define how ageing affects the overall organization of the molecular clock machinery in animals and man. 2) To test the hypothesis that ageing may impact on the balance of acetylation/deacetylation activity or histone methylation state in pacemaker cells, which leads to alterations in overt output rhythms. 3) To probe the possibility that pharmacological/genetic manipulation of the epigenetic-regulated pathways may counteract age-related changes in circadian rhythms.
In this proposal, I will use young and aged transgenic reporter mice to define changes within circadian clocks, including period, amplitude, resetting response and clock gene activity in neural and peripheral pacemaker cells using real-time bioluminescent imaging and biochemical approaches over multiple circadian cycles. I will study age-related changes in expression and activity of CLOCK and SIRT1, acetylation or methylation state of histones and key clock proteins in tissues and primary cells, complemented by the use of an oxidative stress-induced cellular ageing model. The impact of manipulating SIRT1 activity on circadian clocks will also be examined. Translational studies using human fibroblasts isolated from young and elderly subjects will be undertaken using clock gene reporter technologies. The molecular rhythms thereby revealed will be correlated with age and chronotype, as assessed by standard questionnaire.
Circadian clocks have pleiotropic effects and disrupted circadian rhythms correlate with age-associated sleep disorders and other pathologies. This project aims to define the mechanisms underlying age-associated changes within circadian system in animals and man. Long term, outcomes from this work could aid therapeutic drug design against age-related ailments, for which targeting SIRT1 is already an appealing candidate.
The rapid increase in the ageing population represents both a major biological and social challenge. Among these are changes in circadian rhythms, the endogenous 24 hour cycles governing nearly all aspects of mammalian physiology and behavior, including sleep-wake cycle. During ageing, one of the most common and troublesome events are sleep disorders, implying fundamental changes within the circadian pacemakers that gate sleep patterns. It is unclear how ageing impacts on the molecular clockworks and what the underpinning mechanisms are. Epigenetic modifications have recently been implicated in the regulation of circadian clocks. Epigenetic processes are also recognized as a hallmark of ageing. Remarkably, sirtuins are implicated in both processes through their actions on the interface between energy metabolism and cellular senescence. These findings implicate common epigenetic changes in ageing process and altered circadian pacemaker function.
The primary aims of the proposal are: 1) To define how ageing affects the overall organization of the molecular clock machinery in animals and man. 2) To test the hypothesis that ageing may impact on the balance of acetylation/deacetylation activity or histone methylation state in pacemaker cells, which leads to alterations in overt output rhythms. 3) To probe the possibility that pharmacological/genetic manipulation of the epigenetic-regulated pathways may counteract age-related changes in circadian rhythms.
In this proposal, I will use young and aged transgenic reporter mice to define changes within circadian clocks, including period, amplitude, resetting response and clock gene activity in neural and peripheral pacemaker cells using real-time bioluminescent imaging and biochemical approaches over multiple circadian cycles. I will study age-related changes in expression and activity of CLOCK and SIRT1, acetylation or methylation state of histones and key clock proteins in tissues and primary cells, complemented by the use of an oxidative stress-induced cellular ageing model. The impact of manipulating SIRT1 activity on circadian clocks will also be examined. Translational studies using human fibroblasts isolated from young and elderly subjects will be undertaken using clock gene reporter technologies. The molecular rhythms thereby revealed will be correlated with age and chronotype, as assessed by standard questionnaire.
Circadian clocks have pleiotropic effects and disrupted circadian rhythms correlate with age-associated sleep disorders and other pathologies. This project aims to define the mechanisms underlying age-associated changes within circadian system in animals and man. Long term, outcomes from this work could aid therapeutic drug design against age-related ailments, for which targeting SIRT1 is already an appealing candidate.