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The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing

Projectomschrijving

Age-related vascular diseases can be prevented

The world population is getting older and older. Unfortunately this increased life expectancy is generally associated by so-called age-related vascular diseases, such as dementia, heart infarct and stroke. However, these age-related chronic disorders can be delayed or even prevented by interference with common critical mechanisms underlying these diseases. Neurodegenerative and cardiovascular diseases share an underlying, mechanistic framework with involvement of increased oxidative stress, inflammation and insulin resistance.

Unrepaired DNA damage

In this project the researchers have strong indications that vascular ageing is caused by accumulation of unrepaired DNA damage and mitochondrial dysfunction in the vessel wall, which both increase with age. The project therefore proposes that age-related chronic disorders, despite their very diverse symptom profiles, share vascular ageing as common factor. These events induce progressive aging, inflammation and functional loss of the vessel wall, which eventually will manifest as cardiovascular dysfunction or neurodegeneration, two hallmarks of ageing.

International collaboration of researchers

In this Dutch-Brazilian NWO-FAPESP project, experts in the field of ageing, DNA damage and repair, mitochondrial dysfunction and cardiovascular inflammation will collaborate to establish this age-related cardiovascular and neurodegenerative disease axis, to detect signs of (accelerated) ageing at an earliest possible stage, and intend to design precision medicine. To do so they will combine cutting edge technologies.

Reducing age-related diseases in the future

The insights gained in this project will be used to design new biomarkers of vascular ageing and for new therapeutic measures to turn back the harmful causes. By targeting a unique common mechanism in vascular ageing we expect that this project will help to reduce these age-related diseases thus improving quality of life for the elderly, and bringing the vista of healthy ageing within reach.

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Samenvatting van de aanvraag

The ageing process increases the organism’s vulnerability to disease and death, making ageing the primary risk factor of major pathologies such as cardiovascular and neurodegenerative diseases. The world population is getting older and older. Unfortunately this increased life expectancy is generally associated by so-called age-related vascular diseases, such as dementia, heart infarct and stroke, which profoundly compromise the quality of life of the elderly. However, while ageing of the population is inevitable, these age-related chronic disorders can be delayed or even prevented by interference with common critical mechanisms underlying these diseases. Neurodegenerative and cardiovascular diseases share an underlying, mechanistic framework with involvement of increased oxidative stress, inflammation and insulin resistance. Our consortium has shown that accumulation of unrepaired DNA damage and mitochondrial dysfunction drive the ageing process. This new paradigm is underpinned by human disorders with deficiencies in DNA repair showing a plethora of premature ageing phenotypes. Likewise, established mouse models with compromised DNA damage repair experience numerous ageing characteristics such as neurodegeneration and cardiovascular ageing. In this project, we postulate that vascular ageing is caused by accumulation of unrepaired DNA damage and mitochondrial dysfunction in the vessel wall, which both increase with age. Our project therefore proposes that age-related chronic disorders, despite their very diverse symptom profiles, share vascular ageing as common denominator. These events interplay and induce progressive senescence, inflammation and functional loss of the vessel wall, which eventually will manifest as cardiovascular dysfunction or neurodegeneration, two hallmarks of ageing. Hypothesis and study aim: While DNA damage contributes to age-related diseases, the actual mechanisms and regulators of this process are not well understood. Based on our earlier work, we propose that unrepaired DNA damage and mitochondrial dysfunction act in concert to induce vascular ageing and inflammation, the major cornerstones in age-related cardiovascular and neurodegenerative diseases. Objectives: I. Identify the underlying shared molecular mechanism of cardiovascular and neurodegenerative disease in model systems: WP1: Determine the effect of DNA damage, mitochondrial function and inflammation on neurodegeneration and cardiovascular disease in unique tissue-specific progeroid mouse models WP2: Effect of exposure to cardiovascular/neurodegenerative risk factors on vascular DNA damage and mitochondrial function in mouse models and human cohort samples (single-cell and functional analysis) WP3: Dissect the molecular pathways that link DNA damage, via oxidative stress and mitochondrial dysfunction to vascular ageing and inflammation, using state of the art systems biology approaches and iPS-based cell culture systems (neurodegeneration and vascular) II. Early detection and intervention in accelerated ageing in high risk populations WP4: Biomarker design: detecting accelerated biological ageing and associated functional decline at the earliest possible stage (WP4) WP5: Therapy design and validation: rejuvenating the vascular system (WP5) In this NWO-FAPESP project, experts in the field of ageing (Hoeijmakers, van der Pluijm), DNA damage and repair (Hoeijmakers, Menck), mitochondrial dysfunction (Moreas-Vieira) and cardiovascular inflammation (Biessen, Camara) will synergistically collaborate to establish this age-related cardiovascular and neurodegenerative disease axis, to detect signs of (accelerated) ageing at an earliest possible stage, and will design precision medicine in tailor-made iPS-based model systems, the potential of which will be validated in unique cellular and mouse models for age-related disease. The consortium will deploy and share their knowhow to unravel this common disease axis. To do so they will combine cutting edge technologies including scRNASEq, MitoNGS, CRISPR-Cas mediated genome editing, cardiovascular and neuronal organoids and 3D culture, a MacroScreen functionomics platform and intravital or multispectral imaging. The insights gained in this project will be harnessed to the design of new (metabolic) biomarkers of vascular ageing and for novel therapeutic measures to revert this deleterious axis. By targeting a unique common mechanism in vascular ageing we expect that this project will help to reduce these age-related diseases thus improving quality of life for the elderly, and bringing the vista of healthy ageing within reach.

Kenmerken

Projectnummer:
457002001
Looptijd: 77%
Looptijd: 77 %
2020
2025
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. J.H.J. Hoeijmakers
Verantwoordelijke organisatie:
Erasmus Medisch Centrum