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Nutritional prevention of dementia


Hoe ouder iemand wordt, hoe groter de kans op dementie. Ondanks intensief onderzoek zijn er nog geen effectieve behandelingen of mogelijkheden voor preventie. Belangrijke onbeantwoorde vragen over dementie gaan over het ontstaan van eiwitophopingen bij Alzheimer en andere vormen van dementie en daarbij de rol van veroudering als grootste risicofactor voor dementie.

Eerder ontdekten de onderzoekers dat ophoping van DNA-schade een belangrijke oorzaak van veroudering is en dat erfelijke defecten in de reparatie van DNA-schade bij muizen en patiënten versnelde veroudering veroorzaken - waaronder neurodegeneratie - die vrijwel identiek is aan alzheimer. Ook ontdekten zij dat een vermindering van het aantal calorieën veroudering in het algemeen, maar vooral neurodegeneratie enorm vertraagt. In dit project wordt dit proces verder onderzocht. Ook wordt gekeken naar de vertaling van deze resultaten naar een effectieve behandeling van dementie bij mensen in de vorm van voedingsinterventies.

Meer informatie


Titel: Verminderde intake als anti-veroudering en anti-dementie behandeling
Auteur: Dr. Ing. Wilbert P. Vermeij
Titel: Compromised DNA Repair Promotes the Accumulation of Regulatory T Cells With an Aging-Related Phenotype and Responsiveness
Auteur: Daan K. J. Pieren1, Noortje A. M. Smits1, Sandra Imholz2, Bhawani Nagarajah2, Conny T. van Oostrom2, Renata M. C. Brandt3, Wilbert P. Vermeij4,5, Martijn E. T. Dollé2 and Teun Guichelaar1*
Magazine: Frontiers in Aging Neuroscience
Titel: Protein instability associated with AARS1 and MARS1 mutations causes Trichothiodystrophy
Auteur: Elena Botta 1, Arjan F Theil 2, Anja Raams 2, Giuseppina Caligiuri 1, Sarah Giachetti 1, Silvia Bione 1, Maria Accadia 3, Anita Lombardi 1, Desiree E C Smith 4, Marisa I Mendes 4, Sigrid M A Swagemakers 5, Peter J van der Spek 5, Gajja S Salomons 4 6, Jan H J Hoeijmakers 2 7 8, Dhanya Yesodharan 9, Sheela Nampoothiri 9, Tomoo Ogi 10, Alan R Lehmann 11, Donata Orioli 1, Wim Vermeulen 2
Magazine: Human Molecular Genetics
Titel: Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging
Auteur: Winnie M.C. van den Boogaard,1,2 Marry M. van den Heuvel-Eibrink,3 Jan H.J. Hoeijmakers,1,2,4,5 and Wilbert P. Vermeij1,2
Magazine: Annual Review of Biochemistry
Titel: In vivo 5-ethynyluridine (EU) labelling detects reduced transcription in Purkinje cell degeneration mouse mutants, but can itself induce neurodegeneration
Auteur: Lisanne J. van’t Sant, Joshua J. White, Jan H. J. Hoeijmakers, Wilbert P. Vermeij & Dick Jaarsma
Magazine: Acta Neuropathologica communications
Titel: The central role of DNA damage in the ageing process
Auteur: Björn Schumacher 1 2, Joris Pothof 3, Jan Vijg 4 5, Jan H J Hoeijmakers 6 7 3 8
Magazine: Nature
Titel: Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice
Auteur: María B. Birkisdóttir1 | Dick Jaarsma2 | Renata M. C. Brandt3 | Sander Barnhoorn3 | Nicole van Vliet3 | Sandra Imholz4 | Conny T. van Oostrom4 | Bhawani Nagarajah4 | Eliana Portilla Fernández5 | Anton J. M. Roks5 | Ype Elgersma2 | Harry van Steeg4 | José A. Ferreira6 | Jeroen L. A. Pennings4 | Jan H. J. Hoeijmakers1,3,7 | Wilbert P. Vermeij1 | Martijn E. T. Dollé4
Magazine: Aging Cell


Samenvatting van de aanvraag

Most dementias are age-related diseases characterized by severe cognitive decline. Alzheimer’s disease (AD), the best studied and most frequent form of dementia, is recognized by the presence of Amyloid-beta plaques and tangles in the brain. While genetic and pathological data converge on A-beta pathophysiology as key pathogenic step in AD, it becomes evident that other confounding factors are essential in dementia etiology: i) some patients with dementia do not display plaques and tangles, ii) many aged people display plaques and tangles in their brain, but do not show overt cognitive decline, and iii) mouse models with engineered human plaques and tangles only show at best modest neurodegeneration and mild cognitive decline. Hence, it is important to identify the confounding factors and understand their impact on etiology of dementia. Aging is the foremost determinant of AD and other dementias, but is largely lacking in current dementia and AD models, as research on aging is time-consuming, laborious and expensive and aging occurs anyway “by default”. By generating mouse models for various human DNA repair syndromes we have disclosed a very strong connection between accumulation of DNA damage and aging. DNA repair deficient mice which rapidly accumulate endogenous DNA lesions display dramatically accelerated, but otherwise normal aging even for some organs beyond the level reached by wild-type mice. This is most notable for the severe neurodegeneration and progressive cognitive decline, which exhibit striking similarities with human dementia. DNA repair mutant mice show i) progressive severe cognitive decline as apparent from many (immuno)histochemical, physiological and behavioral parameters which parallel dementia in man. ii) Full genome expression profiles resembling human AD to a similar degree as observed when different human AD profiles are compared with each other. iii) A strikingly similar progression of the profile during disease development in man and mice, and iv) a 20-fold higher overlap with human AD profiles than displayed by widely used AD mouse models, e.g. APP/PS1 transgenic mice. Hence, our accelerated aging mice represent superior models for research on dementia. Additionally we found that cumulative DNA damage in normal and accelerated aging leads to transcription stress and also occurs in AD and other proteinopathies. Importantly, we crossed a DNA repair mutant mouse with a transgenic AD mouse model and not only observed increased pathological tau phosphorylation, but also a synergistic increase in P53-positive cells, which reflects a pro-apoptotic stress response. Finally, we discovered a connection between transcriptional stress and activation of the unfolded protein response, which may provide a link between aging, DNA damage and protein aggregation. These critical data indicate that age-related DNA damage synergizes with proteinopathy to aggravate the disease phenotype. We propose to further explore this novel model. In this application we aim to i) examine neurodegenerative pathways shared by our DNA repair deficient/accelerated aging mouse models and AD nervous system using proteomic, transcriptomic and comparative neuropathological approaches, and ii) to systematically dissect the up- and downstream interaction between age-related DNA damage and associated transcription stress and dementia / A-beta pathophysiological pathways, amongst others by crossing A-beta APP mouse models with our DNA repair mutant mouse models. iii) We recently published that dietary restriction (DR) dramatically improves neurological health in DNA repair mutants by alleviating transcription stress and DNA damage accumulation (Vermeij et al., Nature, 2016). This provides realistic, very promising opportunities to design preventive nutritional strategies to maintain neurological health. We will therefore analyze how DR impinges on age-related neurodegeneration and dementia. iv) Since DR for humans is difficult to maintain, we propose to analyze which nutritional components mediate the protective effect to develop preventive dietary strategies that are more feasible and screen for (combinations of) compounds that mimic DR to serve as alternative therapeutic intervention. In conclusion, the proposed studies will not only delineate the intricate connection between age-related damage and proteotoxicity, but also generate novel mouse models that combine both the aging aspect and A-beta pathophysiology of AD. We anticipate that these mice will become novel translational AD mouse models that reproduce central AD pathophysiological pathways in a realistic aging context. Moreover, dissecting the impact of nutrition and diet on neurological health will have tremendous translational potential by designing and developing preventive strategies that delay the detrimental effects of dementia for people at risk.


Looptijd: 100%
Looptijd: 100 %
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. J.H.J. Hoeijmakers
Verantwoordelijke organisatie:
Erasmus Medisch Centrum