Obesity in relation to aging and neurogenerative disease
Obesity is one of the most threatening health burdens around the globe and its prevalence has increased continuously [1] causing considerable socio-economic challenges. It is well known that obesity shortens life span [2] and is related to a number of metabolic diseases such as type 2 diabetes (T2D), dyslipidemia, coronary artery disease etc. but also non-metabolic co-morbidities (e.g. including several types of cancer, sleep apnoe, depression) [3-5, 6].
Particularly, metabolic alterations such as dysregulated insulin signaling are hallmarks of T2D and result in both peripheral and central insulin resistance. Peripheral insulin resistance is characterized by reduced response of normally insulin-sensitive organs, whilst, as recently reviewed by Cardoso S et al. [7], central insulin resistance in brain, however, affects central mechanisms related to learning, memory and regulation of whole body metabolism.
Indeed, diabetes and insulin resistance were suggested to potentially contribute to age-related cognitive impairment and function [e.g. 8, 9]. Moreover, an increased risk for Alzheimer´s disease has been associated with type 2 diabetes and insulin resistance [10, 11, 12, 13, 14] whilst in addition there is evidence for an increased prevalence of insulin resistance in individuals suffering from Parkinson´s disease [reviewed in 7, 15, 16]. In addition to impaired insulin signaling, mitochondrial dysfunction is potentially linking Alzheimer´s disease and T2D [11, 17]. Most interestingly, Fabbri et al. 2017 [18] suggest by using the Baltimore Longitudinal Study of Aging (BLSA) that impaired mitochondrial oxidative capacity is already present in insulin resistant individual who are still non-diabetic implying that mitochondrial dysfunction might be a crucial therapeutic angle for treating insulin resistance before establishing T2D.
Moreover, there is evidence that obesity itself drives epigenetic ageing. It has been shown that increased BMI (10 units) is strongly correlated to accelerated epigenetic liver age [19]. Further evidence comes from immune-senescence studies such as Yang H et al. 2009 [20]. The authors describe that obesity accelerates thymic ageing by reducing T-cell repertoire diversity and “thymic involution” that might lead to higher risk of infections. Others recently reported an association between obesity and accelerated epigenetic ageing in blood cells of middle-aged individuals [21]. Such tissue-specific ageing effects induced by obesity in turn affect health in obese individuals. Important insights in the role of mitochondrial dysfunction in impaired insulin signaling and epigenetic tissue-specific ageing underline the importance of maintaining normal body weight.
Conclusion
Better understanding of epigenetic mechanisms in driving tissue-specific ageing and mitochondrial dysfunction in obesity and T2D can potentially help elucidating shared biological mechanisms with neurodegenerative diseases such as Alzheimer´s disease and Parkinson´s disease.
Written by Prof. Yvonne Böttcher (NO-Age Network member)
Figure 1. Proposed linkage between obesity and neurodegenerative diseases. AD, Alzheimer’s disease, PD, Parkin’s disease. (Obesity cartoon was from br.freepik.com, others were from Dr. Evandro Fang).
Fedme i relasjon til aldring og nevrogenerative sykdommer
Fedme er en av de største utfordringene helsevesenet står ovenfor globalt, og forekomsten av fedme er økende [1], noe som fører til betydelige sosioøkonomiske utfordringer. Det er godt dokumentert at fedme reduserer forventet levealder [2] og er relatert til en rekke metabolske følgesykdommer, slik som type 2 diabetes (T2D), dyslipidemi og hjerte/kar-sykdom, men også ikke-metabolske følgesykdommer slik som kreft, søvnapné og depresjon [3-6].
Metabolske endringer, slik som dysregulert insulinsignalering er typisk for T2D og resulterer i insulinresistens i både sentrale og perifere vev. Perifer insulinresistens karakteriseres ved en redusert insulinrespons i normalt insulin-sensitive organer (som skjelettmuskulatur og fettvev), mens sentral insulinresistens i hjernen, kan påvirke sentrale mekanismer involvert i læring, minne og regulering av metabolismen i kroppen [7].
Det har i denne sammenheng blitt foreslått at insulinresistens og diabetes bidrar til aldersrelatert redusert kognitiv funksjon [blant andre 8,9]. Det har blitt vist at T2D og insulinresistens øker risikoen for å utvikle Alzheimers sykdom [10-14], i tillegg er det observert økt prevalens av insulinresistens i individer som lider av Parkinsons sykdom [oppsummert i 7,15,16]. I tillegg til endret insulinsignalering, er også mitokondriell dysfunksjon en mulig mekanistisk link mellom T2D og nevrogenerativ sykdom [11,17]. Resultater fra Baltimore Longitudinal Study of Aging (BLSA) viste at insulinresistente individer som ikke ennå har utviklet diabetes har en nedsatt oksidativ kapasitet i mitokondriene [18]. Mitokondriell dysfunksjon kan derfor være et viktig terapeutisk mål for å behandle insulinresistens før T2D oppstår.
Videre finnes det også bevis for at fedme fører til akselerert aldring via epigenetiske mekanismer. Det har blitt vist at økt BMI (10 enheter) har en høy korrelasjon med epigenetisk aldring i form av DNA-metylering i lever [19]. Videre har det blitt gjort studier på immunsystemet, blant annet av Yang et al, 2009 [20]. Her viser forfatterene at fedme akselererer aldring av thymus (brissel) ved thymisk involusjon (reduksjon i størrelse av thymus), og redusert T-celle repertoar, som igjen kan gi økt risiko for infeksjoner. Det er også vist sammenhenger mellom fedme og økt epigenetisk aldring i blodceller [21]. Slike vevsspesifikke aldringseffekter kan påvirke helse og livskvalitet. Rollen til mitokondriell dysfunksjon, insulin signalering og vevsspesifikk epigenetisk aldring i fedme fremhever viktigheten av å opprettholde normal kroppsvekt.
Konkusjon
Bedre forståelse av epigenetiske mekanismer som driver vevsspesifikk aldring og mitokondriell dysfunksjon i fedme og T2D kan potensielt bidra til å identifisere felles biologiske mekanismer med nevrogenerative sykdommer slik som Alzheimers og Parkinsons sykdom.
Skrevet af Prof. Yvonne Böttcher (NO-Age network member)
References
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Written by Prof. Yvonne Böttcher (NO-Age network member)
More about the Böttcher lab: https://adilabs.wordpress.com
Norwegian: Dr. Torunn Rønningen
Editors: Drs. Sofie Lautrup and Evandro Fang