Obesity in neurogeneration

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)

Screen Shot 2018-10-31 at 12.41.08 AM
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
[1] Ng M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England). 2014;384:766-81.
[2] Fontaine KR et al. Years of life lost due to obesity. Jama. 2003;289:187-93.
[3] Bluher M. Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance? Clinical science (London, England : 1979). 2016;130:1603-14.
[4] Long E, Beales IL. The role of obesity in oesophageal cancer development. Therapeutic advances in gastroenterology. 2014;7:247-68.
[5] Rosso N et al. Translational approaches: from fatty liver to non-alcoholic steatohepatitis. World journal of gastroenterology. 2014;20:9038-49.
[6] Rohde K et al. Genetics and epigenetics in obesity. Metabolism-Clinical and Experimental 2018, accepted.
[7] Cardoso S, Moreira PI. Diabesity and brain disturbances: A metabolic perspective. Mol Aspects Med. 2018, in press; doi: 10.1016/j.mam.2018.10.002.
[8] Geroldi C et al. Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 2005 62, 1067-1072.
[9] Watson GS, Craft S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 2004 490, 97-113.
[10] Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004, 3, 169-178.
[11] Moreira, P.I. Sweet mitochondria: a shortcut to Alzheimer’s disease. J Alzheimers Dis 2018, 62 (3), 1391–1401.
[12] Macpherson H et al. Brain functional alterations in Type 2 Diabetes – A systematic review of fMRI studies. Front Neuroendocrinol 2017, 47, 34-46.
[13] Ristow M Neurodegenerative disorders associated with diabetes mellitus. J Mol Med (Berl) 2004, 82, 510-529.
[14] Xu W, et al. Mid- and late-life diabetes in relation to the risk of dementia: A population-based twin study. Diabetes 2009, 58, 71-77.
[15] Aviles-Olmos I, et al. Parkinson’s disease, insulin resistance and novel agents of neuroprotection. Brain 2013 136, 374-384.
[16] Sandyk R The relationship between diabetes mellitus and Parkinson’s disease. Int J Neurosci 1993, 69, 125-130.
[17] Moreira, P.I., et al. Brain mitochondrial dysfunction as a link between Alzheimer’s disease and diabetes. J. Neurol. Sci. 2007, 257 (1–2), 206–214.
[18] Fabbri E et al. Insulin Resistance Is Associated With Reduced Mitochondrial Oxidative Capacity Measured by 31P-Magnetic Resonance Spectroscopy in Participants Without Diabetes From the Baltimore Longitudinal Study of Aging. Diabetes. 2017, 66(1):170-176. doi: 10.2337/db16-0754. Epub 2016 Oct 13.
[19] Horvath S et al. Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci U S A. 2014;111(43):15538-43.
[20] Yang H et al. Obesity accelerates thymic aging. Blood. 2009;114(18):3803-12.
[21] Nevalainen T et al. Obesity accelerates epigenetic aging in middle-aged but not in elderly individuals. Clin Epigenetics. 2017 Feb 14;9:20.

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

noage100

A Norwegian integrated, interdisciplinary, world-class centre for human ageing research