# Exercise as it relates to Disease/Benefits of Running on the Ageing Brain

This page is an analysis of the journal article titled ‘Running for REST: Physical activity attenuates neuroinflammation in the hippocampus of aged mice’ by Dallagnol et al. 2017

## What is the Background to this Research?

Current medical literature supports the premise that exercise positively affects brain health both in the long term and short term. A widely noted benefit exercise has on the brain is its ability to suppress inflammation which has shown to be linked to many neurological diseases such as Alzheimer’s disease (AD). Inflammation is one of the main contributors to ageing and age related diseases which comes into existence through a reduction in certain hormones, vitamin D and infections.
The following study focuses largely on the role of exercise on the expression of the RE1-silencing transcption factor (REST), an RNA regulator involved in neurogenesis and neuroprotection, a counter force to inflammation. The literature shows an increase in REST expression as the brain ages to provide neuroprotection, however, those suffering from neurodegenerative diseases show a decrease in REST expression. If exercise has a neuroprotective effect on the brain, is it possible that it affects REST to do so? Other focuses of this study were whether exercise alters levels of Brain Derived Neurotrophic Factor (BDNF), IL-1β and IL-10. Research has shown that BDNF plays a key role in neural plasticity and neuroprotection while IL-1β nd IL-10 have shown to be inflammatory markers. The aim of the analysed study, although not mentioned by the authors, was to add additional validity and scope to the understanding of the positive impact of exercise on the ageing brain.

## Where is the Research From?

This study was conducted by researchers from the Universidade Federal de Santa Catarina, Brazil who have extensive backgrounds in brain biochemistry research, suggesting this paper to be well researched. Additionally, several of the authors have worked together on previous papers published in peer reviewed journals. The researchers stated that there was no personal or financial conflict of interest and cited where the funding for the study was received from suggesting no bias was present in conducting the study.

## What Kind of Research Was This?

This was a quantitative experimental study using a C57BL/6 male mice animal model. The authors did not state their reason for using this genetic strain, however, it has been used widely in the literature. Randomisation of the mice into each respectable group was conducted and the housing environment was controlled by the researchers (lighting, food, cage type, temperature). Due to the nature of the variables in the study (exercise and sedentary), the researchers were not blinded to these. Through controlling most significant variables the researchers minimised error potentials in the data to a reasonable extent.

## What Did the Research Involve?

Four groups of mice were exposed to two variables, a running wheel (RW) and the absence of a RW to create a sedentary environment (SED). Of the four groups of mice, two groups were young (12-14 weeks) and the other two groups were old (19-21 months). All up the four groups were sedentary-young (SED-young), RW-young, sedentary-aged (SED-aged) and RW-aged. Each group was exposed to its specific variable over 8 weeks and remained in isolation for this period with controlled lighting, variables that can contribute to changes in mood. Measurements for distance, speed, rearings, open field exploration and immobility were taken after the 8 weeks and before the harvesting of the animals hippocampus upon sacrifice. Notably, open field tests and immobility have been used widely in scientific literature as indications of depression and anxiety, or reflections of mood, in mice, therefore, these measurements will hold validity in their results. The tissue samples were analysed for mRNA expression of BDNF, REST, IL-1β and IL-10 indicating their altered effects within the mice.

## What Were the Basic Results?

The results can be broken down into two parts: 1)The effect of exercise, namely running, on the mood of the mice and 2) the effect of exercise on inflammatory and neuroprotective mechanisms. In regards to the effect of exercise on the mood of the mice, the SED-aged mice showed significantly more thigmotaxis, an indication of anxiety, than the RW-aged mice and the young mice suggesting that exercise had a positive effect on the mood of the mice and anxiety may increase as one ages. These results support previous evidence that depression-like symptoms may increase as one ages and exercise can ameliorate these symptoms. In regards to the effect of exercise on neuroprotective mechanisms and inflammation, there was a significantly increased expression of BDNF and REST mRNA in the RW-aged mice compared to the SED-aged controls demonstrating that exercise was able to influence these two factors. This suggests an increase in neuroprotection after only 8 weeks of RW exercise. Additionally, measurements of IL-1β and IL-10 were significantly less in the RW-aged mice compared to the SED-aged mice further supporting the evidence that exercise has an anti-inflammatory role.

## What Conclusions Can We Take From This Research?

As this study was the first to look at the direct effects of exercise on REST and evidence shows that it’s fundamental in healthy neuronal ageing, conclusions we can take from this research is that healthy brain ageing likely requires exercise. Although this study was performed in mice, the evidence is promising enough for clinical studies in humans to be conducted. As this particular animal model has been used widely in pre-clinical studies, it would be expected that the physiological changes seen here will also occur in humans. Further studies should also determine whether this change was dose dependent as a specified running dosage was not controlled in this study.
According to this research, exercise decreases inflammation, a cause for neuronal ageing, and improves REST and BDNF expression in the brain, two known neuroprotective factors. Ultimately, it appears that exercise may not only ensure healthy cognitive functioning in the elderly, but also reduce the incidence of neurodegenerative diseases.

## Practical Advice

In Australia, less than half of people over 65 exercise the recommended amount which may have potential links to the increase in neurodegenerative diseases in the ageing population of Australia. With the understanding from this study, more emphasis needs to be placed on the importance of exercise for the elderly for quality of life and economic disease burden reduction. It is paramount that health professionals aid the elderly in exercise prescription and the elderly population educates themselves on this matter (see 'Further Information/Resources).

## Further Information/Resources

Australian exercise recommendations: http://www.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act-guidelines
Your brain matters - brain health: https://yourbrainmatters.org.au/
Physical Activity Guidelines for Older Adults (Australia): https://www.healthdirect.gov.au/physical-activity-guidelines-for-older-adults

## References

* 1 2 3 Dallagnol, KMC, Remor, AP, da Silva, RA, Prediger, RD, Latini, A, Aguiar Jr, AS 2017, ‘Running for REST: Physical activity attenuates neuroinflammation in the hippocampus of aged mice’, Brain, Behaviour and Immunity, vol. 61, pp. 31-35
* ↑ Erikson, KI, Prakash, RS, Voss, MW, Chaddock, L, Hu, L, Morris, KS, et al. 2009, ‘Aerobic fitness is associated with hippocampal volume in elderly humans’, Hippocampus, vol. 19, no. 10, pp. 1030-1039
* ↑ Colcombe, SJ, Erickson, KI, Scalf, PE, Kim, JS, Prakash, R, McAuley, E, et al. 2006, ‘Aerobic exercise training increases brain volume in ageing humans’, The Journals of Gerontology: Series A, vol. 61, no. 11, pp. 1166-1170
* ↑ Vega, SR, Struder, HK, Wahrmann, BV, Schmidt, A, Bloch, W, Hollmann, W 2006, ‘Acute BDNF and cortisol response to low intensity exercise following ramp incremental exercise to exhaustion in humans’, Brain Research, vol. 1121, no. 1, pp. 59-65
* ↑ Nouchi, R, Taki, Y, Takeuchi, H, Sekiguchi, A, Hashizume, H, Nozawa, T, et al. 2014, ‘Four weeks of combination exercise improved executive functions, episodic memory and processing speed in healthy elderly people: evidence from a randomised controlled trial’, Age, vol. 36, no. 2, pp. 787-799
* ↑ Svensson, M, Lexell, J, Deierborg, T 2015, ‘Effects of physical exercise on neuroinflammation, neuroplasticity, neurodegeneration and behaviour: What we can learn from animal models in clinical settings’, Neurorehabilitation and Neural Repair, vol. 29, no. 6, pp. 577-589
* ↑ Chung, HY, Cesari, M, Anton, S, Marzetti, E, Giovannini, S, Seo, AY, et al. 2009, ‘Molecular inflammation: underpinnings of ageing and age-related diseases’, Ageing Research Reviews, vol. 8, no. 1, pp. 18-30
* ↑ Hubbard, RE, Woodhouse, KW 2010, ‘Frailty, inflammation and the elderly’, Biogerontology, vol. 11, no. 5, pp. 635-641
* 1 2 Zhao, Y, Zhu, M, Yu, Y, Qiu, L, Zhang, Y, He, L, et al. 2017, ‘Brain REST/NRSF is not only a silent repressor but also an active protector’, Molecular Neurobiology, vol. 54, no. 1, pp. 541, 550
* ↑ Tapia-Arancibia, L, Aliga, E, Silhol, M, Arancibia, S 2008, ‘New insights into brain BDNF function in normal ageing and Alzheimer’s disease’, Brain Research Reviews, vol. 59, no. 1, pp. 201-220
* ↑ Aguiar, AS, Stragier, E, da Luz Scheffer, D, Remor, AP, Oliveira, PA, Prediger, RD, et al. 2014, ‘Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behaviour of mice’, Neuroscience, vol. 271, pp. 56-63
* ↑ Aguiar, AS, Duzzioni, M, Remor, AP, Tristao, FSM, Matheus, FC, Raisman-Vozari, R, et al. 2016, ‘Moderate-intensity physical exercise protects against experimental 6-Hydroxydopamine-induced hemiparkinsonism through Nrf2-antioxidant response element pathway’, Neurochemical Research, vol. 41, no. 1-2, pp. 64-72
* ↑ Aguiar, AS, Moreira, ELG, Hoeller, AA, Oliveira, PA, Cordova, FM, Glaser, V, et al. 2013, ‘Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice’, Neuroscience, vol. 243, pp. 46-53
* ↑ Mekad, K, Abe, K, Murakami, A, Nakamura, S, Nakata, H, Moriwaki, K, et al. 2009, ‘Genetic differences among C57BL/6 substrains’, Experimental Animals, vol. 58, no. 2, pp. 141-149
* ↑ Zurita, E, Chagoyen, M, Cantero, M, Alonso, R, Gonzalez-Neira, Lopez-Jimenez, A, et al. 2011, ‘Genetic polymorphisms among C57BL/6 mouse inbred strains’, Transgenic Research, vol. 20, no. 3, pp. 481-489
* 1 2 Huang, Y, Zhou, W, Zhang, Y 2012, ‘Bright lighting conditions during testing increase thigmotaxis and impair water maze performance in BALB/c mice’, Behavioural Brain Research, vol. 226, no. 1, pp. 26-31
* ↑ Cryan, JF, Holmes, A 2005, ‘The ascent of mouse: Advances in modelling human depression and anxiety’, Nature Reviews. Drug Discovery, vol. 4, no. 9, pp. 775-790
* ↑ Stordal, E, Mykletun, A, Dahl, AA 2003, ‘The association between age and depression in the general population: a multivariate examination’, Act Psychiatrica Scandinavica, vol. 107, no. 2, pp. 132-141
* ↑ Alexopoulas, GS 2005, ‘Depression in the elderly’, The Lancet, vol. 365, no. 9475, pp. 1961-1970
* ↑ Arent, SM, Lnders, DM, Etnier, JL 2000, ‘The effects of exercise on mood in older adults: A meta-analytic review’, Journal of Ageing and Physical Activity, vol. 8, pp. 407-430
* ↑ Petersen, AMW, Pedersen, BK 2005, ‘The anti-inflammatory effect of exercise’, Journal of Applied Physiology, vol. 98, no. 4, pp. 1154-1162
* ↑ Sims, J, Hill, K, Hunt, S, Haralambous, B 2010, ‘Physical activity recommendations for older Australians’, Australasian Journal on Ageing, vol. 29, no. 2, pp. 81-87
* ↑ Begg, Stephen, Vos, Theo, Barker, Bridget, Stevenson, Chris, Stanley, Lucy and Lopez, Alan D. 2007, The burden of disease and injury in Australia 2003, Australian Institute of Health and Welfare, [Canberra, A. C. T.]