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Amelioration of the autonomic imbalances of old age with exercise: exploring the molecular and physiological mechanisms

Grant number: 15/07863-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2015
Effective date (End): January 31, 2016
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Cooperation agreement: BBSRC, UKRI
Principal Investigator:Lisete Compagno Michelini
Grantee:Nilson Carlos Ferreira Junior
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:11/51410-9 - Amelioration of the autonomic imbalances of old age with exercise: exploring the molecular and physiological mechanisms, AP.TEM


The main neural mechanisms controlling cardiovascular functions lose their strength in aged individuals causing an imbalance between sympathetic (the accelerator, which predominates) and vagal outflow (decreased brake) and resulting in a drastic reduction of dynamic flexibility of the system with increased mortality. The deficit in the autonomic control of the circulation has been indicated as the common final pathway for different diseases such as hypertension, heart failure, stroke, obesity, diabetes, insulin resistance, etc. The deterioration imposed by aging not only impacts on the individual, but also causes considerably economic and social burdens on families and society. There are two approaches to the problem of frailty on old age: increased medical interventions or lifestyle modifications. It is known that lifestyle changes (such as improvement of physical activity) are important conditioners of wellbeing benefits. However our knowledge of physiological mechanisms underlying these changes is still scant. Experimental evidence indicated that spontaneously hypertensive rats (SHR, the best experimental model for essential hypertension) exhibited a strong autonomic imbalance already observed in young rats, even before the blood pressure elevation. In previous studies we showed that adult SHR vs. normotensive WKY showed marked sympathetic overactivity and depressed parasympathetic activity, accompanied by a differential expression of several genes within brain areas involved in autonomic control (namely hypothalamic paraventricular nucleus, PVN; the nucleus tractus solitarii, NTS; the rostroventrolateral medulla, RVLM and area postrema, Stewart et al 201; Hindmarch et al, 2011), some of which showed the ability to alter cardiovascular homeostasis when challenged by drugs or viral vectors (Sellers et al, 2005). We also identified in SHR that low intensity aerobic training (T), as opposed to the sedentary lifestyle, improves the reflex control of circulation, increases vagal outflow and reduces sympathetic activity, determining partial pressure and heart rate reduction (Ceroni et al, 2009). Simultaneously to the functional adjustments, marked changes on neuronal plasticity/activity (Michelini & Stern, 2009; Stern et al, 2012) and gene/protein expression changes in autonomic control areas such as increased oxytocin content in the PVN (Cavalleri et al, 2011), augmented expression of glutamic acid decarboxilase in the PVN and RVLM (Ruggeri, 2012) and increased ratio of anti-inflammatory/pro-inflammatory cytokines expression in the NTS and RVLM (Masson et al, submitted) and reduced expression of angiotensinogen and AT1a receptor within the PVN and NTS of SHR (unpublished data). It is not known whether and how aging interferes with gene expression in autonomic areas, how these changes affect cardiovascular homeostasis and importantly whether T is able to modify/correct aging-induced deficits. Knowing that autonomic balance is ideal in young normotensive rats we hypothesized that establishment/maintenance of autonomic imbalance (and consequent functional deficits) induced by aging/hypertension is associated with altered expression of a large number of genes in integrative autonomic areas, which can be corrected/ modified by T. To investigate the effects of hypertension, aging and T and their association on gene expression we sought now to investigate and compare in young (aged 1 month) and old (aged 12 month) SHR and WKY the effects of T on gene profile into the PVN, NTS and RVLM, associating the observed mRNA changes with sympathetic/parasympathetic outflow and cardiovascular responses. We also sought to analyze in SHR and WKY at different ages the effects of T on the transcriptome in order to identify possible gene networks determining the functional effects of aging and exercise training. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FERREIRA-JUNIOR, NILSON C.; RUGGERI, ADRIANA; SILVA JR, SEBASTIAO D.; ZAMPIERI, THAIS T.; CERONI, ALEXANDRE; MICHELINI, LISETE C. Exercise training increases GAD65 expression, restores the depressed GABA(A) receptor function within the PVN and reduces sympathetic modulation in hypertension. PHYSIOLOGICAL REPORTS, v. 7, n. 13 JUL 2019. Web of Science Citations: 0.

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