Ageing is a complex biological process that increases the probability of disease and death, which affects the organs of all species. The accumulation of oxidative damage in the brain contributes to a progressive loss of cognitive functions or even declined the energy metabolism. In this study, we tested the effects of exercise training on the apoptosis, survival, and antioxidant signaling pathways in the cerebral cortex of three age groups of male rats; 3, 12, and 18 months. We observed that H2S and the expression of Nrf2-related antioxidant pathways declined with age and increased after exercise training. IGF1R survival pathway was less increased in middle-aged rats; however, significantly increased after exercise training. The expression of mitochondrial-dependent apoptotic pathway components, such as Bak, cytochrome C, and caspase 3 in the ageing control group, were much higher than those of the exercise training groups. This study demonstrated that exercise training could reduce the apoptosis and oxidative stress that accrues throughout ageing, which causes brain damage.
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Nuclear factor E2-related factor 2
Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16(3):1066–1071
Brancaleone V, Roviezzo F, Vellecco V, De Gruttola L, Bucci M, Cirino G (2008) Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice. Br J Pharmacol 155(5):673–680
Calvert JW, Jha S, Gundewar S, Elrod JW, Ramachandran A, Pattillo CB, Kevil CG, Lefer DJ (2009) Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res 105(4):365–374
Chae CH, Kim HT (2009) Forced, moderate-intensity treadmill exercise suppresses apoptosis by increasing the level of NGF and stimulating phosphatidylinositol 3-kinase signaling in the hippocampus of induced ageing rats. Neurochem Int 55(4):208–213
Choi DH, Lee KH, Lee J (2016) Effect of exercise-induced neurogenesis on cognitive function deficit in a rat model of vascular dementia. Mol Med Rep 13(4):2981–2990
Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30(9):464–472
Culmsee C, Landshamer S (2006) Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders. Curr Alzheimer Res 3(4):269–283
Erdoğan ME, Aydın S, Yanar K, Mengi M, Kansu AD, Cebe T, Belce A, Çelikten M, Çakatay U (2017) The effects of lipoic acid on redox status in brain regions and systemic circulation in streptozotocin-induced sporadic Alzheimer’s disease model. Metab Brain Dis 32(4):1017–1031
Eto K, Asada T, Arima K, Makifuchi T, Kimura H (2002) Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem Biophys Res Commun 293(5):1485–1488
Giuliani D, Ottani A, Zaffe D, Galantucci M, Strinati F, Lodi R, Guarini S (2013) Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol Learn Mem 104:82–91
Glorioso C, Sibille E (2011) Between destiny and disease: genetics and molecular pathways of human central nervous system ageing. Prog Neurobiol 93(2):165–181
Grabowska W, Sikora E, Bielak-Zmijewska A (2017) Sirtuins, a promising target in slowing down the ageing process. Biogerontology 18(4):447–476
Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS (2010) Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models. Ageing Cell 9(2):135–146
Hu LF, Wong PT, Moore PK, Bian JS (2007) Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem 100(4):1121–1128
Huang CY, Kuo WW, Yeh YL, Ho TJ, Lin JY, Lin DY, Chu CH, Tsai FJ, Tsai CH, Huang CY (2014) ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation. Cell Death Differ 21(8):1262–1274
Kaliman P, Parrizas M, Lalanza JF, Camins A, Escorihuela RM, Pallas M (2011) Neurophysiological and epigenetic effects of physical exercise on the ageing process. Ageing Res Rev 10(4):475–486
Kim SE, Ko IG, Kim BK, Shin MS, Cho S, Kim CJ, Kim SH, Baek SS, Lee EK, Jee YS (2010) Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus. Exp Gerontol 45(5):357–365
Koay KP, Tsai BCK, Kuo CH, Kuo WW, Luk HN, Day CH, Chen RJ, Chen MYC, Padma VV, Huang CY (2021) Hyperglycemia-Induced Cardiac Damage Is Alleviated by Heat-Inactivated Lactobacillus reuteri GMNL-263 via Activation of the IGF1R Survival Pathway. Probiotics Antimicrob Proteins. https://doi.org/10.1007/s12602-021-09745-z
Koike S, Ogasawara Y, Shibuya N, Kimura H, Ishii K (2013) Polysulfide exerts a protective effect against cytotoxicity caused by t-buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells. FEBS Lett 587(21):3548–3555
Kolluru GK, Shen X, Kevil CG (2013) A tale of two gases: NO and HS, foes or friends for life? Redox Biol 1(1):313–318
Lai C-H, Ho T-J, Kuo W-W, Day C-H, Pai P-Y, Chung L-C, Liao P-H, Lin F-H, Wu E-T, Huang C-Y (2014) Exercise training enhanced SIRT1 longevity signaling replaces the IGF1 survival pathway to attenuate ageing-induced rat heart apoptosis. Age 36(5):1–13
Lai PF, Baskaran R, Kuo CH, Day CH, Chen RJ, Ho TJ, Yeh YL, Padma VV, Lai CH, Huang CY (2021) Bioactive dipeptide from potato protein hydrolysate combined with swimming exercise prevents high fat diet induced hepatocyte apoptosis by activating PI3K/Akt in SAMP8 mouse. Mol Biol Rep 1–9
Lay S, Kuo W-W, Shibu MA, Ho T-J, Cheng S-M, Day CH, Ban B, Wang S, Li Q, Huang C-Y (2021) Exercise training restores IGFIR survival signaling in d-galactose induced-ageing rats to suppress cardiac apoptosis. J Adv Res 28:35–41
Lee H-P, Wang S-W, Wu Y-C, Tsai C-H, Tsai F-J, Chung J-G, Huang C-Y, Yang J-S, Hsu Y-M, Yin M-C (2019) Glucocerebroside reduces endothelial progenitor cell-induced angiogenesis. Food Hydrocolloids 30(1):1033–1045
Liao P-H, Hsieh DJ-Y, Kuo C-H, Day C-H, Shen C-Y, Lai C-H, Chen R-J, Padma VV, Kuo W-W, Huang C-Y (2015) Moderate exercise training attenuates ageing-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts. Oncotarget 6(34):35383
Lin CC, Chen KB, Tsai CH, Tsai FJ, Huang CY, Tang CH, Yang JS, Hsu YM, Peng SF, Chung JG (2019) Casticin inhibits human prostate cancer DU 145 cell migration and invasion via Ras/Akt/NF-κB signaling pathways. J Food Biochem 43(7):e12902
Lin J-Y, Kuo W-W, Baskaran R, Kuo C-H, Chen Y-A, Chen WS-T, Ho T-J, Day CH, Mahalakshmi B, Huang C-Y (2020) Swimming exercise stimulates IGF1/PI3K/Akt and AMPK/SIRT1/PGC1α survival signaling to suppress apoptosis and inflammation in ageing hippocampus. Ageing (albany NY) 12(8):6852
Liu YY, Nagpure BV, Wong PT, Bian JS (2013) Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int 62(5):603–609. https://doi.org/10.1016/j.neuint.2012.12.010
Liu SP, Shibu MA, Tsai FJ, Hsu YM, Tsai CH, Chung JG, Yang JS, Tang CH, Wang S, Li Q, Huang CY (2020) Tetramethylpyrazine reverses high-glucose induced hypoxic effects by negatively regulating HIF-1alpha induced BNIP3 expression to ameliorate H9c2 cardiomyoblast apoptosis. Nutr Metab (lond) 17:12
Loprinzi PD, Frith E (2018) The role of sex in memory function: considerations and recommendations in the context of exercise. J Clin Med 7(6):132
Marosi K, Bori Z, Hart N, Sarga L, Koltai E, Radak Z, Nyakas C (2012) Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 226:21–28
Metkus TS Jr, Baughman KL, Thompson PD (2010) Exercise prescription and primary prevention of cardiovascular disease. Circulation 121(23):2601–2604
Radak Z, Chung HY, Koltai E, Taylor AW, Goto S (2008) Exercise, oxidative stress and hormesis. Ageing Res Rev 7(1):34–42
Radak Z, Suzuki K, Posa A, Petrovszky Z, Koltai E, Boldogh I (2020) The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol 35:101467
Schirrmacher V (2021) Less can be more: the hormesis theory of stress adaptation in the global biosphere and its implications. Biomedicines 9(3):293
Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H (2009) 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11(4):703–714
Tan BH, Wong PT, Bian JS (2010) Hydrogen sulfide: a novel signaling molecule in the central nervous system. Neurochem Int 56(1):3–10
Tay AS, Hu LF, Lu M, Wong PT, Bian JS (2010) Hydrogen sulfide protects neurons against hypoxic injury via stimulation of ATP-sensitive potassium channel/protein kinase C/extracellular signal-regulated kinase/heat shock protein 90 pathway. Neuroscience 167(2):277–286
Tsai BC-K, Hsieh DJ-Y, Lin W-T, Tamilselvi S, Day CH, Ho T-J, Chang R-L, Viswanadha VP, Kuo C-H, Huang C-Y (2020a) Functional potato bioactive peptide intensifies Nrf2-dependent antioxidant defense against renal damage in hypertensive rats. Food Res Int 129:108862
Tsai BC-K, Kuo W-W, Day CH, Hsieh DJ-Y, Kuo C-H, Daddam J, Chen R-J, Padma VV, Wang G, Huang C-Y (2020b) The soybean bioactive peptide VHVV alleviates hypertension-induced renal damage in hypertensive rats via the SIRT1-PGC1α/Nrf2 pathway. J Funct Foods 75:104255
Tsou YH, Shih CT, Ching CH, Huang JY, Jen CJ, Yu L, Kuo YM, Wu FS, Chuang JI (2015) Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity. Exp Neurol 263:50–62
Vargas-Mendoza N, Morales-González Á, Madrigal-Santillán EO, Madrigal-Bujaidar E, Álvarez-González I, García-Melo LF, Anguiano-Robledo L, Fregoso-Aguilar T, Morales-Gonzalez JA (2019) Antioxidant and adaptative response mediated by Nrf2 during physical exercise. Antioxidants 8(6):196
Vecchio LM, Meng Y, Xhima K, Lipsman N, Hamani C, Aubert I (2018) The neuroprotective effects of exercise: maintaining a healthy brain throughout ageing. Brain Plasticity 4(1):17–52
Wu KM, Hsu YM, Ying MC, Tsai FJ, Tsai CH, Chung JG, Yang JS, Tang CH, Cheng LY, Su PH, Viswanadha VP, Kuo WW, Huang CY (2019) High-density lipoprotein ameliorates palmitic acid-induced lipotoxicity and oxidative dysfunction in H9c2 cardiomyoblast cells via ROS suppression. Nutr Metab (Lond) 16:36
Yanar K, Aydın S, Çakatay U, Mengi M, Buyukpınarbaşılı N, Atukeren P, Sitar ME, Sönmez A, Uslu E (2011) Protein and DNA oxidation in different anatomic regions of rat brain in a mimetic ageing model. Basic Clin Pharmacol Toxicol 109(6):423–433
Yanar K, Simsek B, Çaylı N, Övül Bozkır H, Mengi M, Belce A, Aydin S, Çakatay U (2019) Caloric restriction and redox homeostasis in various regions of ageing male rat brain: is caloric restriction still worth trying even after early-adulthood? Redox homeostasis and caloric restriction in brain. J Food Biochem 43(3):e12740
Yang G, Zhao K, Ju Y, Mani S, Cao Q, Puukila S, Khaper N, Wu L, Wang R (2013) Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid Redox Signal 18(15):1906–1919
Yin J, Tu C, Zhao J, Ou D, Chen G, Liu Y, Xiao X (2013) Exogenous hydrogen sulfide protects against global cerebral ischemia/reperfusion injury via its anti-oxidative, anti-inflammatory and anti-apoptotic effects in rats. Brain Res 1491:188–196
Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47
Zhao W, Ndisang JF, Wang R (2003) Modulation of endogenous production of H2S in rat tissues. Can J Physiol Pharmacol 81(9):848–853
We thank that this work is supported grants from Hualien Tzu Chi Hospital (Buddhist Tzu Chi Medical Foundation), China Medical University, Asia University, and China Medical University Hospital in Taiwan (IMAR-110-01-16, CMU107-ASIA-01, and DMR-105-011).
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The authors declare that there are no conflicts of interest.
All protocols were approved by the Institutional Animal Care and Use Committee of Central Taiwan University of Science and Technology, Taichung, Taiwan.
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Lin, JY., Ho, TJ., Tsai, B.CK. et al. Exercise renovates H2S and Nrf2-related antioxidant pathways to suppress apoptosis in the natural ageing process of male rat cortex. Biogerontology 22, 495–506 (2021). https://doi.org/10.1007/s10522-021-09929-8