Hyperbaric oxygen therapy effectively alleviates D-galactose-induced-age-related cardiac dysfunction via attenuating mitochondrial dysfunction in pre-diabetic rats.

Currently, the prevalence of obesity in aging populations is fast growing worldwide. Aging induced by D-galactose (D-gal) is proven to cause the worsening of cardiac dysfunction in pre-diabetic rats via deteriorating cardiac mitochondrial function. Hyperbaric oxygen therapy (HBOT) has been shown to attenuate D-gal-induced cognitive deterioration through decreased inflammation and apoptosis. We tested the hypothesis that HBOT alleviates D-gal induced cardiac dysfunction via improving mitochondrial function in pre-diabetic rats. Wistar rats (n=56) were fed normal diet or high-fat diet for 12 weeks. For subsequent 8 weeks, they were subcutaneously injected either vehicle (0.9% normal saline) or D-gal (150mg/kg/day). Rats were randomly subdivided into 7 groups at week 21: sham-treated (normal diet fed rats with vehicle (NDV), high-fat diet fed rats with vehicle (HFV), normal diet fed rats with D-gal (NDDg), high-fat diet fed rats with D-gal (HFDg)) and HBOT-treated (HFV, NDDg, HFDg). Sham rats received ambient pressure of oxygen while HBOT-treated ones received 100% oxygen given once daily for 60 minutes at 2 atmosphere absolute. HBOT reduced metabolic impairments, mitochondrial dysfunction and increased autophagy, resulting in an improvement of cardiac function in aged pre-diabetic rats.

Hyperbaric oxygen therapy restores cognitive function and hippocampal pathologies in both aging and aging-obese rats.

The population of obese-elderly has increased prominently around the world. Both aging and obesity are major factors of neurodegeneration. The present study hypothesizes that HBOT attenuates metabolic disturbance, cognitive decline, hippocampal pathologies in aging and aging-obese model. Sixty Wistar rats were separated into 2 groups to receive normal-diet (ND) or high-fat diet (HFD) for 22 weeks. At week 13, ND rats were divided into two subgroups to receive vehicle (0.9 % NSS, s.c) or d-gal (150 mg/kg/d, s.c) for total 10 weeks. HFD rats were injected only d-gal (150 mg/kg/d, s.c; HFDD) for total 10 weeks. At week 20, rats in each subgroup were given sham-treatment (1ATA, 80 L/min, 80 min/day), or HBOT (2ATA, pure O2, 250 L/min, 80 min/day) for 14 days. Novel object location test, metabolic parameters, and hippocampal pathologies were determined after HBOT. d-gal induced insulin resistance, increased oxidative stress, autophagy impairment, microglial hyperactivation, apoptosis, synaptic dysplasticity which resulted in cognitive impairment. d-gal-treated HFD-fed rats had the highest levels of oxidative stress, apoptosis, dendritic spine loss. HBOT attenuated insulin resistance, cognitive impairment, hippocampal aging and pathologies in both models. These findings suggest that HBOT restored insulin sensitivity, hippocampal functions, cognition in aging and aging-obese models.

D-galactose-induced aging does not cause further deterioration in brain pathologies and cognitive decline in the obese condition.

Largely as a consequence of changes in modern lifestyle, a significant proportion of global population have become obese. When obese people grow old, pathologies aggravate neurodegeneration. Several studies have demonstrated that both aging and obesity have deleterious impact on brain. However, the time course effects of combined aging-induced by d-galactose and obesity caused by high-fat diet on cognitive and brain function have not been explored. We hypothesize that D-galactose accelerates and aggravates brain pathologies and cognitive dysfunction in the state of obesity. Ninety-six Wistar rats were separated into two groups to be fed with either a normal diet (ND) or a high-fat diet (HFD) for 16 to 20 weeks. At the end of 12 weeks, ND and HFD-fed rats were injected with vehicle (0.9% NSS, s.c) or d-galactose (150 mg/kg/d, s.c) for 4 or 8 weeks. Data from behavioral test, metabolic parameters and brain pathologies were determined at 4 and 8-weeks after d-galactose administration. The results from both d-galactose-treated rats and HFD-fed rats showed that there was an equal increase in advanced glycation end products, and microglial activation, and an impairment in long-term depression, long-term potentiation, and synaptic protein and dendritic spine density in hippocampus, resulting in cognitive decline. However, d-galactose did not accelerate or aggravate these parameters and cognitive decline in HFD-fed rats. These results suggest that aging, obesity, and combined model have equally adverse effects on cognition. These findings can be used to increase public awareness of the negative impact of both aging and obesity on neurodegeneration.

Aging induced by D-galactose aggravates cardiac dysfunction via exacerbating mitochondrial dysfunction in obese insulin-resistant rats.

The prevalence of obesity and an aging population are increasing worldwide. Both obesity and aging are independently known to be associated with cardiac dysfunction. However, in obese insulin-resistant subjects, the effects of aging on metabolic status and cardiac and mitochondrial functions are not completely understood. We hypothesized that in the obese insulin-resistant condition, aging induced by D-galactose increases cardiac senescence markers and aggravates the impairment of metabolic parameters, cardiac and mitochondrial function, and increases oxidative stress, inflammation, apoptosis, and autophagy. Sixty-four male Wistar rats were fed with either normal diet (ND) or high-fat diet (HFD) for 12 weeks. Then, rats were divided into vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-galactose groups (150 mg/kg/day, SC). After 0.9%NSS or D-galactose treatment for 4 weeks and 8 weeks, metabolic and cardiac functions were determined. The heart was then removed to determine mitochondrial functions and enable biochemical studies. After 4 weeks of D-galactose injection, ND rats treated with D-galactose (NDD4), HFD rats treated with vehicle (HFV4), and HFD rats treated with D-galactose (HFD4) had reduced cardiac function, impaired cardiac mitochondrial function and autophagy, and increased oxidative stress, inflammation, and apoptosis. Interestingly, after 8 weeks, HFD rats treated with D-galactose (HFD8) had the worst impairment of cardiac and mitochondrial function, autophagy, and apoptosis in comparison to the other groups. Aging induced by D-galactose aggravated cardiac dysfunction in obese insulin-resistant rats through the worsening of cardiac mitochondrial function, autophagy, and increased apoptosis in a time-dependent manner.

Effects of d-galactose-induced ageing on the heart and its potential interventions.

Ageing is a strong independent risk factor for disability, morbidity and mortality. Post-mitotic cells including those in the heart are a particular risk to age-related deterioration. As the occurrence of heart disease is increasing rapidly with an ageing population, knowledge regarding the mechanisms of age-related cardiac susceptibility and possible therapeutic interventions needs to be acquired to prevent advancing levels of heart disease. To understand more about the ageing heart, numerous aged animal models are being used to explore the underlying mechanisms. Due to time-consuming for investigations involving naturally aged animals, mimetic ageing models are being utilized to assess the related effects of ageing on disease occurrence. d-galactose is one of the substances used to instigate ageing in various models, and techniques involving this have been widely used since 1991. However, the mechanism through which d-galactose induces ageing in the heart remains unclear. The aim of this review was to comprehensively summarize the current findings from in vitro and in vivo studies on the effects of d-galactose-induced ageing on the heart, and possible therapeutic interventions against ageing heart models. From this review, we hope to provide invaluable information for future studies and based on the findings from experiments involving animals, we can inform possible therapeutic strategies for the prevention of age-related heart diseases in clinical settings.