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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    436—Aging: Oxidative Stress

    Monday, November 11, 2013, 1:00 pm - 5:00 pm

    436.04: Oxidative stress and testosterone in aging men and women: Role in Alzheimer’s disease and neurodegeneration

    Location: Halls B-H

    ">*R. L. CUNNINGHAM, S. O'BRYANT, J. HALL, M. SINGH, R. BARBER;
    Pharmacol. & Neurosci., Univ. North Texas Hlth. Sci. Ctr., Fort Worth, TX

    Abstract Body: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with memory loss, inflammation, and depression. Women are more likely to be diagnosed with AD than men. This gender discrepancy has lead to several studies examining AD in women but not men. However, recent studies and the Alzheimer’s Association have found no differences between women and men in the incidence of AD when stratified by age. A key component of aging is oxidative stress (OS). Previous studies by our laboratory have shown that OS and the male sex hormone, testosterone, have a significant impact on neuronal viability. Analysis of plasma biomarker proteins for OS (homocysteine) and testosterone were conducted on 105 AD participants (60 women and 45 men) and 265 control participants (177 women and 88 men) with a mean age of 72 from the Texas Alzheimer’s Research and Care Consortium (TARCC) to determine their role on disease severity, inflammation, and depression in men and women. Our results show that OS was significantly higher in men compared to women. Further, OS significantly increased disease severity scores, inflammation, and depression, regardless of gender. Interesting, when OS levels were separated into three groups: low (< 10 Mol/L homocysteine), medium (10.1-14.9 Mol/L homocysteine), and high (> 15 Mol/L homocysteine), testosterone levels in men had opposite effects on disease severity, inflammation, and depression that was dependent on the level of OS. In low OS conditions, hypogonadal men (< 2 ng/ml total testosterone) had increased disease severity scores, inflammation, and depression, whereas men with normal testosterone levels (> 4 ng/ml total testosterone) had improved outcomes. However, in mid to high OS conditions normal testosterone levels had a significant negative impact on disease severity scores, inflammation, and depression. These effects of testosterone and OS were evident in AD participants compared to control participants, in whom normal testosterone levels in low OS conditions were associated with positive outcomes, while normal testosterone levels in high OS conditions were associated with negative outcomes. No testosterone-associated effects were observed in females, which may be a result of generally low testosterone levels in women. Collectively, the data support the hypothesis that 1) OS mediates negative disease outcomes in men and women, 2) interactions between low OS and testosterone may mediate positive disease outcomes, and 3) interactions between mid-high OS and testosterone may underlie negative disease outcomes in men.

    Lay Language Summary: We have found that oxidative stress and the male sex hormone, testosterone, are important for the health of cells in the brain. Testosterone in men with low oxidative stress may have a beneficial effect on brain health and function. However, testosterone in men with high oxidative stress may have the opposite effect. Therefore, these results have broad implications for testosterone replacement therapy in aging men.
    Testosterone is related to men’s health and cognitive aging. In aging men, low testosterone levels are predictive of future development of mobility limitations and frailty. Symptoms of testosterone deficiency in aging men include low muscle mass and strength, decreased ratio of lean body mass to adipose tissue, osteoporosis, decreased libido, decreased hematocrit, impaired cognition, and mood disorders. Testosterone replacement therapy in aging men has been considered as a restorative/protective treatment against various disorders associated with aging, including increased risk for neurodegenerative disease. Because of these purported positive effects, testosterone replacement therapy has become popular in aging men, as evidenced by the three-fold increase in testosterone replacement therapy prescription sales this past decade for men over 40 years of age. However, studies on testosterone replacement therapy outcomes have been equivocal. These inconsistent reports may be due to testosterone replacement therapy effects being dependent on oxidative stress. This is important because a key factor in aging is an increase in oxidative stress, which is produced when tissues are damaged or immune cells are otherwise activated.
    Testosterone and a protein that is an indicator for oxidative stress (homocysteine) were measured in 370 participants (237 women and 133 men) with a broad spectrum of cognitive function, ranging from cognitively normal to moderate Alzheimer’s disease from the Texas Alzheimer’s Research and Care Consortium in an effort to find out if testosterone and oxidative stress were important for cognitive function, inflammation, and depression. Caucasian and Mexican American men and women were studied separately.
    Our results show that oxidative stress was higher in men compared to women. Further, oxidative stress was higher in both men and women who had more cognitive dysfunction, inflammation, and depression. When men were divided into groups based on levels of oxidative stress (low or high oxidative stress), testosterone had different effects on cognitive function, inflammation, and depression, which were dependent on the level of oxidative stress and ethnicity. In the low oxidative stress group, Caucasian men with low levels of testosterone had more inflammation and Mexican American men had more depression. However, in the high oxidative stress group, Caucasian men with normal testosterone levels had more cognitive dysfunction, inflammation, and depression, and Mexican American men had worse depression. Clinical diagnosis of Alzheimer’s disease did not have an impact on the observed effects of testosterone. No testosterone effects were observed in females, which may be a result of lower testosterone levels in women.
    Previous studies have shown that the response to testosterone replacement therapy is variable, with 20-28% of aging men showing either no response or a negative adverse event. Interestingly, approximately this same percentage (20%) of Caucasian men in our study had evidence of adverse consequences (cognitive dysfunction, inflammation, and depression) due to an interaction between testosterone and oxidative stress. In conclusion, these studies suggest that 1) oxidative stress affects cognitive function in both men and women, 2) ethnicity affects oxidative stress, 3) normal testosterone levels in men with low oxidative stress may have a beneficial effect on brain health and function and 4) normal testosterone levels in men with high oxidative stress may have the opposite effect.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    436—Aging: Oxidative Stress

    Monday, November 11, 2013, 1:00 pm - 5:00 pm

    436.04: Oxidative stress and testosterone in aging men and women: Role in Alzheimer’s disease and neurodegeneration

    Location: Halls B-H

    ">*R. L. CUNNINGHAM, S. O'BRYANT, J. HALL, M. SINGH, R. BARBER;
    Pharmacol. & Neurosci., Univ. North Texas Hlth. Sci. Ctr., Fort Worth, TX

    Abstract Body: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with memory loss, inflammation, and depression. Women are more likely to be diagnosed with AD than men. This gender discrepancy has lead to several studies examining AD in women but not men. However, recent studies and the Alzheimer’s Association have found no differences between women and men in the incidence of AD when stratified by age. A key component of aging is oxidative stress (OS). Previous studies by our laboratory have shown that OS and the male sex hormone, testosterone, have a significant impact on neuronal viability. Analysis of plasma biomarker proteins for OS (homocysteine) and testosterone were conducted on 105 AD participants (60 women and 45 men) and 265 control participants (177 women and 88 men) with a mean age of 72 from the Texas Alzheimer’s Research and Care Consortium (TARCC) to determine their role on disease severity, inflammation, and depression in men and women. Our results show that OS was significantly higher in men compared to women. Further, OS significantly increased disease severity scores, inflammation, and depression, regardless of gender. Interesting, when OS levels were separated into three groups: low (< 10 Mol/L homocysteine), medium (10.1-14.9 Mol/L homocysteine), and high (> 15 Mol/L homocysteine), testosterone levels in men had opposite effects on disease severity, inflammation, and depression that was dependent on the level of OS. In low OS conditions, hypogonadal men (< 2 ng/ml total testosterone) had increased disease severity scores, inflammation, and depression, whereas men with normal testosterone levels (> 4 ng/ml total testosterone) had improved outcomes. However, in mid to high OS conditions normal testosterone levels had a significant negative impact on disease severity scores, inflammation, and depression. These effects of testosterone and OS were evident in AD participants compared to control participants, in whom normal testosterone levels in low OS conditions were associated with positive outcomes, while normal testosterone levels in high OS conditions were associated with negative outcomes. No testosterone-associated effects were observed in females, which may be a result of generally low testosterone levels in women. Collectively, the data support the hypothesis that 1) OS mediates negative disease outcomes in men and women, 2) interactions between low OS and testosterone may mediate positive disease outcomes, and 3) interactions between mid-high OS and testosterone may underlie negative disease outcomes in men.

    Lay Language Summary: We have found that oxidative stress and the male sex hormone, testosterone, are important for the health of cells in the brain. Testosterone in men with low oxidative stress may have a beneficial effect on brain health and function. However, testosterone in men with high oxidative stress may have the opposite effect. Therefore, these results have broad implications for testosterone replacement therapy in aging men.
    Testosterone is related to men’s health and cognitive aging. In aging men, low testosterone levels are predictive of future development of mobility limitations and frailty. Symptoms of testosterone deficiency in aging men include low muscle mass and strength, decreased ratio of lean body mass to adipose tissue, osteoporosis, decreased libido, decreased hematocrit, impaired cognition, and mood disorders. Testosterone replacement therapy in aging men has been considered as a restorative/protective treatment against various disorders associated with aging, including increased risk for neurodegenerative disease. Because of these purported positive effects, testosterone replacement therapy has become popular in aging men, as evidenced by the three-fold increase in testosterone replacement therapy prescription sales this past decade for men over 40 years of age. However, studies on testosterone replacement therapy outcomes have been equivocal. These inconsistent reports may be due to testosterone replacement therapy effects being dependent on oxidative stress. This is important because a key factor in aging is an increase in oxidative stress, which is produced when tissues are damaged or immune cells are otherwise activated.
    Testosterone and a protein that is an indicator for oxidative stress (homocysteine) were measured in 370 participants (237 women and 133 men) with a broad spectrum of cognitive function, ranging from cognitively normal to moderate Alzheimer’s disease from the Texas Alzheimer’s Research and Care Consortium in an effort to find out if testosterone and oxidative stress were important for cognitive function, inflammation, and depression. Caucasian and Mexican American men and women were studied separately.
    Our results show that oxidative stress was higher in men compared to women. Further, oxidative stress was higher in both men and women who had more cognitive dysfunction, inflammation, and depression. When men were divided into groups based on levels of oxidative stress (low or high oxidative stress), testosterone had different effects on cognitive function, inflammation, and depression, which were dependent on the level of oxidative stress and ethnicity. In the low oxidative stress group, Caucasian men with low levels of testosterone had more inflammation and Mexican American men had more depression. However, in the high oxidative stress group, Caucasian men with normal testosterone levels had more cognitive dysfunction, inflammation, and depression, and Mexican American men had worse depression. Clinical diagnosis of Alzheimer’s disease did not have an impact on the observed effects of testosterone. No testosterone effects were observed in females, which may be a result of lower testosterone levels in women.
    Previous studies have shown that the response to testosterone replacement therapy is variable, with 20-28% of aging men showing either no response or a negative adverse event. Interestingly, approximately this same percentage (20%) of Caucasian men in our study had evidence of adverse consequences (cognitive dysfunction, inflammation, and depression) due to an interaction between testosterone and oxidative stress. In conclusion, these studies suggest that 1) oxidative stress affects cognitive function in both men and women, 2) ethnicity affects oxidative stress, 3) normal testosterone levels in men with low oxidative stress may have a beneficial effect on brain health and function and 4) normal testosterone levels in men with high oxidative stress may have the opposite effect.