Sex differences in health and aging: a dialog between the brain and gonad?

Austad, Steven N.

doi:10.1007/s11357-019-00081-3

Cited by 31 publications

(21 citation statements)

References 51 publications

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“…Furthermore, altered endocannabinoid signaling is linked to infertility in human sperm (Lewis et al, 2012), and the strongest evidence for the negative effects of cannabis on humans is its impacts on semen parameters such as reduced concentration (Reviewed in: Payne et al, 2019). Sex-specific effects in aging are frequently reported (Austad, 2019), and our current study supports previous research on sex-specific effects of THC (reviewed in: Brents, 2016). THC alters the hypothalamic-pituitaryovarian (HPO) axis functionality, while hormones produced by the HPO axis impact the physiological and behavioral effects of THC (Brents, 2016).…”

Section: Discussionsupporting

confidence: 79%

Developmental exposure to Δ9-tetrahydrocannabinol (THC) causes biphasic effects on longevity, inflammation, and reproduction in aged zebrafish (Danio rerio)

et al. 2020

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Increased availability of cannabis and cannabinoid-containing products necessitates the need for an understanding of how these substances influence aging. In this study, zebrafish (Danio rerio) were exposed to different concentrations of THC (0.08, 0.4, 2 μM) during embryonic-larval development and the effects on aging were measured 30 months later and in the offspring of the exposed fish (F1 generation). Exposure to 0.08 μM THC resulted in increased male survival at 30 months of age. As the concentration of THC increased, this protective effect was lost. Treatment with the lowest concentration of THC also significantly increased egg production, while higher concentrations resulted in impaired fecundity. Treatment with the lowest dose of THC significantly reduced wet weight, the incidence of kyphosis, and the expression of several senescence and inflammatory markers (p16 ink4ab , tnfα, il-1β, il-6, pparα and pparγ) in the liver, but not at higher doses indicating a biphasic or hormetic effect. Exposure to THC did not affect the age-related reductions in locomotor behavior. Within the F1 generation, many of these changes were not observed. However, the reduction in fecundity due to THC exposure was worse in the F1 generation because offspring whose parents received high dose of THC were completely unable to reproduce. Together, our results demonstrate that a developmental exposure to THC can cause significant effects on longevity and healthspan of zebrafish in a biphasic manner.

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Section: Discussionsupporting

confidence: 79%

Developmental exposure to Δ9-tetrahydrocannabinol (THC) causes biphasic effects on longevity, inflammation, and reproduction in aged zebrafish (Danio rerio)

et al. 2020

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“…In addition, the fish displayed similar healthy (k = 1) condition factors which further supports that while their size differed, their health did not. While sex-specific difference in life span and health span are commonly observed in aging studies (Austad 2019), caloric restriction or density affects alone should have impacted both male and female fish. While not likely, it should be acknowledged that food availability due to changes in tank density could have confounded the F0 results.…”

Section: Discussionmentioning

confidence: 96%

Developmental exposure to cannabidiol (CBD) alters longevity and health span of zebrafish (Danio rerio)

et al. 2020

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Consumption of cannabinoid-containing products is on the rise, even during pregnancy. Unfortunately, the long-term, age-related consequences of developmental cannabidiol (CBD) exposure remain largely unknown. This is a critical gap given the established Developmental Origins of Health and Disease (DOHaD) paradigm which emphasizes that stressors, like drug exposure, early in life can instigate molecular and cellular changes that ultimately lead to adverse outcomes later in life. Thus, we exposed zebrafish (Danio rerio) to varying concentrations of CBD (0.02, 0.1, 0.5 μM) during larval development and assessed aging in both the F0 (exposed generation) and their F1 offspring 30 months later. F0 exposure to CBD significantly increased survival (~20%) and reduced size (wet weight and length) of female fish. While survival was increased, the age-related loss of locomotor function was unaffected and the effects on fecundity varied by sex and dose. Treatment with 0.5 μM CBD significantly reduced sperm concentration in males, but 0.1 μM increased egg production in females. Similar to other model systems, control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16 ink4ab , tnfα, il1b, il6, and pparγ) in the liver. Exposure to CBD significantly reduced the expression of several of these genes in a dose-dependent manner relative to the age-matched controls. The effects of CBD on size, gene expression, and reproduction were not reproduced in the F1 generation, suggesting the influence on aging was not cross-generational. Together, our results demonstrate that developmental exposure to CBD causes significant effects on the health and longevity of zebrafish.

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“…However, there have been no studies beyond the age of 14 months ( 23 ). Considering that male C57BL/6 mice have an average lifespan of 28 months, 14 months is widely considered to be middle-aged ( 24 , 25 ). We sought to determine the levels of AlloP in 24-month-old mice, which is more indicative of physiological aging and is consistent with the decline in cognitive function that is generally observed beginning at 21 months of age ( 26 – 28 ).…”

Section: Discussionmentioning

confidence: 99%

Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice

Parks

Logan

Yeganeh

et al. 2020

Journal of Lipid Research

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Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter Allopregnanolone levels, an important neurosteroid in the brain. We assessed the levels and regulation of allopregnanolone and the effects of allopregnanolone supplementation on cognitive function in 4 month old and 24 month old male C57BL/6 mice. With age, the expression of enzymes involved in the allopregnanolone synthetic pathway were decreased and corticosterone synthesis increased. Supplementation of allopregnanolone improved cognitive function. Interestingly, IL-6 infusion in young animals significantly reduced the production of allopregnanolone compared to controls. Of note, inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein gp130 (sgp130), significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of allopregnanolone and increases corticosterone levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in allopregnanolone levels and an increase in corticosterone. Furthermore, our results indicate that allopregnanolone is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

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Sex differences in health and aging: a dialog between the brain and gonad?

Cited by 31 publications

References 51 publications

Developmental exposure to Δ9-tetrahydrocannabinol (THC) causes biphasic effects on longevity, inflammation, and reproduction in aged zebrafish (Danio rerio)

Developmental exposure to Δ9-tetrahydrocannabinol (THC) causes biphasic effects on longevity, inflammation, and reproduction in aged zebrafish (Danio rerio)

Developmental exposure to cannabidiol (CBD) alters longevity and health span of zebrafish (Danio rerio)

Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice

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