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Sex Differences in Aging and Longevi...

Jiang, Nisi,

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Sex Differences in Aging and Longevity: The Impact of Castration and Potential Castration Mimetics /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Sex Differences in Aging and Longevity: The Impact of Castration and Potential Castration Mimetics // Nisi Jiang.
Author:	Jiang, Nisi,
Description:	1 electronic resource (151 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-08, Section: B.
Contained By:	Dissertations Abstracts International86-08B.
Subject:	Aging. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31635573
ISBN:	9798304911566

Sex Differences in Aging and Longevity: The Impact of Castration and Potential Castration Mimetics /
Jiang, Nisi,

Sex Differences in Aging and Longevity: The Impact of Castration and Potential Castration Mimetics /Nisi Jiang. - 1 electronic resource (151 pages)

Source: Dissertations Abstracts International, Volume: 86-08, Section: B.

Sex differences in aging are well-established in human populations. Males typically have shorter lifespans and face significantly higher mortality risks during early to middle adulthood compared to females. However, the underlying mechanisms remain unclear, partly due to the lack of experimental animal models. Our lab previously reported that genetically diverse UM-HET3 mice exhibit consistent sex differences in survival and mortality similar to humans, establishing it as a useful model for exploring the factors underlying these sex differences.In this study, we first found that prepubertal castration completely eliminated the sex difference in longevity of UM-HET3 mice by selectively reducing mortality during early-to-middle adulthood. We then explored the duration and ages when testicular hormones exert their detrimental effects on mortality. By castrating mice at 20, 60, and 240 days of age. The finding that castration as late as 8 months was as effective in reducing mortality as castration at 20 days, indicated that neither the pubertal surge in gonadal hormones nor their actions during a substantial period of adult life play any role in limiting longevity of males. In fact, later-life castration at 240 days was associated with a significantly extended lifespan and healthspan compared to castration at earlier ages. Together these results indicate that exposure to testicular hormones up to 8 months may offer long-term benefits, whereas exposure after 8 months is detrimental for longevity and health.We next investigated whether any life-extending compounds identified by the NIA Interventions Testing Program (ITP) could function as "castration mimetics," offering similar mortality benefits without compromising reproductive function. To address this, we employed two complementary approaches that significantly expanded the pool of life-extending candidates. First, we applied the Gehan test, which is more sensitive to the effects of interventions during early-to-middle adulthood, leading to the identification of six additional compounds that enhance survival. Next, we developed a novel analytical tool designed to detect age-specific drug effects on mortality. This tool nearly doubled the number of interventions associated with reduced mortality. From this expanded pool of candidates, we identified several compounds that exhibited similar efficacy and duration of benefit as castration. Among these, we anticipate that some may provide the mortality benefits of castration without negatively affecting reproductive function.In conclusion, this study is the first to demonstrate that testicular hormones are responsible for the higher mortality rates observed in male genetically diverse mice. Additionally, using a novel analytical tool, we found that testicular hormones do not negatively impact survival until at least 8 months of age and may even contribute positively to healthspan later in life. The discovery that several compounds identified by the ITP mimic the selective effect of castration on male mortality suggests the potential for drugs that offer the longevity benefits of castration without compromising reproductive function. However, many questions remain, such as whether these findings extend to other aging models, including humans, and what mechanisms underlie the mortality and dysfunction-reducing effects of castration.

English

ISBN: 9798304911566Subjects--Topical Terms:

543123
Aging.
Subjects--Index Terms:

Age-specific mortality

Sex Differences in Aging and Longevity: The Impact of Castration and Potential Castration Mimetics /
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500 $a Source: Dissertations Abstracts International, Volume: 86-08, Section: B.
500 $a Advisors: Nelson, James F.; Zhao, Shangang Committee members: Salmon, Adam B.; Promislow, Daniel; Kokovay, Erzsebet K.; Strong, Randy J.
502 $b Ph.D. $c The University of Texas Health Science Center at San Antonio $d 2024.
520 $a Sex differences in aging are well-established in human populations. Males typically have shorter lifespans and face significantly higher mortality risks during early to middle adulthood compared to females. However, the underlying mechanisms remain unclear, partly due to the lack of experimental animal models. Our lab previously reported that genetically diverse UM-HET3 mice exhibit consistent sex differences in survival and mortality similar to humans, establishing it as a useful model for exploring the factors underlying these sex differences.In this study, we first found that prepubertal castration completely eliminated the sex difference in longevity of UM-HET3 mice by selectively reducing mortality during early-to-middle adulthood. We then explored the duration and ages when testicular hormones exert their detrimental effects on mortality. By castrating mice at 20, 60, and 240 days of age. The finding that castration as late as 8 months was as effective in reducing mortality as castration at 20 days, indicated that neither the pubertal surge in gonadal hormones nor their actions during a substantial period of adult life play any role in limiting longevity of males. In fact, later-life castration at 240 days was associated with a significantly extended lifespan and healthspan compared to castration at earlier ages. Together these results indicate that exposure to testicular hormones up to 8 months may offer long-term benefits, whereas exposure after 8 months is detrimental for longevity and health.We next investigated whether any life-extending compounds identified by the NIA Interventions Testing Program (ITP) could function as "castration mimetics," offering similar mortality benefits without compromising reproductive function. To address this, we employed two complementary approaches that significantly expanded the pool of life-extending candidates. First, we applied the Gehan test, which is more sensitive to the effects of interventions during early-to-middle adulthood, leading to the identification of six additional compounds that enhance survival. Next, we developed a novel analytical tool designed to detect age-specific drug effects on mortality. This tool nearly doubled the number of interventions associated with reduced mortality. From this expanded pool of candidates, we identified several compounds that exhibited similar efficacy and duration of benefit as castration. Among these, we anticipate that some may provide the mortality benefits of castration without negatively affecting reproductive function.In conclusion, this study is the first to demonstrate that testicular hormones are responsible for the higher mortality rates observed in male genetically diverse mice. Additionally, using a novel analytical tool, we found that testicular hormones do not negatively impact survival until at least 8 months of age and may even contribute positively to healthspan later in life. The discovery that several compounds identified by the ITP mimic the selective effect of castration on male mortality suggests the potential for drugs that offer the longevity benefits of castration without compromising reproductive function. However, many questions remain, such as whether these findings extend to other aging models, including humans, and what mechanisms underlie the mortality and dysfunction-reducing effects of castration.
546 $a English
590 $a School code: 0853
650 4 $a Aging. $3 543123
650 4 $a Endocrinology. $3 610914
650 4 $a Bioinformatics. $3 553671
653 $a Age-specific mortality
653 $a Anti-aging interventions
653 $a Longevity
653 $a Sex differences
653 $a Human populations
690 $a 0493
690 $a 0409
690 $a 0715
710 2 $a The University of Texas Health Science Center at San Antonio. $b Physiology. $e degree granting institution. $3 3827210
720 1 $a Nelson, James F. $e degree supervisor.
720 1 $a Zhao, Shangang $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-08B.
790 $a 0853
791 $a Ph.D.
792 $a 2024
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31635573