scholarly journals Late-Onset Pharmacological or Dietary Interventions Improve Healthspan and Lifespan in Male and Female Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 125-125
Author(s):  
Sarah Mitchell ◽  
Michael MacArthur ◽  
Alice Kane ◽  
Margaret Torrence ◽  
Huseyin Mehmet ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Late Onset ◽  
Frailty Index ◽  
Pharmacological Intervention ◽  
Blood Collection ◽  
Dietary Interventions ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Extended Lifespan

Abstract While late-onset dietary or pharmacological interventions can extend longevity in rodents, whether or not they can be used to reverse or forestall onset of aging-related symptoms (i.e. frailty) remains untested. Here, we employed three interventions to test this hypothesis. Male and female C57BL/6 mice were randomized to one of four groups: control, 15% calorie restriction (15CR), 0.1% Methionine Restriction (MR)or ZGN1062 (1.5mg/kg, drug in feed) starting at 21mo. Healthspan measurements (mouse clinical frailty index (FI), blood collection, and hematology) were performed every three months, and survival was assessed for all mice. At baseline there were no significant differences in frailty index. After 6mo FI increased consistent with reduced healthspan in control males (0.23□0.01 to 0.34□0.01 A.U, p<0.0001) and females at this age (0.19□0.03 to 0.24□0.01, p<0.0001). Male 15CR, MR and ZGN1062 mice had significantly lower FI scores at 27mo age (15CR: 0.32□0.01, p=0.02; MR: 0.31□0.01, p=0.0009; ZGN1062: 0.30□0.01, p<0.0001). Female mice were less frail than males at 27mo, suggesting sexual dimorphism in the timing of frailty onset in mice. ZGN1062 significantly extended lifespan in males (HR=0.56, p=0.007) and females (HR=0.46, p=0.001). There was a sexual dimorphism in the ability of 15CR and MR to extend lifespan, and a trend towards increased lifespan in males (HR=0.69, p=0.057 and HR=0.71, p=0.09) but not in females. Histological analysis for cause-of-death is ongoing. Taken together these data suggest that a pharmacological intervention associated with weight loss, which may be a more practical therapeutic strategy towards mitigation of age-related healthspan decline than dietary restriction-based interventions.

scholarly journals IMPROVED HEALTHSPAN AND LIFESPAN WITH LATE ONSET PHARMACOLOGICAL OR DIETARY INTERVENTIONS IN MICE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S875-S875
Author(s):  
Sarah Mitchell ◽  
Michael MacArthur ◽  
Alice Kane ◽  
Margaret Torrence ◽  
Brendan Manning ◽  
...  
Keyword(s):  
Weight Loss ◽  
Dietary Intervention ◽  
Late Onset ◽  
Frailty Index ◽  
Pharmacological Intervention ◽  
Dietary Interventions ◽  
Age Related ◽  
Modest Weight Loss ◽  
Survival Studies ◽  
Multiple Species

Abstract While late-onset dietary (e.g. calorie restriction) or pharmacological (e.g. rapamycin) interventions can extend longevity in rodents, whether or not they can be used to reverse or forestall onset of aging-related symptoms (i.e. frailty) remains untested. Here, we employed methionine restriction (MR), a dietary intervention associated with weight loss and longevity extension, or a fumagillin derivative, ZGN-1062, as a pharmacological agent associated with weight loss across multiple species. 21mo Male and female C57BL/6 mice were randomized to one of three groups: control, 0.1% MetR, or ZGN-1062 (1.5mg/kg). There was no difference in frailty index (FI) amongst groups at baseline (21 mo age). MetR and ZGN-1062 treatments resulted in modest weight loss independent of sex. After 6 months, FI increased consistent with reduced healthspan in control males (0.23+/-0.01 to 0.34+/-0.01 A.U, p<0.0001) and females at this age (0.19+/-0.03 to 0.24+/-0.01, p<0.0001). Male MetR and ZGN-1062 mice had significantly lower FI scores after 6 mo of treatment (MetR: 0.28+/-0.04, p<0.0001; ZGN-1062: 0.29+/-0.05, p=0.0002). While female mice were not significantly different from controls, they were, overall, less frail than males at 26 months, suggesting sexual dimorphism in the timing frailty onset in mice. Although the end points of this study have not been reached (survival studies are ongoing), the data obtained to date suggest that late-life treatments can improve healthspan markers, at least in male mice. Such treatments include a pharmacological intervention associated with weight loss, which may be a more practical therapeutic strategy towards mitigation of age-related healthspan decline than dietary restriction-based interventions.

Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

2021 ◽  
Author(s):  
Jazmin A Cole ◽  
Mackenzie N Kehmeier ◽  
Bradley R Bedell ◽  
Sahana Krishna Kumaran ◽  
Grant D Henson ◽  
...  
Keyword(s):  
Sex Differences ◽  
Endothelial Function ◽  
Vascular Function ◽  
Mesenteric Artery ◽  
Frailty Index ◽  
Mesenteric Arteries ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia

2021 ◽  
Vol 13 (590) ◽  
pp. eabd6434
Author(s):  
Patrick Sweeney ◽  
Michelle N. Bedenbaugh ◽  
Jose Maldonado ◽  
Pauline Pan ◽  
Katelyn Fowler ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Feeding Behavior ◽  
Critical Role ◽  
Brain Regions ◽  
Sexually Dimorphic ◽  
Male And Female ◽  
Female Mice ◽  
Bidirectional Regulation ◽  
Fear And Anxiety ◽  
Agouti Related Protein

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.

scholarly journals NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

Abstract 220: Transcriptional Analysis Of Caveolin And Cavin In The Male And Female Ageing Mouse Heart Following Ischemic Stress

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Can J Kiessling ◽  
Melissa Reichelt ◽  
John Headrick ◽  
Kevin Ashton
Keyword(s):  
G Protein ◽  
Ischemic Tolerance ◽  
Transcriptional Analysis ◽  
Membrane Microdomains ◽  
G Protein Coupled Receptor ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
G Protein Coupled ◽  
Ischemic Stress

Cardioprotection against infarction and dysfunction in the myocardium involves G-protein-coupled receptor signalling orchestrated by specialised membrane microdomains termed caveolae. The caveolin protein family consist of three subtypes: caveolin-1, −2 and −3 (Cav1-3) and are responsible for the formation of caveolae and hypothesized to orchestrate cardioprotective signalling. Caveolin-3 deficiency and overexpression has been shown to attenuate and restore cardioprotection, respectively. Recently, a family of four related proteins known as cavins (Cavin1-4) have been implicated as regulators of caveolae formation and function. The roles and expression distribution of the cavin family is currently unknown in cardiac tissue. In this study hearts were isolated from 8, 16, 32 and 48 week male and female mice and subjected to normoxic perfusion (80 min) or ischemic stress (20 min global ischemia, 60 min reperfusion). RT-qPCR was used to assess differential gene expression of caveolin and cavin subtypes across these ages in both sexes. Decreased post-ischemic pressure development and increased LDH release were observed in 32 and 48 week old relative to 8 week old male hearts hearts, indicative of age-related loss of ischemic tolerance. Females showed greater tolerance to ischemia at 32 and 48 week old hearts when compared to male counterparts. In normoxic male 48 week old hearts, Cav1,-2,-3 and Cavin1 were significantly repressed, whilst post-ischemic male 48 week old hearts demonstrated significant repression of Cav3 and Cavin1 only. Normoxic female hearts showed no significant changes in caveolin and cavin transcript expression over the aging time course. However, post-ischemic female 48 week old hearts showing significant down-regulation of Cav3 only. Taken together, alterations in caveolin and cavin expression may contribute to the age-related loss of ischemic tolerance and G-protein-coupled receptor-mediated protection in aging male and female mice hearts.

scholarly journals Gonad-related factors promote muscle performance gain during postnatal development in male and female mice

2017 ◽  
Vol 313 (1) ◽  
pp. E12-E25 ◽  
Author(s):  
Vanessa Ueberschlag-Pitiot ◽  
Amalia Stantzou ◽  
Julien Messéant ◽  
Megane Lemaitre ◽  
Daniel J. Owens ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Postnatal Development ◽  
Muscle Fiber ◽  
Muscle Performance ◽  
Performance Gain ◽  
Related Factors ◽  
Muscle Weight ◽  
Male And Female ◽  
Female Mice ◽  
Muscle Contractile

To better define the role of male and female gonad-related factors (MGRF, presumably testosterone, and FGRF, presumably estradiol, respectively) on mouse hindlimb skeletal muscle contractile performance/function gain during postnatal development, we analyzed the effect of castration initiated before puberty in male and female mice. We found that muscle absolute and specific (normalized to muscle weight) maximal forces were decreased in 6-mo-old male and female castrated mice compared with age- and sex-matched intact mice, without alteration in neuromuscular transmission. Moreover, castration decreased absolute and specific maximal powers, another important aspect of muscle performance, in 6-mo-old males, but not in females. Absolute maximal force was similarly reduced by castration in 3-mo-old muscle fiber androgen receptor (AR)-deficient and wild-type male mice, indicating that the effect of MGRF was muscle fiber AR independent. Castration reduced the muscle weight gain in 3-mo mice of both sexes and in 6-mo females but not in males. We also found that bone morphogenetic protein signaling through Smad1/5/9 was not altered by castration in atrophic muscle of 3-mo-old mice of both sexes. Moreover, castration decreased the sexual dimorphism regarding muscle performance. Together, these results demonstrated that in the long term, MGRF and FGRF promote muscle performance gain in mice during postnatal development, independently of muscle growth in males, largely via improving muscle contractile quality (force and power normalized), and that MGFR and FGRF also contribute to sexual dimorphism. However, the mechanisms underlying MGFR and FGRF actions remain to be determined.

scholarly journals Allodynia by Splenocytes From Mice With Acid-Induced Fibromyalgia-Like Generalized Pain and Its Sexual Dimorphic Regulation by Brain Microglia

2020 ◽  
Vol 14 ◽  
Author(s):  
Hiroshi Ueda ◽  
Naoki Dozono ◽  
Keigo Tanaka ◽  
Shuji Kaneko ◽  
Hiroyuki Neyama ◽  
...  
Keyword(s):  
Animal Model ◽  
T Cells ◽  
Electrical Stimulation ◽  
Mechanical Allodynia ◽  
Gastrocnemius Muscle ◽  
Late Onset ◽  
Unknown Etiology ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice

Fibromyalgia (FM), a disease of unknown etiology characterized by chronic generalized pain, is partly recapitulated in an animal model induced by repeated acid saline injections into the gastrocnemius muscle. Here, we attempted to investigate the sex difference in pain hypersensitivity (mechanical allodynia and hypersensitivity to electrical stimulation) in the repeated acid saline-induced FM-like generalized pain (AcGP) model. The first unilateral acid injection into gastrocnemius muscle at day 0/D0 and second injection at D5 (post day 0, P0) induced transient and long-lasting mechanical allodynia, respectively, on both sides of male and female mice. The pretreatment with gonadectomy did not affect the first injection-induced allodynia in both sexes, but gradually reversed the second injection-induced allodynia in male but not female mice. Moreover, the AcGP in male mice was abolished by intracerebroventricular minocycline treatments during D4–P4 or P5–P11, but not by early treatments during D0–D5 in male but not female mice, suggesting that brain microglia are required for AcGP in late-onset and sex-dependent manners. We also found that the intravenous treatments of splenocytes derived from male but not female mice treated with AcGP caused allodynia in naive mice. In addition, the purified CD4+ T cells derived from splenocytes of acid-treated male mice retained the ability to cause allodynia in naive mice. These findings suggest that FM-like AcGP has multiple sexual dimorphic mechanisms.

scholarly journals Rapid Changes in Anterior Pituitary Cell Phenotypes in Male and Female Mice after Acute Cold Stress

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2159-2167 ◽  
Author(s):  
Laura Senovilla ◽  
Lucía Núñez ◽  
Carlos Villalobos ◽  
Javier García-Sancho
Keyword(s):  
Sexual Dimorphism ◽  
Cold Stress ◽  
Relative Abundance ◽  
Anterior Pituitary ◽  
Cell Types ◽  
Male And Female ◽  
Female Mice ◽  
Rapid Changes ◽  
Cell Phenotypes ◽  
Different Cell Types

The anterior pituitary (AP) is made of five different cell types. The relative abundance and phenotype of AP cells may change in different physiological situations as an expression of pituitary plasticity. Here, we analyze in detail the phenotype of mouse corticotropes and the effects of acute cold stress on AP cell populations. The hormone content and the expression of hypothalamic-releasing hormone (HRH) receptors in all the five AP cell types were studied in the male and female mice at rest and after a 30-min cold stress. Expression of HRH receptors was evidenced by imaging the single-cell cytosolic Ca2+ responses in fura-2-loaded cells. Hormone contents were studied by multiple, simultaneous immunofluorescence of all the five hormones. Corticotropes displayed a striking sexual dimorphism, even in the resting condition. Male corticotropes showed the orthodox phenotype. They were monohormonal, storing only ACTH, and monoreceptorial, responding only to CRH. In contrast, female corticotropes were made of about equal parts of orthodox cells and multifunctional cells, which co-stored additional AP hormones and expressed additional HRH receptors. Cold stress did not modify the number of ACTH containing cells, but, according to immunostaining, it increased the relative abundance of other AP cell types at the expense of the pool of cells storing no hormones. Cold stress also modified the response to CRH and other HRHs. Most of these phenotypical changes presented a strong sexual dimorphism. These results indicate that pituitary plasticity is even larger than previously thought.

scholarly journals Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

2020 ◽  
Vol 21 (4) ◽  
pp. 1279
Author(s):  
Marianne K.O. Grant ◽  
Ibrahim Y. Abdelgawad ◽  
Christine A. Lewis ◽  
Beshay N. Zordoky
Keyword(s):  
Sex Differences ◽  
Cytochrome P450 ◽  
Sexual Dimorphism ◽  
Inflammatory Response ◽  
Systemic Inflammation ◽  
Dependent Manner ◽  
Male And Female ◽  
Female Mice ◽  
Organ Toxicity ◽  
Hepatic Cytochrome

Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. In addition to its multi-organ toxicity, DOX treatment has been shown to induce systemic inflammation in patients and experimental animals. Inflammation alters the expression of hepatic cytochrome P450 (CYP) enzymes, which play important roles in drug metabolism and DOX-induced toxicity. Significant sex differences have been reported in DOX-induced toxicity; however, sex differences in DOX-induced systemic inflammation and the potential effects on hepatic CYP expression have not been determined. In the current work, male and female C57Bl/6 mice were administered DOX (20 mg/kg by intraperitoneal injection), and groups of mice were sacrificed 24 and 72 h after DOX administration. DOX elicited a systemic inflammatory response in both male and female mice, but the inflammatory response was stronger in male mice. DOX altered the expression of hepatic CYP isoforms in a sex-dependent manner. Most notably, inhibition of Cyp2c29 and Cyp2e1 was stronger in male than in female mice, which paralleled the sex differences in systemic inflammation. Therefore, sex differences in DOX-induced systemic inflammation may lead to sexually dimorphic drug interactions, in addition to contributing to the previously reported sexual dimorphism in specific DOX-induced organ toxicity.

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