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The extension of life expectancy is a global phenomenon. The growth in the ageing population has created a new health scenario in which there is a higher prevalence of frailty and multimorbidity. The attention received by both conditions derives from their strong association with disability, hospitalization, and death. The aim of the present paper is to conceptualize and differentiate these terms and to discuss their interrelations. We conclude that, yet related, they represent two different clinical conditions. Frailty identifies the increased vulnerability to stressors due to a dynamic, non-linear, and multidimensional depletion of physiological reserve and redundancy, whereas multimorbidity refers to the coexistence of two or more clinically manifest chronic diseases., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Most human demographic data, particularly those on natural fertility populations, find no relationship or even a positive association between fertility and longevity. The present study aims to ascertain whether there is a trade-off between fertility and longevity in the mouse model., Methods: The study was focused on the first litter produced by 10- to 14-wk-old hybrid (C57BL/6JIco female X CBA/JIco male) mice. A single female/male per litter was individually housed with a male/female at the age of 25 and 52 wk, respectively, until the end of reproductive life in females or natural death in males under controlled housing conditions. Post-reproductive females and virgin mice were reared until natural death. Cox regression models with forward stepwise variable selection were fitted to examine the effect of several fertility variables on expectation of survival times., Results: Virgin females displayed higher life expectancy than virgin males. The relative risk of dying for a virgin male at a particular age was 2.116 [99% confidence interval: 1.317, 3.398] times that of a virgin female. No significant differences on expectation of survival times between virgin and mated females, and between virgin and mated males were found. Furthermore, total number of pups at weaning and total number of litters produced by a dam/stud, time interval between mating and last litter, time interval between litters, and age at last litter were not significant predictors of expectation of survival times in both mated females and mated males., Conclusions: Like in most human studies, the present study evidences no relationship between total number of offspring/litters produced by a dam/stud and expectation of survival times. Moreover, the present data are in agreement with the general phenomenon of a bias in life expectancy in favor of females.

This study aims to determine in the mouse whether oocytes from reproductively old females exhibit a different susceptibility to be parthenogenetically activated when compared to oocytes from young females. At the age of 10-12 (young-female group) or 60-62 (old-female group) weeks, hybrid female mice were superovulated using pregnant mare's serum gonadotropin (PMSG) followed by human chorionic gonadotropin (hCG) 48 hr later. After removing the cumulus cells, oocytes were exposed to any of two different activating protocols: (a) 6-min exposure to 8% ethanol; and (b) treatment with 200 microM thimerosal for 15 min followed by 8 mM dithiothreitol (DTT) for 30 min. Oocytes from old female mice displayed (1) lower total percentage of parthenogenetic activation and extrusion of the second polar body after treatment with either thimerosal + DTT or ethanol; (2) higher M-phase-promoting factor (MPF) and mitogen-activated protein kinases (MAPKs) activities; and (3) lower intracytoplasmic levels of glutathione S-transferases (GSTs) activity and thiols than oocytes from young females. These data show that female aging is associated with higher resistance of oocytes to be parthenogenetically activated, higher MPF and MAPKs activities and lower intracytoplasmic levels of GSTs activity and thiols., (Copyright 2004 Wiley-Liss, Inc.)

This study aims to compare the effect of early and late onset administration of oral antioxidants on number and quality of oocytes retrieved from aged mice after exogenous ovarian stimulation. Control hybrid females were fed a standard diet supplemented or not supplemented with pharmacological doses of vitamins C and E either from the first day of weaning or from the age of 32 weeks until they were autopsied at the age 40-42, 50-52, or 57-62 weeks after exogenous ovarian stimulation. Analysis of chromosomal distribution, DNA organization and cellular morphology was performed in ovulated cumulus-enclosed and -free oocytes, ovarian non-germinal vesicle oocytes enclosed by or free of mucous cumulus cells and in vitro-matured ovarian germinal-vesicle oocytes. Both early and late onset administration of oral antioxidants counteracted the negative effects of female aging on number of ovarian oocytes and total percentage of oocytes retrieved from oviducts and ovaries exhibiting a normal distribution of chromosomes in the metaphase-II plate and/or morphological traits of apoptosis. Although both early and late onset administration of oral antioxidants can counteract the negative effects of female aging on number and quality of oocytes, transference of these results to human beings should be made with caution because of the potential side effects of high doses of vitamins on reproductive function as well as many other undesirable systemic disorders., (Copyright 2002 Wiley-Liss, Inc.)

The present study aims to shed light on the origin of abnormal oocytes ovulated by aged females. In order to reach this goal, cellular and morphological traits of ovulated oocytes from hybrid (C57Bl/6JIco female x CBA/JIco male) female mice retrieved after exogenous ovarian stimulation at the age of 12, 40-42, 50-52, or 57-62 wk were analyzed. Aging of female mice was associated with 1) decreased number of ovulated oocytes; 2) increased percentage of cumulus-free oocytes; 3) raised percentage of oocytes with intracellular mitochondrial aggregates; 4) reduced percentage of oocytes displaying a normal distribution of chromosomes in the metaphase-II plate; 5) increased percentage of normal oocytes exhibiting a DNA-containing polar body (PB); 6) higher percentage of oocytes with chromosome scattering; 7) increased percentage of chromosome-scattered oocytes without a DNA-containing PB and with intracytoplasmic mitochondrial aggregates; 8) raised percentage of oocytes exhibiting chromosome decondensation; 9) lower percentage of chromosome-decondensed oocytes lacking both a DNA-containing PB and intracytoplasmic mitochondrial aggregates; 10) increased percentage of abnormal/degenerated oocytes; 11) reduced percentage of abnormal/degenerated oocytes displaying cellular fragmentation; and 12) higher percentage of abnormal/degenerated oocytes with mitochondrial aggregates exhibiting no nuclear/chromosomal DNA fluorescence, cellular fragmentation, milky or dark cytoplasm, or cellular remains enclosed by the zona pellucida. Although several studies suggest aging females may ovulate aged or overripened oocytes, these data support the hypothesis that old females ovulate an increased percentage of atretic/apoptotic oocytes coming from rescued follicles that would have become atretic earlier in life.

Age and menopausal status were evaluated as potential modulators of the progesterone action in the initiation of the mid-cycle luteinizing hormone (LH) surge in women. Three distinct levels of oestradiol priming were used, in combination with two different two-step ranks of progesterone stimulation (10/25 mg and 25/50 mg i.m. injections of progesterone in oil, over 2 consecutive days) in two groups of women, ten premenopausals, aged between 18 and 25 years, and 14 postmenopausals, aged between 48 and 57 years. The low, moderate and high levels of oestradiol priming were defined in the premenopausal group by days 5 and 9 of the cycle, and 0.4 mg transdermal oestradiol applied in the early follicular phase respectively. The corresponding situation in the postmenopausal women was defined by the absence of treatment, 0.1 mg transdermal oestradiol, and 0.4 mg transdermal oestradiol respectively. The oestradiol patches were maintained for 5 days, and the first progesterone dose administered on day 3 of treatment. Unambiguous LH surges, detected in serum and urine, were restricted to the protocols using 0.4 mg oestradiol in both groups, with an onset soon after progesterone administration. The surge was higher in the postmenopausal group in serum and urine. The percentage LH increase above baseline, however, was higher in the premenopausal women. The dose of progesterone did not result in any changes in pituitary LH release. Therefore, the oestradiol threshold for the progesterone stimulatory effect on LH release was similar in both groups. The postmenopausal women did not yield defective LH surges when adequately primed with oestradiol and progesterone.

This study aims (i) to ascertain whether oxidative-stress-induced disturbances in chromosomal distribution in the metaphase-II spindle of mouse oocytes can be counteracted by supplementing culture medium with antioxidants; and (ii) to determine whether supplemental intake of antioxidants neutralizes the disturbing effects of maternal ageing on segregation of chromosomes during the first meiotic division and distribution of chromosomes in the metaphase-II spindle. (i): Germinal vesicle oocytes from unstimulated 10-12 week old mice were matured in vitro in the presence or absence of diamide and/or dithiothreitol. Metaphase-II oocytes were fixed and stained with 4',6-diamidino-2-phenylindole (DAPI) to detect abnormalities in chromosomal distribution. The percentage of oocytes arrested in metaphase I (12.9% vs 28.4%; P < or = 0.05) or with a telophase-I chromosome configuration (0.0% vs 8.2%; P < or = 0.0005) was decreased in diamide-DTT-treated oocytes when compared to diamide-treated oocytes. (ii): Mice were fed, from the first day of weaning until their death, a diet supplemented or not with an antioxidant mixture of vitamin C and vitamin E. Ovulated oocytes were fixed and stained with DAPI or C-banded for chromosome analysis. The percentage of abnormal (chromosome scattering and nulloploidy) or asynchronous (anaphase I or telophase I) oocytes was 2.7-fold higher in controls than in females fed an antioxidant diet (24.4% vs 8.9%, P < or = 0.05). Furthermore, the percentage of aneuploidy (2.2% vs 0.0%; P < or = 0.01) and diploidy (5.8% vs 1.7%; P < or = 0.05) was significantly higher in controls than in females fed an antioxidant diet. These findings support Tarin's oxidative stress hypothesis of aneuploidy and have clinical implications for preventing both laboratory-induced and maternal-age-associated aneuploidy in human beings.

The present study aims to ascertain whether dietary administration of a mixture of vitamins C and E may prevent the negative effects of paternal age on male fertility variables in the mouse. Experimental males were fed a standard diet supplemented with either a low or high dose of vitamins C and E. Oocytes enclosed in cumulus masses were inseminated using a 2 x 2 factorial design established according to whether males were young (3-4 months of age) or aged (22-24 months of age) and whether they were fed a control or antioxidant diet. Aged males showed a significant decrease in number of spermatozoa/mg epididymis when compared to young males. Dietary supplementation with low doses of vitamins C and E did not have any effect on sperm quality, fertilization and conceptus development in vitro. However, high doses of dietary vitamins C and E decreased the number of spermatozoa/mg epididymis, and increased the percentage of spermatozoa with misshapen heads distended in the distal part. These findings suggest that dietary supplementation with pharmacological doses of vitamins C and E may disturb spermatogenesis. The mechanism involved may be associated with either the antioxidant properties of vitamins C and E or their inhibitory action on steroidogenesis by Leydig and/or Sertoli cells.

A general model is put forward to explain the mechanism by which age-associated aneuploidies are produced. This is based on the free radical theory of ageing, which assumes a rise in oxidative stress with age. It is proposed that determination of indicators of oxidative stress in oocytes from various sources could be a first step in the testing of this hypothesis.

Objective: To investigate the changes induced by age in the function and secretory pattern of the human ovary. Immunoreactive alpha-inhibin, E2, and P secretion in vivo and in vitro have been compared in two different populations., Design: Prospective study. Women undergoing IVF-ET were divided into two groups according to age: group 1 (32.0 +/- 0.7 years; mean +/- SEM) and group 2 (40.3 +/- 0.3 years)., Setting: In vitro fertilization program at the Instituto Valenciano de Infertilidad., Patients: A total of 33 infertile women with regular menses, undergoing IVF-ET., Interventions: Follicle aspiration performed by transvaginal ultrasound. Four follicles per patient were aspirated in individual plastic tubes. Granulosa-luteal cells isolated with Percoll columns and cultured in vitro up to 4 days in the presence of hCG., Main Outcome Measures: In vitro fertilization parameters, serum levels of E2, immunoreactive alpha-inhibin, and P, as well as the secretion of immunoreactive alpha-inhibin and P by the cultured granulosa-luteal cells., Results: Serum immunoreactive alpha-inhibin levels the day of ovum pick-up were significantly lower in group 2 compared with group 1. Incubation of cells for 96 hours showed a significantly higher ability to accumulate immunoreactive alpha-inhibin in group 1 than 2. Human chorionic gonadotropin stimulated immunoreactive alpha-inhibin production after 96 hours. Cells from younger women displayed a significantly higher ability to secrete P than cells from older women. Human chorionic gonadotropin was able to significantly stimulate P production in group 1., Conclusions: These results confirm previous observations showing a reduced production of immunoreactive alpha-inhibin and steroids of ovaries from older women and suggest that a reduced cellular function, rather than a decrease in the follicular population, is the main mechanism by which these changes are produced.