Testes‐specific transgene expression in insulin‐like growth factor‐I transgenic mice

Insulin‐like growth factor‐I (IGF‐I) is a low molecular weight peptide that mediates the cell proliferating actions of growth hormone. Evidence exists indicating that IGF‐I is produced by various cell types and this growth factor has been implicated in a variety of reproductive processes. To investigate the effect of IGF‐I over‐expression on reproductive systems, we generated three independent lines of transgenic mice harbouring a human IGF‐I cDNA (hIGF‐I) under the control of a Cytomegalovirus immediate early (CMV) promoter. The CMV promoter was used in an attempt to direct expression of IGF‐I into a variety of tissues both reproductive and non‐reproductive. Yet expression of the foreign hIGF‐I gene, determined by Northern blot, was found to occur only in the testicular tissues of the male mice, apparently due to methylation of the transgene in all the tissues tested except the testes, which demonstrate transgene hypomethylation. Evaluation of the transgene expression during testicular development revealed that expression begins between 10 and 15 days of development, coinciding with the appearance of the zygotene and pachytene primary spermatocytes during early spermatogenesis, therefore indicating germ line expression of the transgene. Extensive study of the CMV‐hIGF‐I transgenic lines of mice has revealed that the effects of the transgene expression do not extend beyond the testicular tissues. No significant differences (P > 0.05) in the IGF‐I serum levels, growth rates, or testicular histology have been observed between transgenic and non‐transgenic male siblings. The ability of transgenic males to produce offspring also appears unaffected. Evaluation of the IGF binding protein (IGFBP) levels in the testicular tissues of CMV‐hIGF‐I transgenic mice by Western ligand blot revealed an increase in the concentration of testicular proteins with molecular weights corresponding to IGFBP‐2 and IGFBP‐3. These results suggest that the testicular over‐expression of IGF‐I induces increased IGFBP localization in this tissue. Inhibition of IGF activity by the IGFBPs would explain the lack of a dramatic physiological effect in the CMV‐hIGF‐I transgenic mice, despite the presence of elevated testicular IGF‐I. The observation that testis specific IGF‐I overexpression induces localization of IGFBPs in this tissue confirms the existence of a well regulated testicular IGF system and supports the convention that this growth factor plays an important role in testicular function. Mol. Reprod. Dev. 54:32–42, 1999. © 1999 Wiley‐Liss, Inc.     

Ontogenetic timing as a condition‐dependent life history trait: High‐condition males develop quickly,peak early,and age fast

Within‐population variation in ageing remains poorly understood. In males, condition‐dependent investment in secondary sexual traits may incur costs that limit ability to invest in somatic maintenance. Moreover, males often express morphological and behavioral secondary sexual traits simultaneously, but the relative effects on ageing of investment in these traits remain unclear. We investigated the condition dependence of male life history in the neriid fly Telostylinus angusticollis. Using a fully factorial design, we manipulated male early‐life condition by varying nutrient content of the larval diet and, subsequently, manipulated opportunity for adult males to interact with rival males. We found that high‐condition males developed more quickly and reached their reproductive peak earlier in life, but also experienced faster reproductive ageing and died sooner than low‐condition males. By contrast, interactions with rival males reduced male lifespan but did not affect male reproductive ageing. High‐condition in early life is therefore associated with rapid ageing in T. angusticollis males, even in the absence of damaging male–male interactions. Our results show that abundant resources during the juvenile phase are used to expedite growth and development and enhance early‐life reproductive performance at the expense of late‐life performance and survival, demonstrating a clear link between male condition and ageing.     

Early‐life telomere length predicts lifespan and lifetime reproductive success in a wild bird

Poor conditions during early development can initiate trade‐offs that favour current survival at the expense of somatic maintenance and subsequently, future reproduction. However, the mechanisms that link early and late life‐history are largely unknown. Recently it has been suggested that telomeres, the nucleoprotein structures at the terminal end of chromosomes, could link early‐life conditions to lifespan and fitness. In wild purple‐crowned fairy‐wrens, we combined measurements of nestling telomere length (TL) with detailed life‐history data to investigate whether early‐life TL predicts fitness prospects. Our study differs from previous studies in the completeness of our fitness estimates in a highly philopatric population. The association between TL and survival was age‐dependent with early‐life TL having a positive effect on lifespan only among individuals that survived their first year. Early‐life TL was not associated with the probability or age of gaining a breeding position. Interestingly, early‐life TL was positively related to breeding duration, contribution to population growth and lifetime reproductive success because of their association with lifespan. Thus, early‐life TL, which reflects growth, accumulated early‐life stress and inherited TL, predicted fitness in birds that reached adulthood but not noticeably among fledglings. These findings suggest that a lack of investment in somatic maintenance during development particularly affects late life performance. This study demonstrates that factors in early‐life are related to fitness prospects through lifespan, and suggests that the study of telomeres may provide insight into the underlying physiological mechanisms linking early‐ and late‐life performance and trade‐offs across a lifetime.     

The role of fecundity and reproductive effort in defining life‐history strategies of North American freshwater mussels

Selection is expected to optimize reproductive investment resulting in characteristic trade‐offs among traits such as brood size, offspring size, somatic maintenance, and lifespan; relative patterns of energy allocation to these functions are important in defining life‐history strategies. Freshwater mussels are a diverse and imperiled component of aquatic ecosystems, but little is known about their life‐history strategies, particularly patterns of fecundity and reproductive effort. Because mussels have an unusual life cycle in which larvae (glochidia) are obligate parasites on fishes, differences in host relationships are expected to influence patterns of reproductive output among species. I investigated fecundity and reproductive effort (RE) and their relationships to other life‐history traits for a taxonomically broad cross section of North American mussel diversity. Annual fecundity of North American mussel species spans nearly four orders of magnitude, ranging from < 2000 to 10 million, but most species have considerably lower fecundity than previous generalizations, which portrayed the group as having uniformly high fecundity (e.g. > 200000). Estimates of RE also were highly variable, ranging among species from 0.06 to 25.4%. Median fecundity and RE differed among phylogenetic groups, but patterns for these two traits differed in several ways. For example, the tribe Anodontini had relatively low median fecundity but had the highest RE of any group. Within and among species, body size was a strong predictor of fecundity and explained a high percentage of variation in fecundity among species. Fecundity showed little relationship to other life‐history traits including glochidial size, lifespan, brooding strategies, or host strategies. The only apparent trade‐off evident among these traits was the extraordinarily high fecundity of Leptodea, Margaritifera, and Truncilla, which may come at a cost of greatly reduced glochidial size; there was no relationship between fecundity and glochidial size for the remaining 61 species in the dataset. In contrast to fecundity, RE showed evidence of a strong trade‐off with lifespan, which was negatively related to RE. The raw number of glochidia produced may be determined primarily by physical and energetic constraints rather than selection for optimal output based on differences in host strategies or other traits. By integrating traits such as body size, glochidial size, and fecundity, RE appears more useful in defining mussel life‐history strategies. Combined with trade‐offs between other traits such as growth, lifespan, and age at maturity, differences in RE among species depict a broad continuum of divergent strategies ranging from strongly r‐selected species (e.g. tribe Anodontini and some Lampsilini) to K‐selected species (e.g. tribes Pleurobemini and Quadrulini; family Margaritiferidae). Future studies of reproductive effort in an environmental and life‐history context will be useful for understanding the explosive radiation of this group of animals in North America and will aid in the development of effective conservation strategies.     

Differential insulin‐like growth factor (IGF)‐independent interactions of IGF binding protein‐3 and IGF binding protein‐5 on apoptosis in human breast cancer cells. Involvement of the mitochondria.

We have demonstrated previously in Hs578T cells that insulin‐like growth factor binding protein (IGFBP)‐3 can significantly accentuate ceramide (C2)‐induced apoptosis, but has no effect on cell death induced by integrin detachment [using an arginine‐glycine‐aspartic acid (RGD)‐containing peptide]. In contrast we found that IGFBP‐5 could inhibit apoptosis induced by either C2 or integrin detachment. It is now clear that the mitochondria not only provide the energy required for cell viability, but can also play an important role during the commitment phase to apoptosis. We used a mitochondrial respiratory chain inhibitor, antimycin A, at both apoptotic and nonapoptotic doses to further investigate the IGF‐independent actions of IGFBP‐3 and IGFBP‐5 on C2 and RGD‐induced apoptosis in the Hs578T cells. Hs578T cells had one of three treatments. 1: They were incubated with increasing doses of antimycin A for 24 h. 2: They were coincubated with an apoptotic dose of either C2 or RGD together with a nonapoptotic dose of antimycin A for 24 h. 3: They were incubated with a binding protein (100 ng/ml) for 24 h followed by coincubation of the binding protein with an apoptotic dose of antimycin A for a further 24 h. Cell viability was assessed by trypan blue dye exclusion and MTT assay, and apoptosis was confirmed and measured by morphologic assessment and flow cytometry. We found that antimycin A initiated apoptosis at 10 μmol/L and above. We also demonstrated that a nonapoptotic dose of antimycin A (0.1 μmol/L) significantly inhibited C2‐induced apoptosis, whereas it significantly accentuated RGD‐induced cell death. In addition, we found that cell death induced by antimycin A can be accentuated by IGFBP‐3 but is not affected by IGFBP‐5. These data indicate that IGFBP‐3 can directly enhance apoptosis triggered via the mitochondria; either directly by a mitochondrial inhibitor or by C2 (which we demonstrate to act via effects on the mitochondria in this model). IGFBP‐5, however, appears to confer survival effects via a distinct pathway not involving the mitochondria. J. Cell. Biochem. 80:248–258, 2000. © 2000 Wiley‐Liss, Inc.     

Reproductive and post‐reproductive life history of wild‐caught Drosophila melanogaster under laboratory conditions

The life history of the fruit fly (Drosophila melanogaster) is well understood, but fitness components are rarely measured by following single individuals over their lifetime, thereby limiting insights into lifetime reproductive success, reproductive senescence and post‐reproductive lifespan. Moreover, most studies have examined long‐established laboratory strains rather than freshly caught individuals and may thus be confounded by adaptation to laboratory culture, inbreeding or mutation accumulation. Here, we have followed the life histories of individual females from three recently caught, non‐laboratory‐adapted wild populations of D. melanogaster. Populations varied in a number of life‐history traits, including ovariole number, fecundity, hatchability and lifespan. To describe individual patterns of age‐specific fecundity, we developed a new model that allowed us to distinguish four phases during a female's life: a phase of reproductive maturation, followed by a period of linear and then exponential decline in fecundity and, finally, a post‐ovipository period. Individual females exhibited clear‐cut fecundity peaks, which contrasts with previous analyses, and post‐peak levels of fecundity declined independently of how long females lived. Notably, females had a pronounced post‐reproductive lifespan, which on average made up 40% of total lifespan. Post‐reproductive lifespan did not differ among populations and was not correlated with reproductive fitness components, supporting the hypothesis that this period is a highly variable, random ‘add‐on’ at the end of reproductive life rather than a correlate of selection on reproductive fitness. Most life‐history traits were positively correlated, a pattern that might be due to genotype by environment interactions when wild flies are brought into a novel laboratory environment but that is unlikely explained by inbreeding or positive mutational covariance caused by mutation accumulation.     

萼花臂尾轮虫种复合体内三个姐妹种生活史特征的比较研究

应用生命表统计学方法,在13℃、18℃、23℃和28℃下对采自芜湖市莲塘湖和荷花塘水体中的萼花臂尾轮虫三个姐妹种HE1、HE3和LE9的生活史特征进行了比较研究。结果表明,三个姐妹种生命表参数间的差异因温度的不同而异。13℃下,姐妹种LE9的生命期望、平均寿命和世代时间都显著长于姐妹种HE3,LE9的净生殖率和种群内禀增长率均最大,三个姐妹种所产后代中的混交雌体百分率无显著的差异。18℃下,姐妹种LE9的生命期望和平均寿命显著长于姐妹种HE3,姐妹种LE9的世代时间显著长于姐妹种HE1和HE3,姐妹种 HE3的种群内禀增长率显著高于姐妹种LE9,姐妹种HE3所产后代中的混交雌体百分率最高,三个姐妹种的净生殖率无显著的差异。23℃下,姐妹种HE1的生命期望、平均寿命和世代时间均最长,姐妹种HE1所产后代中的混交雌体百分率显著低于HE3,三个姐妹种的净生殖率和种群内禀增长率均无显著的差异。28℃下,三个姐妹种的生命期望、平均寿命、世代时间和种群内禀增长率均无显著的差异;姐妹种HE1的净生殖率最低;姐妹种HE3所产后代中的混交雌体百分率最高。三个姐妹种的生命表参数对升高的温度的响应也不相同。温度、姐妹种及两者间的交互作用对轮虫的世代时间、平均寿命、出生时的生命期望和轮虫所产后代中的混交雌体百分率均有显著的影响;温度和姐妹种对轮虫的净生殖率和种群内禀增长率均有极显著影响,但两者的交互作用对其无显著性影响。     

Apolipoprotein A‐I possesses an anti‐obesity effect associated with increase of energy expenditure and up‐regulation of UCP1 in brown fat

Apolipoprotein A‐I (ApoA‐I) is the most abundant protein constituent of high‐density lipoprotein (HDL). Reduced plasma HDL and ApoA‐I levels have been found to be associated with obesity and metabolic syndrome in human beings. However, whether or not ApoA‐I has a direct effect on obesity is largely unknown. Here we analysed the anti‐obesity effect of ApoA‐I using two mouse models, a transgenic mouse with overexpression of ApoA‐I and the mice administered with an ApoA‐I mimetic peptide D‐4F. The mice were induced to develop obesity by feeding with high fat diet. Both ApoA‐I overexpression and D‐4F treatment could significantly reduce white fat mass and slightly improve insulin sensitivity in the mice. Metabolic analyses revealed that ApoA‐I overexpression and D‐4F treatment enhanced energy expenditure in the mice. The mRNA level of uncoupling protein (UCP)1 in brown fat tissue was elevated by ApoA‐I transgenic mice. ApoA‐I and D‐4F treatment was able to increase UCP1 mRNA and protein levels as well as to stimulate AMP‐activated protein kinase (AMPK) phosphorylation in brown adipocytes in culture. Taken together, our results reveal that ApoA‐I has an anti‐obesity effect in the mouse and such effect is associated with increases in energy expenditure and UCP1 expression in the brown fat tissue.     

Physiological dynamics,reproduction‐maintenance allocations,and life history evolution

Allocation of resources to competing processes of growth, maintenance, or reproduction is arguably a key process driving the physiology of life history trade‐offs and has been shown to affect immune defenses, the evolution of aging, and the evolutionary ecology of offspring quality. Here, we develop a framework to investigate the evolutionary consequences of physiological dynamics by developing theory linking reproductive cell dynamics and components of fitness associated with costly resource allocation decisions to broader life history consequences. We scale these reproductive cell allocation decisions to population‐level survival and fecundity using a life history approach and explore the effects of investment in reproduction or tissue‐specific repair (somatic or reproductive) on the force of selection, reproductive effort, and resource allocation decisions. At the cellular level, we show that investment in protecting reproductive cells increases fitness when reproductive cell maturation rate is high or reproductive cell death is high. At the population level, life history fitness measures show that cellular protection increases reproductive value by differential investment in somatic or reproductive cells and the optimal allocation of resources to reproduction is moulded by this level of investment. Our model provides a framework to understand the evolutionary consequences of physiological processes underlying trade‐offs and highlights the insights to be gained from considering fitness at multiple levels, from cell dynamics through to population growth.     

Plasma proteomic profiles of bovine growth hormone transgenic mice as they age

Attenuation of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis results in extended lifespan in many organisms including mice. Conversely, GH transgenic mice have excess GH action and die prematurely. We have studied bovine (b) GH transgenic mice (n = 9) and their wild type (WT) littermates (n = 8) longitudinally and have determined several age-related changes. Compared to WT mice, bGH mice lost fat mass, became hypoglycemic and had lower insulin levels at older ages despite being hyperinsulinemic when young. To examine plasma protein differences in bGH mice relative to controls, samples at 2, 4, 8, 12 and 16 months of age were analyzed by two-dimensional gel electrophoresis followed by identification using mass spectrometry. We found several differences in plasma proteins of bGH mice compared to controls, including increased apolipoprotein E (five isoforms), haptoglobin (four isoforms) and mannose-binding protein-C (one out of three isoforms), and decreased transthyretin (six isoforms). In addition, clusterin (two out of six isoforms) and haptoglobin (four isoforms) were up-regulated in bGH mice as a function of age. Finally, alpha-2 macroglobulin (seven isoforms) was altered in an isoform-specific manner with two isoforms increased and two decreased in bGH mouse plasma compared to controls. In conclusion, identification of these proteins suggests that bGH mice exhibit an increased inflammatory state with an adverse lipid profile, possibly contributing to their diminished life expectancy. Also, these newly discovered plasma proteins may be indicative or ‘biomarkers’ of a shortened lifespan.     

Anti‐aging drugs reduce hypothalamic inflammation in a sex‐specific manner

Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF‐1 signals. Early‐life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM‐HET3 mice in a sex‐specific way: acarbose (ACA), 17‐α‐estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti‐aging drugs on neuro‐inflammation in hypothalamus and hippocampus. We found that age‐associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA‐treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba‐1‐positive microglia and GFAP‐positive astrocytes, as well as age‐associated overproduction of TNF‐α. This effect was not observed in drug‐treated female mice or in the hippocampus of the drug‐treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF‐α in both sexes at 12 months of age. Together, these results suggest that the extent of drug‐induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long‐lived nutrient restricted or mutant mice.     

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

Growth hormone (GH) signaling stimulates the production of IGF‐1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high‐fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet‐induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD.     

Recovery and immune priming modulate the evolutionary trajectory of infection‐induced reproductive strategies

In response to parasite exposure, organisms from a variety of taxa undergo a shift in reproductive investment that may trade off with other life‐history traits including survival and immunity. By suppressing reproduction in favour of somatic and immunological maintenance, hosts can enhance the probability of survival and recovery from infection. By plastically enhancing reproduction through terminal investment, on the other hand, hosts under the threat of disease‐induced mortality could enhance their lifetime reproductive fitness through reproduction rather than survival. However, we know little about the evolution of these strategies, particularly when hosts can recover and even bequeath protection to their offspring. In this study, we develop a stochastic agent‐based model that competes somatic maintenance and terminal investment strategies as they trade off differentially with lifespan, parasite resistance, recovery and transgenerational immune priming. Our results suggest that a trade‐off between reproduction and recovery can drive directional selection for either terminal investment or somatic maintenance, depending on the cost of reproduction to lifespan. However, some conditions, such as low virulence with a high cost of reproduction to lifespan, can favour diversifying selection for the coexistence of both strategies. The introduction of transgenerational priming into the model favours terminal investment when all strategies are equally likely to produce primed offspring, but favours somatic maintenance if it confers even a slight priming advantage over terminal investment. Our results suggest that both immune priming and recovery may modulate the evolution of reproductive shift diversity and magnitude upon exposure to parasites.     

Female access and diet affect insemination success,senescence and the cost of reproduction in the male Mexican fruit fly Anastrepha ludens

Hypotheses exploring the influence of dietary conditions on the life‐history trade‐off between survival and reproductive success are extensively tested in female insects but only rarely explored in males. The present study examines the impact of dietary quality and female access on age‐specific reproduction and survival of the male Mexican fruit fly Anastrepha ludens Loew (Diptera: Tephritidae). There is a clear cost of female access for males with access to dietary protein, measurable as a decrease in life expectancy, which is further influenced by the age when females are introduced. A protein deficient diet reduces the lifespan benefit of virginity and masks the detrimental effect of female access on male life expectancy. Dietary protein is not necessary for reproductive success, although access to protein at eclosion improves the lifetime reproductive success of males compared to when it is delayed. Overall, reproductive success diminishes as the male flies age, regardless of the dietary conditions, providing evidence for reproductive senescence in males. Delaying the males' access to a protein source fails to influence the negative effect of age on reproductive ability. Because age‐specific reproductive rates decline with age, regardless of diet, male fitness does not benefit from lifespan extension. Therefore, males can be expected to allocate available resources towards reproductive effort in favour of an extended lifespan, regardless of mate and protein availability.     

Immunohistochemical localization of insulin-like growth factor binding protein 2 in the central nervous system of SOD1<Superscript>G93A</Superscript> transgenic mice

In the present study, we performed immunohistochemical studies to investigate the changes of insulin-like growth factor binding protein 2 (IGFBP2) in the central nervous system of SOD1^G93A mutant transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS). Decreased immunoreactivity for IGFBP2 was observed in the cerebral cortex, hippocampus and brainstem of SOD1^G93A transgenic mice. In the cerebral cortex, the number of IGFBP2-positive cells was decreased in the somatomotor area, somatosensory area, auditory area, visual area, entorhinal area, piriform area and prefrontal area. In the hippocampal formation, IGFBP2 immunoreactivity was significantly decreased in the CA1-3 areas and the dentate gyrus. In the brainstem, few IGFBP2-immunoreactive cells were observed in the medullary and pontine reticular formation, vestibular nucleus, trigeminal motor nucleus, facial nucleus, hypoglossal nucleus and raphe nucleus. In the spinal cord, IGFBP2 immunoreactivity was not significantly decreased in SOD1^G93A transgenic mice. This study showing decreased IGFBP2 in different brain regions of SOD1^G93A transgenic mice may provide clues for understanding differential susceptibility of neural structures in ALS. S. E. Sim and Y. H. Chung have contributed equally to this work.     

An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility

In the study we report here, we tested the hypothesis that insulin-like growth factor-binding protein 2 (IGFBP2) promotes cell mobility through its interaction with integrin alpha5. Our previous microarray studies showed that IGFBP2 activates the expression of integrin alpha5. In addition, IGFBP2 has an Arg-Gly-Asp (RGD) domain, which is a known integrin binding motif. We first confirmed our microarray results by showing that the expression of integrin alpha5 is indeed up-regulated at the protein level in IGFBP2-overexpressing SNB19 glioma cells. Using co-immunoprecipitation, we confirmed that IGFBP2 does interact with integrin alpha5. To confirm that IGFBP2 interacts directly with integrin alpha5 through the RGD domain, we created an RGD --> RGE mutant (D306E) IGFBP2 and stably overexpressed the mutant IGFBP2 in the same cell line. Co-immunoprecipitation then showed that D306E-IGFBP2 had no detectable binding with integrin alpha5. We further observed that IGFBP2-overexpressing cells have extensive cell surface lamellipodia, whereas D306E-IGFBP2-overexpressing cells show abundant cell surface focal adhesions. Consistent with this, phenotype analysis then showed that IGFBP2-overexpressing cells have elevated migration rates compared with vector control; in contrast, the migration rates of the D306E-IGFBP2-overexpressing cells were not elevated and were comparable with that of vector control. Decreased expression of integrin alpha5 by small interference RNA in IGFBP2-overexpressing cells also reduced cell mobility. Therefore, we have concluded that one mechanism by which IGFBP2 activates IGFBP2-induced cell mobility is through its interaction with integrin alpha5 and this interaction is specifically mediated through the RGD domain on IGFBP2.     

Sex‐specific reproductive investment of summer spawners of Illex argentinus in the southwest Atlantic

Energy investment in reproduction and somatic growth was investigated for summer spawners of the Argentinean shortfin squid Illex argentinus in the southwest Atlantic Ocean. Sampled squids were examined for morphometry and intensity of feeding behavior associated with reproductive maturation. Residuals generated from length‐weight relationships were analyzed to determine patterns of energy allocation between somatic and reproductive growth. Both females and males showed similar rates of increase for eviscerated body mass and digestive gland mass relative to mantle length, but the rate of increase for total reproductive organ weight relative to mantle length in females was three times that of males. For females, condition of somatic tissues deteriorated until the mature stage, but somatic condition improved after the onset of maturity. In males, there was no correlation between somatic condition and phases of reproductive maturity. Reproductive investment decreased as sexual maturation progressed for both females and males, with the lowest investment occurring at the functionally mature stage. Residual analysis indicated that female reproductive development was at the expense of body muscle growth during the immature and maturing stages, but energy invested in reproduction after onset of maturity was probably met by food intake. However, in males both reproductive maturation and somatic growth proceeded concurrently so that energy allocated to reproduction was related to food intake throughout the process of maturation. For both males and females, there was little evidence of trade‐offs between the digestive gland and reproductive growth, as no significant correlation was found between dorsal mantle length‐digestive gland weight residuals. The role of the digestive gland as an energy reserve for gonadal growth should be reconsidered. Additionally, feeding intensity by both males and females decreased after the onset of sexual maturity, but feeding never stopped completely, even during spawning.     

17‐α estradiol ameliorates age‐associated sarcopenia and improves late‐life physical function in male mice but not in females or castrated males

Pharmacological treatments can extend mouse lifespan, but lifespan effects often differ between sexes. 17‐α estradiol (17aE2), a less feminizing structural isomer of 17‐β estradiol, produces lifespan extension only in male mice, suggesting a sexually dimorphic mechanism of lifespan regulation. We tested whether these anti‐aging effects extend to anatomical and functional aging—important in late‐life health—and whether gonadally derived hormones control aging responses to 17aE2 in either sex. While 17aE2 started at 4 months of age diminishes body weight in both sexes during adulthood, in late‐life 17aE2‐treated mice better maintain body weight. In 17aE2‐treated male mice, the higher body weight is associated with heavier skeletal muscles and larger muscle fibers compared with untreated mice during aging, while treated females have heavier subcutaneous fat. Maintenance of skeletal muscle in male mice is associated with improved grip strength and rotarod capacity at 25 months, in addition to higher levels of most amino acids in quadriceps muscle. We further show that sex‐specific responses to 17aE2—metabolomic, structural, and functional—are regulated by gonadal hormones in male mice. Castrated males have heavier quadriceps than intact males at 25 months, but do not respond to 17aE2, suggesting 17aE2 promotes an anti‐aging skeletal muscle phenotype similar to castration. Finally, 17aE2 treatment benefits can be recapitulated in mice when treatment is started at 16 months, suggesting that 17aE2 may be able to improve aspects of late‐life function even when started after middle age.     

IGF‐I regulates the age‐dependent signaling peptide humanin

Aging is influenced by endocrine pathways including the growth hormone/insulin‐like growth factor‐1 (GH/IGF) axis. Mitochondrial function has also been linked to the aging process, but the relevant mitochondrial signals mediating the effects of mitochondria are poorly understood. Humanin is a novel signaling peptide that acts as a potent regulator of cellular stress responses and protects from a variety of in vitro and in vivo toxic and metabolic insults. The circulating levels of humanin decline with age in mice and humans. Here, we demonstrate a negative correlation between the activity of the GH‐IGF axis and the levels of humanin, as well as a positive correlation between humanin and lifespan in mouse models with altered GH/IGF‐I axis. Long‐lived, GH‐deficient Ames mice displayed elevated humanin levels, while short‐lived GH‐transgenic mice have reduced humanin levels. Furthermore, treatment with GH or IGF‐I reduced circulating humanin levels in both mice and human subjects. Our results indicate that GH and IGF are potent regulators of humanin levels and that humanin levels correlate with lifespan in mice. This suggests that humanin represents a circulating mitochondrial signal that participates in modulating the aging process, adding a coordinated mitochondrial element to the endocrine regulation of aging.