Fostering Attachment Security: The Role of Interdependent Situations.

This work adopts an Interdependence Theory framework to investigate how the features of interdependent situations that couples face in their daily life (i.e., situations in which partners influence each other's outcomes) shape attachment security toward their current partners. An experience sampling study examined attachment tendencies and features of interdependent situations that people experience with their partner in daily life to predict satisfaction and trust in their relationship, and changes in attachment avoidance and anxiety toward their partner over time. Results revealed that encountering situations with corresponding outcomes (i.e., situations in which both partners have the same preferences) and with information certainty (i.e., situations in which there is clear knowledge of each partner's preferences) assuage people's insecurity. On the contrary, situations of mutual current and future interdependence (i.e., situations in which each person's current or future outcomes are dependent on their partner's behavior) undermined security for anxiously attached individuals. Power (i.e., the asymmetry in partners' dependence) was not related to attachment security. This work underscores the importance of studying the role of the situations that partners experience in their daily life and the way they are related to relationship feelings and cognitions.

Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin.

The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone--IGF-1--insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (-9.1% and -13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin.

Target of Rapamycin (TOR) is involved in cellular and organismal aging. Rapamycin extends lifespan and delays cancer in mice. It is important to determine the minimum effective dose and frequency of its administration that still extends lifespan and prevents cancer. Previously we tested 1.5 mg/kg of rapamycin given subcutaneously 6 times per two weeks followed by a two-week break (1.5 × 6/bi-weekly schedule: total of 6 injections during a 4-week period). This intermittent treatment prolonged lifespan and delayed cancer in cancer-prone female FVB/N HER-2/neu mice. Here, the dose was decreased from 1.5 mg/kg to 0.45 mg/kg per injection. This treatment was started at the age of 2 months (group Rap-2), 4 months (Rap-4), and 5 months (Rap-5). Three control groups received the solvent from the same ages. Rapamycin significantly delayed cancer and decreased tumor burden in Rap-2 and Rap-5 groups, increased mean lifespan in Rap-4 and Rap-5 groups, and increased maximal lifespan in Rap-2 and Rap-5 groups. In Rap-4 group, mean lifespan extension was achieved without significant cancer prevention. The complex relationship between life-extension and cancer-prevention depends on both the direct effect of rapamycin on cancer cells and its anti-aging effect on the organism, which in turn prevents cancer indirectly. We conclude that total doses of rapamycin that are an order of magnitude lower than standard total doses can detectably extend life span in cancer-prone mice.

Exposure to light at night accelerates aging and spontaneous uterine carcinogenesis in female 129/Sv mice.

The effect of the constant illumination on the development of spontaneous tumors in female 129/Sv mice was investigated. Forty-six female 129/Sv mice starting from the age of 2 mo were kept under standard light/dark regimen [12 h light (70 lx):12 hr dark; LD, control group], and 46 of 129/Sv mice were kept under constant illumination (24 h a day, 2,500 lx, LL) from the age of 5 mo until to natural death. The exposure to the LL regimen significantly accelerated body weight gain, increased body temperature as well as acceleration of age-related disturbances in estrous function, followed by significant acceleration of the development of the spontaneous uterine tumors in female 129/Sv mice. Total tumor incidence as well as a total number of total or malignant tumors was similar in LL and LD group (p > 0.05). The mice from the LL groups survived less than those from the LD group (χ ( 2) = 8.5; p = 0.00351, log-rank test). According to the estimated parameters of the Cox's regression model, constant light regimen increased the relative risk of death in female mice compared with the control (LD) group (p = 0.0041). The data demonstrate in the first time that the exposure to constant illumination was followed by the acceleration of aging and spontaneous uterine tumorigenesis in female 129/Sv mice.

Rodent models for the preclinical evaluation of drugs suitable for pharmacological intervention in aging.

INTRODUCTION: There is a growing scientific and public interest in the development of new antiaging drugs for the purposes of extending mean and/or maximum life span, maintaining normal physiological function, and alleviating the onset and severity of age-associated diseases. This review looks at the current screening approaches used to evaluate the efficacy of such compounds, with a particular focus on those that extend life span. AREAS COVERED: This article reviews the current preclinical approaches for assessing longevity therapy including the assessment of antiaging drugs (aging reversal) and geroprotectors (drugs that prevent premature aging and/or slowdown or postpone aging). This article also discusses the methods and the importance in evaluating the anticarcinogenic potential and safety of antitumor drugs. EXPERT OPINION: Based on more than 30 years of experience in the field, the authors believe that the standard testing protocols for antiaging drugs should include the simultaneous evaluation of the drug's safety, as well as its antitumor and anticarcinogenic activity potential. The authors also believe that the principles of international programs for the expert critical evaluation of pharmacological interventions should be created to improve the range of antiaging interventions available for human studies.

Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice.

The nutrient-sensing TOR (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an inhibitor of TOR, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 y. Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of 2 mo. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Thus we demonstrated for the first time in normal inbred mice that lifespan can be extended by rapamycin. This opens an avenue to develop optimal doses and schedules of rapamycin as an anti-aging modality.

If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice.

Hyperglycemia and hyperinsulinemia accelerate both aging and cancer. Antidiabetic biguanides such as metformin decrease glucose, insulin and IGF-1 level. Metformin increases lifespan and prevents cancer in mice, although its effects vary, depending on mice strain and gender. Here we showed that chronic treatment of female outbred SHR mice with metformin started at the age of 3, 9 or 15 months decreased body temperature and postponed age-related switch-off of estrous function. Surprisingly, metformin did not affect levels of serum cholesterol, triglycerides, glucose and insulin. Treatment with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. The treatment started at the age of 9 months insignificantly increased mean life span by only 6%, whereas the treatment started at the age of 15 months failed to increase life span. The mean life span of tumor-free mice was increased by 21% in 'the youngest group', by 7% in 'middle-aged group' and in contrast was reduced by 13% in 'the oldest group'. When started at the age of 3 and 9 months, metformin delayed the first tumor detection by 22% and 25%, correspondingly. Thus, in female SHR mice, metformin increased life span and postponed tumors when started at the young and middle but not at the old age. In contrast, metformin improves reproductive function when started at any age.

Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. The chronic treatment of inbred 129/Sv mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but failed to influence the dynamics of body weight, decreased by 13.4% the mean life span of male mice and slightly increased the mean life span of female mice (by 4.4%). The treatment with metformin failed influence spontaneous tumor incidence in male 129/Sv mice, decreased by 3.5 times the incidence of malignant neoplasms in female mice while somewhat stimulated formation of benign vascular tumors in the latter.

Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in young but not in old rats.

We evaluated the effect of exposure to constant light started at the age of 1 month and at the age of 14 months on the survival, life span, tumorigenesis and age-related dynamics of antioxidant enzymes activity in various organs in comparison to the rats maintained at the standard (12:12 light/dark) light/dark regimen. We found that exposure to constant light started at the age of 1 month accelerated spontaneous tumorigenesis and shortened life span both in male and female rats as compared to the standard regimen. At the same time, the exposure to constant light started at the age of 14 months failed to influence survival of male and female rats. While delaying tumors in males, constant light accelerated tumors in females. We conclude that circadian disruption induced by light-at-night started at the age of 1 month accelerates aging and promotes tumorigenesis in rats, however failed affect survival when started at the age of 14 months.

Rapamycin extends maximal lifespan in cancer-prone mice.

Aging is associated with obesity and cancer. Calorie restriction both slows down aging and delays cancer. Evidence has emerged that the nutrient-sensing mammalian target of rapamycin (mTOR) pathway is involved in cellular and organismal aging. Here we show that the mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases lifespan, and suppresses carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumor onset as well as decreased the number of tumors per animal and tumor size. We suggest that, by slowing down organismal aging, rapamycin delays cancer.

Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats.

We evaluated the effect of various light/dark regimens on the survival, life span and tumorigenesis in rats. Two hundred eight male and 203 females LIO rats were subdivided into 4 groups and kept at various light/dark regimens: standard 12:12 light/dark (LD); natural lighting of the North-West of Russia (NL); constant light (LL), and constant darkness (DD) since the age of 25 days until natural death. We found that exposure to NL and LL regimens accelerated development of metabolic syndrome and spontaneous tumorigenesis, shortened life span both in male and females rats as compared to the standard LD regimen. We conclude that circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats. This observation supports the conclusion of the International Agency Research on Cancer that shift-work that involves circadian disruption is probably carcinogenic to humans.

Metformin slows down aging and extends life span of female SHR mice.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which resemble effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice. On the other side, treatment with metformin failed influence blood estradiol concentration and spontaneous tumor incidence in female SHR mice. Thus, antidiabetic biguanide metformin dramatically extends life span, even without cancer prevention in this model.

Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice.

Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosyl)ation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosyl)ation and PARP-1 may also play an important role in aging. Here we show that PARP-1(-/-) mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1(-/-) mice. The incidence of spontaneous tumors in both PARP-1(-/-) and PARP-1(+/+) groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1(-/-) mice than PARP-1(+/+) mice (72% and 49%, resp.; P < .05). In addition, spontaneous tumors appear earlier in PARP-1(-/-) mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include DAF-2 and InR and their homologues in mammals, and inactivation of the corresponding genes is followed by increased life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. The chronic treatment of female transgenic HER-2/neu mice with metformin (100 mg/kg in drinking water) slightly decreased the food consumption but failed in reducing the body weight or temperature, slowed down the age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolonged the mean life span by 8% (p < 0.05), the mean life span of last 10% survivors by 13.1%, and the maximum life span by 1 month in comparison with control mice. The demographic aging rate represented by the estimate of respective Gompertz's parameter was decreased 2.26 times. The metformin-treatment significantly decreased the incidence and size of mammary adenocarcinomas in mice and increased the mean latency of the tumors.

Insulin in aging and cancer: antidiabetic drug Diabenol as geroprotector and anticarcinogen.

The effects of new antidiabetic drug Diabenol (9-beta-diethylaminoethyl-2,3-dihydroimidazo-(1,2-alpha)benzimidazol dihydrochloride) on life span and spontaneous tumor incidence in NMRI and transgenic HER-2/neu mice as well as on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats are studied. It is shown that treatment with the drug failed influence body weight gain dynamics, food and water consumption and the body temperature, slowed down age-related disturbances in estrous function and increased life span of all and 10% most long-living NMRI mice. The treatment with Diabenol inhibited spontaneous tumor incidence and increased the mammary tumor latency in these mice. Diabenol treatment slowed down age-related changes in estrous function in HER-2/neu mice, failed influence survival of these mice and slightly inhibited the incidence and decreased the size of mammary adenocarcinoma metastases into the lung. In rats exposed to 1,2-dimethylhydrazine, treatment with Diabenol significantly inhibited multiplicity of all colon tumors, decreased by 2.2 times the incidence of carcinomas in ascending colon and by 3.1 times their multiplicity. Treatment with Diabenol was followed by higher incidence of exophytic and well-differentiated colon tumors as compared with the control rats exposed to the carcinogen alone (76.3% and 50%, and 47.4% and 14.7%, respectively). Thus, the drug increases survival and inhibits spontaneous carcinogenesis in mice and inhibits colon carcinogenesis in rats.

Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules linked to longevity include DAF-2 and insulin receptor (InR) and their homologues in mammals and to inactivation of the corresponding genes followed by increased life span in nematodes, fruit flies, and mice. It is possible that the life-prolonging effect of caloric restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of life span-extending mutations in the insulin/IGF-1 signaling pathway and mimetics of effects of caloric restriction could be a direction in the regulation of longevity. Some literature and our own observations suggest that antidiabetic drugs could be promising candidates for both life span extension and prevention of cancer.

Effect of exposure to light-at-night on life span and spontaneous carcinogenesis in female CBA mice.

The effect of constant illumination on the development of spontaneous tumors in female CBA mice was investigated. Fifty female CBA mice starting from the age of 2 months were kept under standard light/dark regimen (12 hr light:12 hr dark; LD) and 50 CBA mice of similar age were kept under constant illumination (24 hr a day, 2,500 Lux, LL). Exposure to the LL regimen decreased food consumption but did not influence body weight, significantly accelerated age-related disturbances in estrous function, and was followed by a significant increase in spontaneous tumor incidence in female CBA mice. Tumor incidence as well as the number of total or malignant tumors was significantly increased in the LL group compared to the LD group (p < 0.001). The incidence of lung adenocarcinomas, leukemias and hepatocarcinomas was 7/50; 6/50 and 4/50 in the LL group and 1/50; 0/50 and 0/50 in the LD group. Mice from the LL groups had shorter life spans then those from the LD group. The data demonstrate, for the first time, that exposure to constant illumination was followed by increases in the incidence of spontaneous lung carcinoma, leukemias and hepatocarcinoma in female CBA mice.

Body weight is not always a good predictor of longevity in mice.

There have been some observations that low body weight and a low level of some hormones (e.g. IGF-1) during the first half of life are predictors of longer life in mice. However, contradictions in the available data on the biomarkers of aging and predictors of longevity have shown that the research in these fields has become a controversial pursuit. In our study we addressed the following questions: (i) Can particular physiological parameters (body weight, food intake, estrus function, body temperature, incidence of chromosome aberrations in bone marrow cells) measured at the age of 3 and 12 months be a predictor of longevity and the rate of tumor development in five strains of mice? (ii) Can a heavy body weight at the age of 3 and 12 months be a predictor of longevity and high tumor risk in five strains of mice? Mice of five strains-CBA, SHR, SAMR, SAMP and transgenic HER-2/neu (FVB/N)-were under observation from the age of 2-3 months until natural death. Body weight and temperature, food consumption, and estrous cycle were longitudinally studied in all animals. Tumors discovered at autopsy were studied morphologically. We calculated the life span's parameters (mean, maximum, mortality rate, mortality rate doubling time) as well as their correlation with other parameters studied. The longest living CBA mice have the lowest body weight at the ages of 3 and 12 months, the lowest food consumption, body temperature, incidence of chromosome aberrations and spontaneous tumor incidence. In comparison with all other mouse strains they also have the latest disturbances in estrus function and highest body weight gain. The shortest living transgenic HER-2/neu mice have the lowest weight at the ages of 12 months, the lowest body weight gain, maximal body temperature, the most rapid disturbances in estrus function and the highest incidence of chromosome aberrations and tumor incidence in comparison to all other mouse strains. Our findings have shown that heavier body weight at the age of 12 months is a predictor of longevity in female CBA and SAMP mice but not in SHR, SAMR and HER-2/neu mice. Excessive body weight at the ages of 3 or 12 months is not a predictor of increased tumor risk in the strains studied. In general, the existence and direction of a significant correlation between body weight and life span depends upon the animals' age and genotype.

Insulin and longevity: antidiabetic biguanides as geroprotectors.

The results of previous experimental studies of effects of antidiabetic biguanides (phenformin and buformin) on life span and spontaneous tumor incidence in mice and rats were recalculated and reanalyzed using standard demographic models of mortality. The chronic treatment of female C3H/Sn mice with phenformin prolonged the mean life span by 21.1% (P < 0.05), the mean life span of the last 10% survivors by 28.4% and the maximum life span by 5.5 months (by 26%) in comparison with the control. The demographic aging rate represented by the estimate of respective Gompertz's parameter decreased by 31.2% and MRDT increased 1.45-fold. The treatment significantly inhibited (4.0-fold, P < 0.01) the incidence of mammary adenocarcinomas in mice. Administration of phenformin to female LIO rats failed to influence the mean life span. At the same time, the mean life span of the last 10% survivors increased by 10.1% (P < 0.05), and maximum life span increased by 3 months (+9.8%). Phenformin attenuated the development of spontaneous tumors in comparison to the control. The treatment of female rats with another antidiabetic biguanide, buformin, slightly increased their mean life span (by 7.3%; P > 0.05). The mean life span of the last 10% survivors increased by 12% (P < 0.05) and the maximum life span increased by 2 months (+5.5%) as compared with controls. The population aging rate decreased by 18.1% (P < 0.05) and MRDT increased 1.22-fold under the influence of buformin (P < 0.05). The total tumor incidence decreased by 49.5% in buformin-treated rats. Both antidiabetic biguanides slightly decreased the body weight, slowed down the age-related decline of the reproductive function in female rats. The results of our experiments provide evidence that antidiabetic biguanides are promising geroprotectors as well as drugs which can be used in the prevention of cancer.

Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice.

From the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30-40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study show that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%, P<0.05). It also increased by 13.3% the life span of the last 10% of the survivors (P<0.01) and by 12.3% the maximum life span in comparison with the control group. We also found that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector activity of Epitalon and the safety of its long-term administration in mice.