Polyphenols have been examined for their beneficial effects on health, particularly in rodents, but their lifelong effects are unclear. Lemons ( Citrus limon ), containing lemon polyphenols (LPP), are widely consumed but the effects of LPP on aging are unknown. Therefore, we examined the effects of LPP on aging such as aging-related scores, locomotor activity, cognitive functions, and intestinal microbiome using senescence-accelerated mouse prone 1 (SAMP1) and senescence-accelerated resistant mouse 1 (SAMR1). All mice had ad libitum access to water (P1_water group, SAMR1) or 0.1% LPP (P1_LPP group). In the P1_LPP group, LPP intake prolonged the lifespan by approximately 3 weeks and delayed increases in aging-related scores (e.g., periophthalmic lesions) and locomotor atrophy. The P1_water group showed large changes in the intestinal microbiome structure, while the R1 and P1_LPP groups did not. The phylum Bacteroidetes/Firmicutes, which is associated with obesity, in the P1_water group was significantly lower and higher than that in the P1_LPP and R1 groups, respectively. Although the relative abundance of Lactobacillus significantly increased in both P1 groups with aging, the P1_LPP group showed a significantly lower increase than the P1_water group. Thus, lifelong intake of LPP may have anti-aging effects on both phenotypes and the intestinal environment.

-Purpose: Heavy and long-term alcohol consumption increase the risk of alcohol-related diseases. Epidemiological studies show moderate drinking reduces the risk of mortality, cardiovascular diseases, and brain infarction in the J-shaped or U-shaped curve effect. However, why moderate drinkers may be healthy and non-drinkers may be ill in diverse populations remains controversial. Herein, we examined the relationship between moderate/lifelong alcohol intake and aging, especially aging-related cognitive functions in senescenceaccelerated mouse prone 8 (SAMP8) model. Methods: SAMP8 model (5-week-old, male, n = 36), a model of age-related cognitive deficit, were group-housed (n = 6/cage) and provided free access to water (water group, n = 18) or 1% ethanol (EtOH group, n = 18, intake started when mice were 9 weeks old). The object recognition test (ORT) and object location test (OLT) were used to evaluate cognitive functions. The intestinal flora at the age of 87 weeks was analyzed by terminal restriction fragment length polymorphism (T-RFLP). Results: The lifespan of the EtOH-group mice was about 4 weeks longer than that of the water-group mice. In the EtOH group, spatial recognition impairment, assessed by OLT, was observed later (age, 73 weeks) than that in the water group (age, 52 weeks). The spinal curvature and skin conditions progressed significantly slower in the EtOH group than in the water group. Moreover, diarrhea symptoms only appeared in the water group, at the age of 82 weeks. The T-RFLP analysis of the intestinal flora indicated higher Lactobacillales order and lower Clostridium cluster XI in the EtOH group than in the water group, although those were extremely high in some mice close to death in both groups. Water-group mice with diarrhea presented significantly higher Clostridium cluster XI than did those without diarrhea (P = 0.017). Conclusion: Moderate alcohol intake changes intestinal flora and positively affects aging of SAMP8 model.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

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The rewarding effects of alcohol can lead to progressively heavier and more frequent drinking. Since studies of reward have mainly focused on responses to higher alcohol doses, the relations between reward and moderate/sustained alcohol exposure remain unknown. Our objective was to evaluate factors affecting the reward value of low alcohol doses and risk factors for increasing alcohol doses due to reward progression caused by alcohol exposure patterns. We thus performed conditioned place preference (CPP) and ethanol (EtOH)-induced locomotor sensitization tests in mice. Low-dose EtOH (0.5 or 1 g/kg twice/week)-induced CPP was stronger than that produced by saline control treatment, but the effect decreased with increasing numbers of conditioning trials. Moderate-dose/long-term EtOH exposure induced a weaker CPP than high-dose/short-term EtOH (2 g/kg twice/week) exposure with the same total EtOH dose (8 g/kg/experiment). Acamprosate calcium, an anti-relapse drug, preclusively reduced EtOH-induced CPP. EtOH induced CPP and locomotor sensitization in black but not white chamber, although the initial preference and the basal locomotion in each chamber were equal. Therefore the brightness of the chamber had an effect on EtOHinduced sensitization. Moreover, additional studies indicated that EtOH-induced locomotor sensitization also depends on the dose but not the administration interval. Paired associative learning with EtOH exposure is a potent factor influencing the level of reward produced by EtOH. Moreover, exposure to high doses of alcohol, even on an intermittent schedule, carries a higher risk of addiction than exposure to moderate doses over longer periods.Key words moderate alcohol (ethanol: EtOH); conditioned place preference (CPP); reward; sensitization; paired associative learning Alcohol abuse is associated with serious physical and psychiatric illnesses, financial hardships, familial dysfunction, and violence, all of which place a substantial burden on society. Heavy alcohol consumption and long-term drinking increase the risk of alcohol-related diseases such as liver cirrhosis, cancer, pancreatitis, and depression. 1,2) In response, the World Health Organization (WHO) recently approved a Global Strategy to Reduce Harmful Use of Alcohol urging all countries to strengthen national responses to public health problems caused by alcohol use.3) In Japan, 6.45 million people suffer from alcohol-related problems, with an estimated annual economic loss of 4.15 trillion yen associated with alcohol. 4) In December 2013, the Basic Act on Measures against Alcohol-related Health Harm was enacted in Japan, promoting education about drinking in moderation to prevent alcoholrelated problems.Regular consumption of alcohol increases the propensity for addiction because of the rewarding effects of alcohol. Thus, many casual drinkers gradually increase total alcohol consumption, which becomes habitual over time. Although many studies in rodents have been conducted on chronic drinking and reward, 5-7) previous studies have ma...

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