Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice

Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice. Yan Diao et al. Aging, July 8, 2020. https://doi.org/10.18632/aging.103401

Abstract: Numerous epidemiological studies have reported that moderate alcohol drinking has beneficial effects. However, few studies have focused on the beneficial effects of ethanol, the common component in alcoholic beverages. Here we fed the C57BL/6 mice with 3.5% v/v ethanol as drinking water substitute to investigate the effects of long-term low-dose ethanol intake in vivo. We evaluated the metabolic rate and mitochondrial function of the long-term low-dose ethanol-intake (LLE) mice, assessed the exercise ability of LLE mice, and fed the LLE mice with a high-fat diet to investigate the potential impact of ethanol on it. The LLE mice showed improved thermogenic activity, physical performance, and mitochondrial function, as well as resistance against the high-fat diet-induced obesity with elevated insulin sensitivity and subdued inflammation. Our results suggest that long-term low-dose ethanol intake can improve healthspan and resist high-fat diet-induced obesity in mice. It may provide new insight into understanding the protective effects of moderate alcohol drinking.


Discussion

Previous studies on the protection of alcoholic beverages have been primarily focused on the polyphenols such as resveratrol, procyanidins and other substances like catechin and tannin [29–31]. Ironically, the most important common component of all alcoholic beverages, alcohol or ethanol, has received much less attention. Humans have had a long history of ethanol intake. The ‘drunken monkey hypothesis’ proposes that natural selection favored those primates with an attraction to ethanol because it was associated with proximate benefits [32, 33]. Even in modern times, scientists still observed the proactive behavior of wild chimpanzees taking ethanol [34]. In this study, we use ethanol, the common substance in all kinds of alcoholic beverages, as a single variable to explore its effects in vivo. Our data showed that the long-term 3.5% ethanol substitution for drinking water had beneficial effects in mice, the daily performance of ethanol-fed mice was enhanced, the athletic ability and healthspan of ethanol-fed mice drastically improved. Furthermore, the ethanol-fed mice showed the resistance to high-fat diet. When supplemented with 3.5% ethanol, the HFD mice showed reduced multiple organ pathogenicity, increased insulin sensitivity, and decreased NF-kB activation and inflammatory cytokines. These changes caused by ethanol are astonishing and impressive.

It has been well accepted that acute and chronic excessive alcohol exposure is conducive to tissue injury and that alcohol abuse is usually accompanied by a series of organ damages, including liver cirrhosis, cardiovascular disease, and cognition disorder, etc. [35–37]. However, one should be mindful that the injuries caused by the excessive use of alcohol are dose-dependent. In our study, the long term 3.5% ethanol-fed mice did not show the common negative effects of alcohol. At this dose, we did not observe any pathological structural changes in the liver, the heart, or the kidneys; neither did we detect any impairments of learning, memory, and cognition by the water maze. Previous epidemiology studies showed that moderate drinkers those who consumed less than 15.0 g of alcohol per day had better mean cognitive scores than nondrinkers in women [6]. On the other hand, a recent study also claimed that even moderate drinkers (14-21 units/week) had three times the odds of right-sided hippocampal atrophy and has no protective effect for light drinking (1-<7 units/week) [38]. However, the effects of moderate alcohol consumption on brain structure and cognition function need to be further explored.

One of the pathophysiological mechanisms induced by alcohol abuse has been identified as mitochondria dysfunction [39]. When the mitochondrial DNA damages induced by alcohol abuse are not adequately repaired, the mitochondrial function is impaired [40]. On the other hand, the mitochondrial volume was associated with high levels of physical activity [41]. The improved mitochondrial function of LLE mice may be due to their high level of daily physical activity and enhancement of athletic ability of LLE mice. In our experiments, we observed that the mitochondrial density in the liver and the skeletal muscles of the ethanol-fed group increased, and the morphology became stronger with more cristae, indicating improved mitochondrial function under the moderate ethanol feeding. AMPK induces mitochondrial biogenesis and has emerging roles in the regulation of both mitochondrial metabolism and dynamics [21, 22]. Phosphorylation activity of AMPK, necessary for mitochondrial biogenesis via SIRT1 and PGC1a [23, 24], was increased in the liver of the LLE mice. Considering the activation of AMPK by moderate ethanol intake, it seems reasonable to entertain the hypothesis that the rapid acetate metabolism following the ingestion of ethanol generates sufficient AMP to transiently activate AMPK, which in turn induces the synthesis of certain long-lived proteins that act to boost insulin sensitivity and possibly aid the efficiency of fat oxidation as well [42]. Furthermore, skeletal muscle contraction and exercise can stimulate the expression of AMPK [43, 44]. In our previous study, the peroxisome proliferator-activated receptors PPARα and PPARγ were found to be increased in the moderate alcohol-fed mice [17]. Both receptors are positively involved in mitochondrial biogenesis by promoting the transcription of upstream genes such as NRF-1, NRF-2, and Tfam [45, 46].

Obesity is commonly associated with insulin resistance, chronic systemic inflammation, and increased risk of cardiovascular disease [10]. The current consensus is that moderate alcohol consumption is associated with reduced risks of cardiovascular events, and can decrease the risks of type 2 diabetes [9, 12, 14, 15, 47, 48], partly owing to some of non-alcoholic components in the beverages. For instance, resveratrol in red wine has been shown to have anti-inflammatory properties, and can improve glucose tolerance and insulin sensitivity [49, 50]. However, the role of ethanol in the beneficial effects of moderate drinking is inadequately studied in comparison. As shown in our data, when supplemented with ethanol, HFD mice exhibited increased insulin sensitivity, lower level of inflammation, and decreased organ pathology, similar to the effects of resveratrol on HFD mice. These findings may explain why the beneficial effects of moderate alcohol drinking are not limited to red wine but also include most alcoholic beverages.

The health effects of alcohol intake are highly dependent on the amount of consumption, in addition to factors such as species (e.g., the alcohol metabolism rate of mice is faster than humans), gender, age, genotype (e.g., ALDH2 mutation), physical state [51]. A J-shaped dose-dependent relationship between alcohol consumption and effects has been proposed for human recently [52, 53]. In another study, Wood AM et al. analyzed 599912 current drinkers and recorded a positive and curvilinear association of all-cause mortality with the level of alcohol consumption, with the minimum mortality risk around 100 g per week [54]. For the aggregate of cardiovascular disease outcomes, a J-shaped association with the level of alcohol consumption was observed in the same study, with 100 g per week being the most beneficial dose [54]. By contrast, another study used 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and asserted the level of consumption that minimizes health loss is zero [55]. The view on the beneficial effects of moderate drinking is inconclusive from these discussions. Furthermore, “moderate drinking” should be more clearly defined, and the long-term effects further explored with more rigorousness and scrutiny.

In conclusion, our findings showed that not only could long-term low-dose ethanol intake improve the physical performance and the healthspan in mice but also boost the defense mechanism against the high-fat diet. Extended evaluations are needed to assess the long-term impacts of moderate alcohol intake on organs or systems such as the brain, the muscular, and the cardiovascular system. Findings from the current study substantiate opinions on the protective effects of moderate alcohol intake.