We examined the association between overall lifestyle (including eating habits and sleep quality) and glaucoma using large-scale longitudinal data. We revealed that overweight/obese, ≥2.5 units/day of alcohol consumption compared to <2.5 units/day, skipping breakfast, late dinner and daily walking were associated with increased incidence of glaucoma after adjusting for baseline characteristics. In contrast, daily alcohol consumption and regular exercise were associated with reduced incidence of glaucoma.
In the current study, overweight/obesity significantly increased the risk of glaucoma both in males and females. Some previous studies reported that obesity reduced the risk of glaucoma [3,4,5]; however, another study reported that it increased the risk of glaucoma . These conflicting results between studies were attributed to different sociodemographic characteristics of the study population, different definitions of obesity and multiple metabolisms, such as insulin resistance involved in the obesity spectrum . Our results of overweight/obesity were similar to those in Korea , and different from those in the Netherlands , in the U.S.  and those of African Americans . Therefore, we speculate that staying non-obese would work positively to prevent glaucoma for Asian individuals. We presume that the inconsistent association between obesity and glaucoma among the studies were partly owing to the different subtypes of glaucoma prevalent in each population. Unlike in European countries and the U.S., normal tension glaucoma (NTG) is the most prevalent subtype of glaucoma in Asia . NTG is different from other subtypes of glaucoma in that it is not accompanied by increased intraocular pressure, a major cause of glaucoma. Rather, possible causes of NTG include a higher sensitivity to normal pressure, vascular dysregulation, an abnormally high translaminar pressure gradient and a neurodegenerative process due to impaired cerebrospinal fluid dynamics in the optic nerve sheath compartment. The pathogenesis of NTG could be related to obesity; however, further research on the mechanisms of NTG is warranted.
Being underweight was associated with a significantly increased risk of glaucoma only in females. Underweight females have less adipose tissue, which is the major place of estrogen production especially for postmenopausal women . Recently, activation of G protein coupled estrogen receptors exhibited neuroprotective effects against retinal ganglion cell degeneration . Thus, we speculate that insufficient plasma estrogen in underweight females could result in retinal ganglion cell degeneration, which is known to play a key role in the pathogenesis of glaucoma.
In our study, current smoking was associated with a reduced risk of glaucoma compared to non-current smoking. However, in the database used in our study, non-current smokers included both non-smokers and ex-smokers. Moreover, the database lacked data on the smoking volume and duration. Thus, we are unable to draw any conclusion regarding the association between smoking and glaucoma based on our results. Previous studies demonstrated inconsistent results concerning the association between smoking and glaucoma [3, 7, 8]. A previous study reported that the risk of glaucoma was higher in ex-smokers compared to non-smokers and current smokers . The authors speculated that ex-smokers might have consumed a large number of cigarettes resulting in serious medical conditions related to smoking, and they may have been motivated to quit smoking. Among smokers, a greater number of cigarette packs consumed per day was associated with higher odds of glaucoma .
Daily alcohol consumption was associated with a reduced risk of glaucoma. Alcohol is known to have a temporal ocular hypotensive effect, with a peak within 1–3 h following ingestion [10, 11]. Since most people consume alcohol in the evening in Japan, these transient hypotensive effects usually act at night. Cumulative evidence has demonstrated that intraocular pressure peaks at night [20, 21]. Therefore, daily intake of alcohol in the evening may help reduce the peak of intraocular pressure, possibly resulting in prevention of the development of glaucoma. On the other hand, daily volume of alcohol consumption ≥180 ml (2.5 units)/day was associated with increased risk of glaucoma compared to <180 ml/day. Our results were similar to a recent analysis of the UK Biobank that reported that regular drinkers with a greater quantity of alcohol intake demonstrated a higher prevalence of glaucoma in a dose-dependent manner . Chronic excessive alcohol use is known to cause neuropathy through oxidative stress resulting in free radical damage on nerves, nutritional deficiencies, and direct toxic effects, and alcoholic neuropathy is more prevalent in heavy drinkers . Excessive intake of alcohol may damage the optic nerves by mechanisms similar to alcoholic neuropathy. Our results suggested that females tended to be more susceptible to glaucoma than males in terms of alcohol consumption. A previous study showed that females were more susceptible to long-term negative effects of alcohol on health, and developed alcohol-related medical conditions after shorter duration and at lower levels of alcohol consumption compared to males . A meta-analysis revealed that the relative risk of all-cause mortality significantly increased in females who consumed 2.0–2.9 standard drinks per day compared to abstainers, whereas it reached significance only when 4 standard drinks per day were consumed in males . Sex-related biological factors, including differences in alcohol pharmacokinetics and the levels of sex hormones, are considered to contribute to this difference in susceptibility to various medical condition .
Both skipping breakfast and late dinner were significantly associated with an increased risk of glaucoma. Accumulating evidence suggested that skipping breakfast increased the risk of cardiovascular disease . A previous study reported that habitual skipping of breakfast resulted in blood pressure elevation in the morning and altered lipid profiles, thereby increasing the risk of cardiovascular diseases . Having late dinner was also associated with an increased risk of cardiovascular disease . In addition, late dinner reportedly resulted in high blood glucose levels in the following morning . Skipping breakfast and late dinner may predispose to glaucoma through elevated blood pressure and blood glucose levels, since both of them are risk factors for glaucoma [30, 31]. Late dinner was more strongly associated with an increased risk of glaucoma in females compared to males. In a previous study, circadian misalignment increased the risk of obesity in females, but not in males . Thus, females may be prone to medical conditions in disrupted rhythm of life owing to sex-dependent factors, such as sex hormone malfunction.
Walking and exercise
Exercising for more than 30 min twice a week was significantly associated with lower risk of glaucoma, whereas walking for more than 1 h every day was significantly associated with a higher risk of glaucoma. In a previous study, both high and low intensity of exercise were associated with greater glaucoma prevalence compared to moderate intensity of exercise . They also reported that daily vigorous exercise was associated with increased prevalence of glaucoma compared to vigorous exercise performed 3 days per week. Another study reported that moderate amounts of vigorous activity decreased the risk of glaucoma compared to no vigorous activity . Thus, exercise would have both positive and negative effects on the development of glaucoma depending on the intensity and frequency. Excessive exercise has been associated with the accumulation of free radicals that cause structural damage and inflammatory reactions, and this oxidative stress could trigger glaucoma . On the contrary, neuroprotective effects of exercise have also been reported. In animal models, exercise has been shown to increase the expression of brain-derived neurotrophic factors, enhance mitochondrial function, and reduce oxidative stress in the retina, which could be effective in preventing retinal ganglion cell death . Thus, moderate intensity exercise, and not excessive exercise, could be considered ideal. Our results suggest that 1 h of daily walking may be excessive, and 30 min of exercise twice a week may be considered moderate.
Quality of sleep
Good quality of sleep was not associated with the incidence of glaucoma. Previous studies on the association between sleep and glaucoma mainly focused on sleep apnea, which remains controversial [35, 36]. Many factors are involved in the pathogenesis of sleep apnea, such as hypoxia, obesity and hormonal imbalance, and each factor is intricately related to glaucoma . Our study revealed that quality of sleep itself was not associated with the development of glaucoma.
Our study has several limitations. First, we included individuals who were aged between 20 and 75 years and reside in Japan. Second, many of the parameters obtained in the annual health check-ups were self-reported, which may be subject to recall bias. Since it is realistically difficult to collect data on the lifestyle habits from millions of individuals, we used these self-reported variables similar to previous clinical epidemiological studies. Third, the cohort included a higher proportion of males than females. We included interaction terms between sex and lifestyle, and we also performed the analyses stratified by sex. Fourth, we did not differentiate between the subtypes of glaucoma. In a previous study using Japanese claims data, the validity of the diagnostic codes to identify specific subtypes of glaucoma (such as primary open angle glaucoma) was low, although the diagnostic validity for glaucoma was high when not specifying the subtype . Fifth, data on the details of food intake and the amount and past history of smoking were not available. Sixth, we investigated the associations between lifestyle habits and glaucoma; however, the causal relationship remains unknown.
In conclusion, moderate BMI, having breakfast, avoiding late dinner, limiting alcohol intake to <2.5 units/day and 30 min of exercise at least twice a day were associated with a reduced risk of developing glaucoma. These findings could be utilized for promoting the prophylaxis of glaucoma.