Introduction

Meat is a major source of protein and fat in the diet of many countries around the world [1]. Total meat intake is generally reported to be considerably higher in Western countries than in Asia. For instance, a study using the Food and Agriculture Organization (FAO) database showed that per capita consumption of total meat in the United States was approximately three times higher than that in Japan, China and South Korea since the 1990s [2]. Indeed, mean consumption of meat in the United States in 2007 was 122.8 kg per year versus 46.1 to 55.9 kg in these three countries [2].

In Japan, westernization of the diet has seen a near-doubling of meat consumption between 1970 and 2006 [2]. Increased intake of animal fat and/or protein has contributed to reducing stroke among Japanese since the 1960s [3]. However, detrimental effects of meat consumption have also been reported, albeit primarily from Western populations. Epidemiological studies have reported that excessive intake of meat, especially red meat and processed meat, is associated with increased risk of morbidity, including heart disease [4], cardiovascular disease [5], diabetes [6, 7] and certain types of cancer [8, 9]. Elucidating the association of meat intake with overall mortality will aid in assessing the differential impact of meat intake on health among Asians. Current reporting of summary estimates of the link between meat consumption and mortality has primarily been obtained from Western populations [10–13], where meat intake is considerably higher than that in Asian populations. Evidence from Japan is scarce: only a few studies have reported the association of meat intake on mortality [2, 3, 14, 15] and the results are in any case disconcordant. A recent study in 2019 published from the same Japanese cohort reported associations of protein intake with mortality [16]; however, the study primarily assessed the effect of animal and plant-based protein intake on mortality, and did not provide a comprehensive breakdown of item-specific associations.

Here, we aimed to investigate the association between meat intake and all-cause and major causes of death, including cancer, heart disease and cerebrovascular disease in Japan using comprehensive, item-specific information obtained from a large-scale, prospective cohort study.

Methods

Results

During 1,225,257 person-years of follow-up (average 14.0 years), there were 9,886 deaths due to all-cause mortality (6,266 for men, 3,620 for women), 4,174 deaths due to cancer (2,695 for men, 1,479 for women), 940 deaths due to cerebrovascular disease (569 for men, 371 for women), and 1,209 deaths due to heart disease (751 for men, 458 for women). Table 1 shows the characteristics of participants according to quartiles of total meat intake by sex. Those who consumed more meat tended to be younger, and consumed less fruits, vegetables and dairy products.

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Table 1. Basic characteristics of participants by quartile of energy-adjusted total meat intake in the study population.

https://doi.org/10.1371/journal.pone.0244007.t001

Tables 2 and 3 show Hazard Ratios (HRs) and 95% confidence intervals (95% CI) for the association between meat consumption and all-cause and cause-specific mortality separately for men and women, and S1 and S2 Tables show the Hazard Ratios and 95% CIs after excluding deaths that occurred within five years after the 5-year follow-up survey. After adjusting for potential confounders, total meat intake was associated with a higher risk of all-cause mortality in men [Q1: reference; Q4: HR, 1.18 (95% CIs, 1.06–1.31)]. Total meat intake was also associated with an elevated risk of heart disease mortality only in men [Q1: reference; Q4: HR, 1.46 (95% CIs, 1.08–1.99)]. In contrast, an intake of total meat was associated with a lower risk of stroke mortality in women [Q2: HR, 0.70 (95% CIs, 0.51–0.94), Q3: HR, 0.68 (95% CIs, 0.50–0.95), Q4: HR, 0.66 (95% CIs, 0.44–0.99)].

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Table 2. Adjusted hazard ratios of mortality by meat consumption status (men).

https://doi.org/10.1371/journal.pone.0244007.t002

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Table 3. Adjusted hazard ratios of mortality by meat consumption status (women).

https://doi.org/10.1371/journal.pone.0244007.t003

Our analyses by meat type showed that a higher intake of red meat was also associated with all-cause mortality [Q1: reference; Q4: HR, 1.13 (95% CIs, 1.02–1.26)] and heart disease mortality [Q1: reference; Q4: HR, 1.51 (95% CIs, 1.11–2.06)] in men but not in women. Among different types of red meat, beef consumption was associated with an increased risk of cancer mortality only among men in the highest intake quartile [Q1: reference; Q4: HR, 1.18 (95% CIs, 1.04–1.33)]. Higher pork consumption was also associated with an increased risk of total mortality in men [Q1: reference; Q4: HR, 1.11 (95% CIs, 1.01–1.22)]. In contrast, a moderate intake of processed meat was associated with a lower risk of total mortality [Q1: reference; Q2: HR, 0.91 (95% CIs: 0.85–0.98); Q3: 0.92 (95% CIs, 0.85–0.99)] and of cancer mortality [Q1: reference; Q2: HR, 0.88 (95% CI: 0.79–0.98); Q3: 0.89 (95% CIs, 0.79–0.99)] only among men, albeit that associations seen in Q3 were not significant after exclusion of deaths within 5 years. Higher intake of chicken was associated with a lower risk of cancer mortality in men [Q1: reference; Q4: HR, 0.85 (95% CIs: 0.75–0.96)]. This inverse association between chicken consumption and all-cause mortality was also seen after exclusion of deaths occurring within 5 years [Q1: reference, Q4: HR, 0.83 (95% CIs: 0.72–0.96)]. No significant associations were observed between all types of meat and colorectal cancer mortality. In our sub-analysis, no significant association was seen between meat intake and mortality due to ischemic heart disease or intracerebral hemorrhage (S3 Table). Across other types of cause-specific mortality, the same associations remained after exclusion of deaths that occurred within 5 years after the 5-year follow-up survey in both men and women.

Table 4 shows the results of meat intake and all-cause and cause-specific mortality according to age groups at baseline (45–54 years, 55–64 years, and 65 years and older) in men and women, respectively. In men, a significant increase in all-cause mortality risk was observed in those older than 65 years [Q1: reference; Q4: HR, 1.21 (95% CIs: 1.03–1.41)]. Red meat intake was also associated with a higher risk of all-cause mortality in those aged 55–64 years [Q1: reference; Q4: HR, 1.20 (95% CIs: 1.02–1.42)]. The risk difference was significant by age group (p-interaction with age: total meat, 0.004; red meat, 0.018). In women, a significant increase in all-cause mortality risk was seen in those aged 45–54 years who consumed more total meat [Q1: reference; Q2: HR, 1.32 (95% CIs: 1.01–1.72); Q3: HR, 1.37 (95% CIs: 1.03–1.82)] and more red meat [Q1: reference; Q3: HR, 1.34 (95% CIs: 1.01–1.79)].

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Table 4. Adjusted hazard ratios of all-cause mortality according to quartile of meat consumption by age group.

https://doi.org/10.1371/journal.pone.0244007.t004

Discussion

Our study is one of the few conducted in Asia to assess the association between meat intake and mortality due to all-cause and leading causes using data from a large-scale prospective study. Compared with subjects in the lowest quartile of total meat intake, men in the highest quartile had 18% higher risk of dying from all causes, although the associations were not dose-responsive. Our results agree with a 2014 meta-analysis of nine prospective cohort studies in the US, Europe and China, although total red meat intake in that review increased the risk of all-cause mortality by 29% in the highest intake category [10] compared with 18% in our study. This difference in the magnitude of risk increase is because the analyses in both studies were performed using relative consumption categories rather than absolute consumption amounts. The difference may also be due to the fact that the absolute amount of intake of meat differs between the Japanese and Western populations: mean daily intake of total meat in the US population amounted to 127.9 grams per day between 2003 and 2004 [25] versus 77 grams per day in Japan as of 2003 [26]. Mean intake amount in the US is almost twice that in Japan.

In our study population, the crude mean intake (adjusted for the difference between the FFQ and dietary records [20, 21]) of total meat was 71.9 grams per day.

We also noted generational differences in the association patterns between meat intake and all-cause mortality: notably, women aged 45–54 years had significantly higher risk of total mortality. However, these results could be a chance finding resulting from the multiple statistical tests conducted, given that the highest intake quartile showed no significant associations. In men, in contrast, elevated risk of mortality in the highest intake quartile was seen only in the older groups, and not in the younger age group.

Of note, our study found that intake of total meat was associated with a decreased risk of cerebrovascular disease mortality in women. Meat is a major source of animal protein, and a modest amount of protein intake has been reported to suppress blood pressure and thereby prevent stroke [27]. For instance, previous population-based studies—both derived from Japanese populations—showed that dietary animal protein intake was associated with lower blood pressure levels [28] and also a reduced risk of intraparenchymal hemorrhage [29]. Nevertheless, our results did not show any association between meat intake and intracerebral hemorrhage, a finding which warrants further investigation.

On the contrary, our study reported an elevated risk of heart disease mortality in men but not in women if red meat is taken to the level of the highest intake quartile. One possible mechanism of this association between red meat and heart disease is that meat is a major source of saturated fatty acid, which is reported to increase the risk of myocardial infarction [30]. Several cohort studies have also reported an association between red meat consumption and cardiovascular disease mortality [5, 31], although we did not observe any association between red meat intake and ischemic heart disease mortality in the current study.

Our study also found an elevated risk of cancer mortality in men with the highest intake of beef. Although not specifically referring to beef, the World Cancer Research Fund reported that red meat increases the risk of colorectal cancer [32], and showed suggestive evidence that red meat increases the risk of nasopharynx, lung and pancreatic cancer [32]. The International Agency for Research on Cancer (IARC) also reported that red meat intake is associated with the risk of prostate cancer [33]. Potential pathways can be explained as follows: in the process of cooking red meat, the nitrites convert to N-nitroso compounds, which are known carcinogens that function as a series of initiators and promoters in cancer [34–36]. Heme iron from red meat can catalyze lipid peroxidation, and cause DNA damage in tissues [37, 38]. Other carcinogens, including heterocyclic aromatic amines and polycyclic aromatic hydrocarbons, which are produced by cooking of meat at high temperatures (e.g. pan-frying, grilling or barbecuing), also contribute to carcinogenesis of different sites [33, 39–42]. Despite mounting evidence linking red meat intake and colorectal cancer incidence globally [32] and in Japan [23], no association was seen between meat and colorectal cancer mortality in our study; this may have been due to the fact that the survival rate of colorectal cancer is generally high in Japan, for example with a 5-year relative survival rate of 71.1% for cases diagnosed between 2006–2008 [43, 44].

Contrary to previous studies [5, 45], our analysis showed that processed meat consumption was not associated with elevated risk of mortality due to all-cause, cancer, heart disease and cerebrovascular disease. This null association might be explained by the difference in the intake amount of processed meat in Japan: generally, consumption is lower in Japan than in Western countries. For example, average consumption in the US was estimated to be 23.2 grams per day between 2003 and 2004 [25] versus 12 grams per day in Japan as of 2003 [26]. In our study population, the crude mean intake (adjusted for the difference between the FFQ and dietary records [46]) of processed meat was 7.7 grams per day. Such difference in the absolute amount intake of processed meat may have attenuated the adverse effects.

While a moderate intake of processed meat and pork showed a lower risk of mortality in men, this may have been a chance finding as we did not see any significant trend for different quartile intakes of the corresponding meat type. In contrast, our results showed that higher intake of white meat (i.e. chicken) is associated with a modest decrease in the risk of cancer mortality while red meat intake was held constant. A US study reported that poultry intake was inversely associated with esophagus squamous cell carcinoma, liver cancer and lung cancer, assuming no change in the amount intake of red meat [47]. Given that both studies adjusted for red meat intake, the inverse associations are not due to the effect of substituting red meat with poultry. The mechanism whereby chicken intake alone reduces cancer risk is unclear, and further research is required in this area.

The major strength of this study is the fact that the subjects were recruited from a large sample of the Japanese population. The high response rate and low loss to follow-up may have reduced selection bias. With an average of 14.0 years of follow-up, we consider that sufficient numbers of deaths due to all-cause, overall cancer, heart disease and cerebrovascular disease were captured. Second, we used a 5-year follow-up survey containing the FFQ collecting the necessary information about daily diet with reasonable degree of validity. On the other hand, some limitations warrant mention. Given the information on meat intake was collected only at 5-year follow-up, any change in meat intake during follow-up after the five-year follow-up survey may have produced misclassification.

Conclusion

In this prospective, large-scale cohort study, heavy intake of total and red meat was associated with an increased risk of total mortality in men. In contrast, modest intake of total meat was associated with a lower risk of cerebrocascular disease mortality in women.

Supporting information

Acknowledgments

ES and XT analyzed the data, drafted the manuscript, reviewed and edited the manuscript, and contributed to discussion; MI and ST conducted, designed, and supervised the study, reviewed and edited the manuscript, and contributed to discussion; SKA, NS, JI, RT, HI, TS, TY and MIw reviewed and edited the manuscript, and contributed to discussion. All authors read and approved the final manuscript. Members of the Japan Public Health Center-based Prospective Study (JPHC Study; principal investigator, S. Tsugane; e-mail, stsugane@ncc.go.jp) Group are: S. Tsugane, N. Sawada, M. Iwasaki, M. Inoue, T. Yamaji, R. Katagiri, T. Imatoh, H. Ihira, S. K. Abe and S. Tanaka, National Cancer Center, Tokyo; T. Sugie, Iwate Prefectural Ninohe Public Health Center, Iwate; T. Minamizono, Akita Prefectural Yokote Public Health Center, Akita; Y. Shirai, Nagano Prefectural Saku Public Health Center, Nagano; H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; T. Yoshimi, Ibaraki Prefectural Chuo Public Health Center, Ibaraki; H. Sonoda, Niigata Prefectural Nagaoka Public Health Center, Niigata; T. Tagami, Kochi Prefectural Chuo-higashi Public Health Center, Kochi; T. Ando, Nagasaki Prefectural Kamigoto Public Health Center, Nagasaki; Y. Miyasato, Okinawa Prefectural Miyako Public Health Center, Okinawa; Y. Kokubo, National Cerebral and Cardiovascular Center, Osaka; K. Yamagishi, University of Tsukuba, Ibaraki; T. Mizoue, National Center for Global Health and Medicine, Tokyo; K. Nakamura, Niigata University, Niigata; and R. Takachi, Nara Women’s University, Nara; J. Ishihara, Azabu University, Kanagawa; H. Iso and T. Kitamura, Osaka University, Osaka; I. Saito, Oita University, Oita; N. Yasuda, Kochi University, Kochi; M. Mimura, Keio University, Tokyo; K. Sakata, Iwate Medical University, Iwate; M. Noda, Saitama Medical University; A. Goto, Yokohama City University, Kanagawa; H. Yatsuya, Fujita Health University, Aichi.