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Can teatime increase one’s lifetime?
Ageing Research Reviews 2 (2003) 1–10
Can teatime increase one’s lifetime?夽 Kei Nakachi∗ , Hidetaka Eguchi, Kazue Imai Department of Epidemiology, Radiation Effects Research Foundation, Hijiyama, Minami-ku, Hiroshima 732-0815, Japan Received 13 June 2002; accepted 18 June 2002
Abstract Lifestyle-related diseases, including cancer and cardiovascular disease, are also characterized as aging-related diseases, where aging may be the most potent causal factor. In light of this, prevention of lifestyle-related diseases will depend on slowing the aging process and avoiding the clinical appearance of the diseases. Green tea is now accepted as a cancer preventive on the basis of numerous in vitro, in vivo and epidemiological studies. In addition, green tea has also been reported to reduce the risk of cardiovascular disease. We found an apparent delay of cancer onset/death and all cause deaths associated with increased consumption of green tea, specifically in ages before 79 in a prospective cohort study of a Japanese population with 13-year follow-up data. This is consistent with analyses of age-specific cancer death rate and cumulative survival, indicating a significant slowing of the increase in cancer death and all cause death with aging. These results indicate that daily consumption of green tea in sufficient amounts will help to prolong life by avoiding pre-mature death, particularly death caused by cancer. © 2003 Published by Elsevier Science Ireland Ltd. Keywords: Green tea; Cancer; Cardiovascular disease; All death; Cohort study; Lifespan
1. Introduction Incidence of lifestyle-related diseases drastically increases with aging, a major factor limiting healthy lifespan of humans. Most lifestyle-related diseases show chronic progression with multiple processes and, hence the delay of progression in pre-clinical stages can prevent lifestyle-related diseases. Specifically in the cancer field, the concept of cancer prevention has recently been expanded on the basis of numerous studies of green tea in both laboratory and human studies (Fujiki, 1999; Fujiki et al., 2000): the expanded definition 夽
This research was mainly done at Saitama Cancer Center. Corresponding author. Tel.:+81-82-261-3131; fax:+81-82-506-1531. E-mail address: [email protected] (K. Nakachi).
∗
1568-1637/03/$ – see front matter © 2003 Published by Elsevier Science Ireland Ltd. PII: S 1 5 6 8 - 1 6 3 7 ( 0 2 ) 0 0 0 4 7 - 8
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of cancer prevention is, the administration of cancer preventives to delay the carcinogenic processes, no matter when the carcinogenesis starts, thereby blocking the appearance of clinical symptoms. This concept may be applicable for prolonging life by avoiding other age-related diseases. Green tea has obtained significant acceptance as a cancer preventive. Since Yoshizawa et al. (1987) reported the cancer-preventive activity of (−)-epigallocatechin gallate (EGCG), the main constituent of green tea polyphenols, a number of scientists around the world have confirmed the significant cancer-preventive effects of EGCG and green tea extract on various organs, including skin, esophagus, glandular stomach, duodenum, colon, liver, pancreas, lung, breast, bladder, and prostate in rodents (NCI, 1996; Conney et al., 1999; Suganuma et al., 1999; Suganuma et al., 2000; Yang et al., 2000). Although the indications were clear in numerous laboratory studies, epidemiological studies on cancer preventive effects of green tea or black tea have yielded inconsistent results (Kono et al., 1988; Yang and Wang, 1993; Gao et al., 1994; Ohno et al., 1995; Zheng et al., 1996; Inoue et al., 1998; Hakim et al., 2000; Nagano et al., 2001; Setiawan et al., 2001; Tsubono et al., 2001; Joseph and Arab, 2002). This may be in part due to the amount and quality of daily-consumed tea among study subjects; our prospective cohort study among a general population in Saitama Prefecture, which is reputable for the production of high-quality green tea, found cancer-preventive effects of green tea among those drinking 10 cups and over a day, in terms of age-standardized cancer incidence rates, relative risk, and age at cancer onset (Imai et al., 1997). Ten cups (150 ml per cup) of green tea contain 2.0–2.5 g green tea extract or 400–750 mg total tea polyphenols, which is now being used as the standard daily dose for clinical trials in US and Japan. Tea polyphenols have also been reported to reduce the levels of serum lipids in animal models, implying a preventive effect of green tea on cardiovascular disease (Muramatsu et al., 1986; Vinson, 2000). However, epidemiological studies have reported inconsistent results (Hollman et al., 1999; Arts et al., 2001; Peters et al., 2001). We previously reported that drinking green tea resulted in lower serum levels of total cholesterol and triglycerides, along with decreased atherogenic index, a cross-sectional analysis of prospective cohort study (Imai and Nakachi, 1995); a further study using follow-up data has also suggested preventive effects of drinking green tea on cardiovascular disease (Nakachi et al., 2000). Death from cancer and cardiovascular disease accounts for half of all deaths in Japan, as is the case in many other countries. Thus, the prevention of these major diseases is critical for attaining a healthy life. Therefore, in this paper we first studied the preventive effects of drinking green tea on cancer, on the basis of our latest follow-up data, focusing on the delay of cancer onset and death. Second, the effects of drinking green tea on age at cardiovascular death were examined. Finally, we investigated the impact of drinking large amounts of green tea on the prevention of pre-mature death from all causes. Our results reveal new beneficial possibilities of green tea for living long and healthy lives.
2. Subjects and methods In 1986, we began a prospective cohort study in residents over 40 years of age in a town in Saitama Prefecture, Japan. We used a self-administered questionnaire covering 90 lifestyle factors, such as present and past dietary habits including daily consumption of
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green tea, cigarette consumption, alcohol use, history of diseases, present state of health, work load, regularity of meal times and sleep, and mental stress and personality typing. In the questionnaire, green tea consumption was categorized as below 3, 4–9, and over 10 cups a day. The questionnaire covered a total of 8552 individuals. The mean age ± S.E. at the time of the questionnaire was 52.6 ± 0.2 for 4108 men and 54.8 ± 0.2 for 4444 women in the cohort study. Our 13-year follow-up study from 1986 to 1999 found a total of 1449 deaths from all the causes: 449 cancer deaths (591 incidence cases), 284 cardiovascular deaths, 253 cerebrovascular deaths, 378 deaths from other diseases, and 85 deaths from accidents. The mean age of 3301 men and 3742 women in the cohort surviving as of 1999 was 62.2 ± 0.2 and 64.8 ± 0.2 years old, respectively. During the follow-up period, the vital status of only 22 members (0.3%) was unknown. Cumulative proportion surviving (cumulative survival) was compared to green tea by consumption levels, on the basis of life-table analysis with software package SPSS using the life-tables obtained from follow-up data in 1986–1999.
3. Results 3.1. Age at cancer death or onset by consumption of green tea We previously evaluated relative risk of cancer incidence for daily consumption levels of green tea on the basis of follow-up data from 1986 to 1997, adjusting for potent confounding lifestyle-factors (Nakachi et al., 2000). Specifically, women who consumed over 10 cups a day revealed a significantly decreased risk of 0.57 (95% of CI, 0.34–0.98), taking the risk of those consuming below three cups a day as reference; men showed a decreased risk of 0.54 (0.22–1.34): combined risk for both sexes was 0.59 (0.35–0.98). We found that the reduction of cancer risk by green tea was ascribable to the delay of cancer onset (incidence) among those consuming large amounts of green tea, being consistent with a number of in vitro and in vivo studies indicating that green tea inhibits tumor promotion. Analysis of mean age at cancer death or onset among cohort members occurring in 1986–1999 revealed that increased consumption of green tea was associated with delay of cancer death or onset (Table 1). Mean age at cancer onset among men or women who consumed over 10 cups a day was 4.1 or 7.6 years later than among those consuming below three cups (P = 0.01 or 0.02 for trend), respectively. The difference in age at cancer death was 3.9 or 5.9 years among men or women, respectively. Dividing these cancer events into two groups, below and over the average lifespan (79 years) of Japanese, the delay of cancer death or onset was significant in ages below 79, while no significant difference was found in ages over 80. Since cigarette smoking was associated with earlier onset of cancer and, since the highest consumption group of green tea included more smokers than other groups, the difference in the mean age at cancer onset or death among men was smaller than that among women. The differences in age at cancer death were further analyzed, in terms of age-specific cancer death rates among women by daily consumption of green tea (Fig. 1). An obvious slowdown in the increase of cancer death with age was observed specifically among women
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Table 1 Mean age (±S.E., years) at cancer death and onset by daily consumption of green tea, on the basis of follow-up data in 1986–1999 Daily consumption of green tea ≤3 cups
4–9 cups
≥10 cups
P for trend
Men Age ≤ 79 (death) (Onset) Age ≥ 80 (death) (Onset) All ages (death) (Onset) Non-smokersc all ages (death) (Onset) Current smokers all ages (death) (Onset)
64.2 ± 1.2 (57)a 63.0 ± 1.1 (70)a 84.2 ± 1.1 (13)b 84.3 ± 1.1 (12) 67.9 ± 1.4 (70) 66.1 ± 1.3 (82) 73.4 ± 4.5 (11) 70.0 ± 3.7 (15) 65.4 ± 1.6 (43) 63.8 ± 1.5 (50)
68.6 ± 0.8 (98) 66.8 ± 0.7 (141) 84.5 ± 0.5 (17) 84.5 ± 0.1 (17) 70.9 ± 0.9(115) 68.7 ± 0.8 (158) 72.9 ± 2.7 (12) 71.3 ± 1.8 (23) 70.8 ± 1.1(74) 68.3 ± 1.0 (96)
67.7 ± 0.9 (62) 67.0 ± 0.7 (82) 84.5 ± 0.7 (20) 84.4 ± 0.7 (18) 71.8 ± 1.1 (82) 70.2 ± 0.9 (100) 76.6 ± 2.6 (7) 73.5 ± 2.4 (10) 71.7 ± 1.3 (64) 70.1 ± 1.1 (78)
0.03 0.01 0.8 0.9 0.02 0.01 0.6 0.4 0.002 0.001
Women Age ≤ 79 (death) (Onset) Age ≥ 80 (death) (Onset) All ages (death) (Onset)
66.5 ± 1.5 (45) 65.1 ± 1.3 (66) 85.6 ± 1.3 (11) 86.1 ± 1.3 (10) 70.3 ± 1.6 (56) 67.8 ± 1.3 (76)
68.0 ± 1.0 (69) 64.3 ± 0.9 (115) 84.9 ± 0.5 (30) 84.8 ± 0.5 (30) 73.1 ± 1.1 (99) 68.6 ± 1.0 (145)
70.1 ± 2.1 (16) 69.7 ± 1.9 (19) 85.2 ± 0.8 (11) 85.2 ± 0.8 (11) 76.2 ± 1.9 (27) 75.4 ± 1.8 (30)
0.1 0.3 0.7 0.5 0.02 0.02
a
In parentheses, number of deaths or incidence (onset) cases. Including one colon cancer case diagnosed at 77 years who died at 82 years. c Ex-smokers were excluded from the table, due to the small number of subjects. b
below 79 years of age consuming over 10 cups a day, resulting in an overall delay of cancer death before age 79 in the highest consumption group. The convergence of cancer death rates at very advanced ages implies that the cancer-preventive effects of green tea may be demonstrated, specifically for those who do not reach the average lifespan. Cigarette smoking is the most potent cancer cause in our environment, and it was associated with earlier onset of cancer: mean age at cancer onset was 71.3 ± 1.5 (48 cases) and 67.9 ± 0.7 (220 cases) years old for male non-smokers and smokers, respectively. Since drinking green tea was closely associated with cigarette smoking in lifestyle factors, we needed to determine the effects of green tea by smoking status. (Adjustment for cigarette smoking in relative risk estimation may not be sufficient.) We found a delay of cancer onset or death in both non-smokers and smokers consuming over 10 cups of green tea a day (Table 1), although the result in non-smokers did not reach statistical significance due to the small number of subjects for analysis. 3.2. Age at cardiovascular disease death Serum levels of total cholesterol, triglycerides, and atherogenic index are established biomarkers for predicting the risk of cardiovascular disease, and these increase with age. The lowering effects of drinking green tea on these markers have been observed in the
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Fig. 1. Age-specific cancer death rates among women by daily consumption of green tea on the basis of follow-up data in 1986–1999.
same cohort (Imai and Nakachi, 1995); a further follow-up study showed decreased risk of cardiovascular disease (Nakachi et al., 2000): men consuming over 10 cups a day showed a significantly decreased risk of 0.58 (0.34–0.99), compared with those consuming below three cups; women showed a decreased risk of 0.82 (0.49–1.38); both the sexes had a risk of 0.72 (0.50–1.04). We analyzed the association between age at cardiovascular death and consumption of green tea, using up-dated death data in 1986–1999. Mean age ± S.D. at cardiovascular death was 74.9 ± 2.0 (35 deaths), 76.2 ± 1.3 (77), and 76.8 ± 2.3 (25) for ≤3 cups, 4–9 cups, and ≥10 cups a day among men, respectively; 79.5 ± 1.5 (34), 80.6 ± 1.1 (79), and 80.9 ± 1.6 (31) for ≤3 cups, 4–9 cups, and ≥10 cups a day among women, respectively. Those consuming the largest amounts consistently showed later ages at cardiovascular death in all age groups. 3.3. Age at death from all causes Death from cancer and cardiovascular disease account for 51% of death from all causes, on the basis of follow-up data from our cohort in 1986–1999. We, therefore, examined the influence of drinking large amounts of green tea on age at death from all causes (Table 2). Mean age at death among men or women consuming over 10 cups a day was 4.3 and 3.8 years higher, respectively, than those consuming under three cups a day. The association between increased consumption of green tea and higher ages at death was more clearly observed in ages below 79 among both men and women.
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Table 2 Mean age (±S.E., years) at death from all causes by daily consumption of green tea, on the basis of follow-up data in 1986–1999 Daily consumption of green tea ≤3 cups
4–9 cups
≥10 cups
P for trend
Men Age ≤ 79 Age ≥ 80 All ages
64.8 ± 0.9 (135)a 85.2 ± 0.4 (60) 71.1 ± 0.9 (195)
67.6 ± 0.6 (246) 85.4 ± 0.3 (123) 73.5 ± 0.6 (369)
68.5 ± 0.7 (123) 85.3 ± 0.4 (86) 75.4 ± 0.7 (209)
0.001 0.9 <0.001
Non-smokersb Age ≤ 79 Age ≥ 80 All ages
65.6 ± 2.6 (21) 84.9 ± 0.9 (19) 74.8 ± 2.1 (40)
71.4 ± 1.5 (38) 85.7 ± 0.7 (32) 77.9 ± 1.2 (70)
69.3 ± 2.6 (9) 87.0 ± 1.4 (12) 79.4 ± 2.4 (21)
0.1 0.2 0.1
Current smokers Age ≤ 79 Age ≥ 80 All ages
62.9 ± 1.1 (81) 84.9 ± 0.7 (23) 67.7 ± 1.2 (104)
65.9 ± 0.8 (140) 85.5 ± 0.4 (63) 72.0 ± 0.9 (203)
68.9 ± 0.8 (93) 85.0 ± 0.4 (60) 75.2 ± 0.8 (153)
<0.001 0.8 <0.001
Women Age ≤ 79 Age ≥ 80 All ages
68.4 ± 0.9 (108) 86.7 ± 0.5 (78) 76.1 ± 0.9 (186)
69.2 ± 0.6 (172) 86.5 ± 0.3 (185) 78.2 ± 0.6 (357)
71.8 ± 1.0 (52) 87.3 ± 0.5 (74) 80.9 ± 0.8 (126)
0.03 0.4 <0.001
a b
In parentheses, number of deaths. Ex-smokers were excluded from the table, due to the small number of subjects.
Ages at death among male smokers were lower than those among non-smokers, indicating that cigarette smoking is a potent lifetime-limiting factor probably due to increased risk of cancer and other lifestyle-related diseases, specifically for younger ages: in fact, ages at death by smoking status did not differ at ages over 80. On the other hand, increased consumption of green tea was associated with higher ages at death among both non-smokers and smokers, resulting in the largest difference of over 10 years in mean age at death: 79.4 and 67.7 years for non-smokers drinking over 10 cups a day and smokers drinking less than three cups a day. This result demonstrates the impact of combined prevention against early death based on more green tea and no tobacco. Interestingly, mean age (75.2 years) at death among smokers consuming over 10 cups of green tea a day was almost the same as that (74.8) among non-smokers consuming less than three cups a day, implying the possible prevention of early death among smokers using green tea. 3.4. Cumulative survival Consumption of large amounts of green tea was associated with higher ages at death from all causes, specifically in ages under 80. We next confirmed the effect of green tea on lifetime among women in terms of cumulative survival as a function of age, based on life-table analysis of cohort data (Fig. 2). Our cohort members were aged over 40 at baseline, and hence cumulative survival was estimated starting from age 40. Women consuming over 10 cups a day showed improved survival over other groups consuming smaller amounts; surviving proportion ± S.E. at age 80, for instance, was 74 ± 2, 80 ± 1, or 82 ± 2% for
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Fig. 2. Cumulative proportion surviving (cumulative survival) among women calculated by consumption levels of green tea, using life-tables obtained from follow-up data in 1986–1999.
groups consuming below 3 cups, 4–9 cups or over 10 cups a day, respectively. After age 80, the differences in cumulative survival by consumption levels of green tea decreased. Compared with these differences in cumulative surviving proportion, age-differences for given cumulative survival were relatively small: the difference in ages from 70 to 85 was about 3 years between groups consuming below three cups and over 10 cups a day, with the gap decreasing in more advanced ages. The median survival time (equivalent to average lifespan of women who have already lived to age 40) was 87.1, 88.2 or 89.0 years old for groups consuming below 3 cups, 4–9 cups, and over 10 cups a day, respectively, indicating about two years longer lifetime associated with large consumption of green tea. On the other hand, cumulative survival among men did not show such clear differences by consumption of green tea as were seen in women (data not shown). This is in part due to the deleterious effects of cigarette smoking, which apparently disturbs the beneficial effects of green tea. In fact, when we divided men by smoking status, the life-table analysis among non-smokers showed a similar result to that in Fig. 2: current smokers consuming over 10 cups a day showed the highest survival in ages before 70, and there were no substantial differences in cumulative survival in ages after 70 between the groups consuming over 10 cups and 4–9 cups a day, although smokers consuming below three cups had a much lower survival.
4. Discussion Lifestyle-related diseases, including cancer and cardiovascular disease, are characterized as aging-related diseases, where aging may be the most potent causal factor. In the light of this, the target for prevention of lifestyle-related diseases is the aging process. The average
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lifespan of Japanese is 79 years, one of the highest in the world. Therefore, the Japanese population can serve as a model for the reduction of age-related diseases; using green tea may reduce disease risk among those below (middle to advanced age) or above (very advanced age) the average lifespan, where age-related diseases may be avoidable or unavoidable, respectively. In this paper, we demonstrated the impact of drinking large amounts of green tea on the prevention of cancer and death, on the basis of a prospective cohort study among a Japanese general population. We found an apparent delay of cancer onset/death and all deaths associated with increased consumption of green tea, specifically in ages before 79. This is consistent with age-specific cancer death rates (Fig. 1) and cumulative survival (Fig. 2) by consumption of green tea, indicating a significant slowdown of the increase in cancer death and all deaths along with aging, at least before the average lifespan is reached. These results indicate that daily, large consumption of green tea is beneficial for the avoidance of such pre-mature deaths from cancer and other diseases. In the analyses of prospective cohort studies, we often use relative risk as an index for judging the magnitude of risk enhancement or reduction: a major reason is that relative risk can reveal the influence of confounding factors such as cigarette smoking and alcohol consumption. One of the most popular models for relative risk estimation assumes proportional hazard as functions of follow-up years. However, the longer the follow-up continues, the older the cohort members are. In such cases, appropriate evaluation of green tea as cancer preventive may be difficult since the response to green tea seems to vary by age: aging overcomes environmental influences in very advanced ages beyond the average lifespan, as shown in Fig. 1. Another issue to be considered in the analysis may be the fundamental question of whether the influence of a potent confounder, cigarette smoking, on the effects of green tea can be fully and properly estimated by “adjustment” in multivariate analyses. Our experience revealed that the relative risk of cancer by consumption of green tea estimated among men was vague even after adjusting for smoking, and that other approaches, separating smokers and non-smokers, should be used to evaluate the effects of green tea, along with relative risk estimation. In this paper, we attempted to introduce several approaches along these lines. Our conclusion is that daily large consumption of green tea, specifically 10 cups and over a day, will add a little lifetime to those who have already lived the average lifespan of about 80 years, but it will help to prolong the lifetime of those aged below the average lifespan by avoiding pre-mature death, specifically that caused by cancer. Our final target of prevention is not a specific disease, but a category of diseases, such as all cancer, all lifestyle-related diseases, and all death, since we are not sure which disease will shorten our lifetime or reduce life activity in the future. In the light of this, studies of green tea showed a future of holistic prevention, which aims to realize not perennial youth or disease-free life in very advanced ages, but to delay the aging process and avoid pre-mature death.
Acknowledgements This work was supported in part by Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant from the Smoking Research Foundation.
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Can teatime increase one’s lifetime?夽 Kei Nakachi∗ , Hidetaka Eguchi, Kazue Imai Department of Epidemiology, Radiation Effects Research Foundation, Hijiyama, Minami-ku, Hiroshima 732-0815, Japan Received 13 June 2002; accepted 18 June 2002
Abstract Lifestyle-related diseases, including cancer and cardiovascular disease, are also characterized as aging-related diseases, where aging may be the most potent causal factor. In light of this, prevention of lifestyle-related diseases will depend on slowing the aging process and avoiding the clinical appearance of the diseases. Green tea is now accepted as a cancer preventive on the basis of numerous in vitro, in vivo and epidemiological studies. In addition, green tea has also been reported to reduce the risk of cardiovascular disease. We found an apparent delay of cancer onset/death and all cause deaths associated with increased consumption of green tea, specifically in ages before 79 in a prospective cohort study of a Japanese population with 13-year follow-up data. This is consistent with analyses of age-specific cancer death rate and cumulative survival, indicating a significant slowing of the increase in cancer death and all cause death with aging. These results indicate that daily consumption of green tea in sufficient amounts will help to prolong life by avoiding pre-mature death, particularly death caused by cancer. © 2003 Published by Elsevier Science Ireland Ltd. Keywords: Green tea; Cancer; Cardiovascular disease; All death; Cohort study; Lifespan
1. Introduction Incidence of lifestyle-related diseases drastically increases with aging, a major factor limiting healthy lifespan of humans. Most lifestyle-related diseases show chronic progression with multiple processes and, hence the delay of progression in pre-clinical stages can prevent lifestyle-related diseases. Specifically in the cancer field, the concept of cancer prevention has recently been expanded on the basis of numerous studies of green tea in both laboratory and human studies (Fujiki, 1999; Fujiki et al., 2000): the expanded definition 夽
This research was mainly done at Saitama Cancer Center. Corresponding author. Tel.:+81-82-261-3131; fax:+81-82-506-1531. E-mail address: [email protected] (K. Nakachi).
∗
1568-1637/03/$ – see front matter © 2003 Published by Elsevier Science Ireland Ltd. PII: S 1 5 6 8 - 1 6 3 7 ( 0 2 ) 0 0 0 4 7 - 8
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of cancer prevention is, the administration of cancer preventives to delay the carcinogenic processes, no matter when the carcinogenesis starts, thereby blocking the appearance of clinical symptoms. This concept may be applicable for prolonging life by avoiding other age-related diseases. Green tea has obtained significant acceptance as a cancer preventive. Since Yoshizawa et al. (1987) reported the cancer-preventive activity of (−)-epigallocatechin gallate (EGCG), the main constituent of green tea polyphenols, a number of scientists around the world have confirmed the significant cancer-preventive effects of EGCG and green tea extract on various organs, including skin, esophagus, glandular stomach, duodenum, colon, liver, pancreas, lung, breast, bladder, and prostate in rodents (NCI, 1996; Conney et al., 1999; Suganuma et al., 1999; Suganuma et al., 2000; Yang et al., 2000). Although the indications were clear in numerous laboratory studies, epidemiological studies on cancer preventive effects of green tea or black tea have yielded inconsistent results (Kono et al., 1988; Yang and Wang, 1993; Gao et al., 1994; Ohno et al., 1995; Zheng et al., 1996; Inoue et al., 1998; Hakim et al., 2000; Nagano et al., 2001; Setiawan et al., 2001; Tsubono et al., 2001; Joseph and Arab, 2002). This may be in part due to the amount and quality of daily-consumed tea among study subjects; our prospective cohort study among a general population in Saitama Prefecture, which is reputable for the production of high-quality green tea, found cancer-preventive effects of green tea among those drinking 10 cups and over a day, in terms of age-standardized cancer incidence rates, relative risk, and age at cancer onset (Imai et al., 1997). Ten cups (150 ml per cup) of green tea contain 2.0–2.5 g green tea extract or 400–750 mg total tea polyphenols, which is now being used as the standard daily dose for clinical trials in US and Japan. Tea polyphenols have also been reported to reduce the levels of serum lipids in animal models, implying a preventive effect of green tea on cardiovascular disease (Muramatsu et al., 1986; Vinson, 2000). However, epidemiological studies have reported inconsistent results (Hollman et al., 1999; Arts et al., 2001; Peters et al., 2001). We previously reported that drinking green tea resulted in lower serum levels of total cholesterol and triglycerides, along with decreased atherogenic index, a cross-sectional analysis of prospective cohort study (Imai and Nakachi, 1995); a further study using follow-up data has also suggested preventive effects of drinking green tea on cardiovascular disease (Nakachi et al., 2000). Death from cancer and cardiovascular disease accounts for half of all deaths in Japan, as is the case in many other countries. Thus, the prevention of these major diseases is critical for attaining a healthy life. Therefore, in this paper we first studied the preventive effects of drinking green tea on cancer, on the basis of our latest follow-up data, focusing on the delay of cancer onset and death. Second, the effects of drinking green tea on age at cardiovascular death were examined. Finally, we investigated the impact of drinking large amounts of green tea on the prevention of pre-mature death from all causes. Our results reveal new beneficial possibilities of green tea for living long and healthy lives.
2. Subjects and methods In 1986, we began a prospective cohort study in residents over 40 years of age in a town in Saitama Prefecture, Japan. We used a self-administered questionnaire covering 90 lifestyle factors, such as present and past dietary habits including daily consumption of
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green tea, cigarette consumption, alcohol use, history of diseases, present state of health, work load, regularity of meal times and sleep, and mental stress and personality typing. In the questionnaire, green tea consumption was categorized as below 3, 4–9, and over 10 cups a day. The questionnaire covered a total of 8552 individuals. The mean age ± S.E. at the time of the questionnaire was 52.6 ± 0.2 for 4108 men and 54.8 ± 0.2 for 4444 women in the cohort study. Our 13-year follow-up study from 1986 to 1999 found a total of 1449 deaths from all the causes: 449 cancer deaths (591 incidence cases), 284 cardiovascular deaths, 253 cerebrovascular deaths, 378 deaths from other diseases, and 85 deaths from accidents. The mean age of 3301 men and 3742 women in the cohort surviving as of 1999 was 62.2 ± 0.2 and 64.8 ± 0.2 years old, respectively. During the follow-up period, the vital status of only 22 members (0.3%) was unknown. Cumulative proportion surviving (cumulative survival) was compared to green tea by consumption levels, on the basis of life-table analysis with software package SPSS using the life-tables obtained from follow-up data in 1986–1999.
3. Results 3.1. Age at cancer death or onset by consumption of green tea We previously evaluated relative risk of cancer incidence for daily consumption levels of green tea on the basis of follow-up data from 1986 to 1997, adjusting for potent confounding lifestyle-factors (Nakachi et al., 2000). Specifically, women who consumed over 10 cups a day revealed a significantly decreased risk of 0.57 (95% of CI, 0.34–0.98), taking the risk of those consuming below three cups a day as reference; men showed a decreased risk of 0.54 (0.22–1.34): combined risk for both sexes was 0.59 (0.35–0.98). We found that the reduction of cancer risk by green tea was ascribable to the delay of cancer onset (incidence) among those consuming large amounts of green tea, being consistent with a number of in vitro and in vivo studies indicating that green tea inhibits tumor promotion. Analysis of mean age at cancer death or onset among cohort members occurring in 1986–1999 revealed that increased consumption of green tea was associated with delay of cancer death or onset (Table 1). Mean age at cancer onset among men or women who consumed over 10 cups a day was 4.1 or 7.6 years later than among those consuming below three cups (P = 0.01 or 0.02 for trend), respectively. The difference in age at cancer death was 3.9 or 5.9 years among men or women, respectively. Dividing these cancer events into two groups, below and over the average lifespan (79 years) of Japanese, the delay of cancer death or onset was significant in ages below 79, while no significant difference was found in ages over 80. Since cigarette smoking was associated with earlier onset of cancer and, since the highest consumption group of green tea included more smokers than other groups, the difference in the mean age at cancer onset or death among men was smaller than that among women. The differences in age at cancer death were further analyzed, in terms of age-specific cancer death rates among women by daily consumption of green tea (Fig. 1). An obvious slowdown in the increase of cancer death with age was observed specifically among women
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Table 1 Mean age (±S.E., years) at cancer death and onset by daily consumption of green tea, on the basis of follow-up data in 1986–1999 Daily consumption of green tea ≤3 cups
4–9 cups
≥10 cups
P for trend
Men Age ≤ 79 (death) (Onset) Age ≥ 80 (death) (Onset) All ages (death) (Onset) Non-smokersc all ages (death) (Onset) Current smokers all ages (death) (Onset)
64.2 ± 1.2 (57)a 63.0 ± 1.1 (70)a 84.2 ± 1.1 (13)b 84.3 ± 1.1 (12) 67.9 ± 1.4 (70) 66.1 ± 1.3 (82) 73.4 ± 4.5 (11) 70.0 ± 3.7 (15) 65.4 ± 1.6 (43) 63.8 ± 1.5 (50)
68.6 ± 0.8 (98) 66.8 ± 0.7 (141) 84.5 ± 0.5 (17) 84.5 ± 0.1 (17) 70.9 ± 0.9(115) 68.7 ± 0.8 (158) 72.9 ± 2.7 (12) 71.3 ± 1.8 (23) 70.8 ± 1.1(74) 68.3 ± 1.0 (96)
67.7 ± 0.9 (62) 67.0 ± 0.7 (82) 84.5 ± 0.7 (20) 84.4 ± 0.7 (18) 71.8 ± 1.1 (82) 70.2 ± 0.9 (100) 76.6 ± 2.6 (7) 73.5 ± 2.4 (10) 71.7 ± 1.3 (64) 70.1 ± 1.1 (78)
0.03 0.01 0.8 0.9 0.02 0.01 0.6 0.4 0.002 0.001
Women Age ≤ 79 (death) (Onset) Age ≥ 80 (death) (Onset) All ages (death) (Onset)
66.5 ± 1.5 (45) 65.1 ± 1.3 (66) 85.6 ± 1.3 (11) 86.1 ± 1.3 (10) 70.3 ± 1.6 (56) 67.8 ± 1.3 (76)
68.0 ± 1.0 (69) 64.3 ± 0.9 (115) 84.9 ± 0.5 (30) 84.8 ± 0.5 (30) 73.1 ± 1.1 (99) 68.6 ± 1.0 (145)
70.1 ± 2.1 (16) 69.7 ± 1.9 (19) 85.2 ± 0.8 (11) 85.2 ± 0.8 (11) 76.2 ± 1.9 (27) 75.4 ± 1.8 (30)
0.1 0.3 0.7 0.5 0.02 0.02
a
In parentheses, number of deaths or incidence (onset) cases. Including one colon cancer case diagnosed at 77 years who died at 82 years. c Ex-smokers were excluded from the table, due to the small number of subjects. b
below 79 years of age consuming over 10 cups a day, resulting in an overall delay of cancer death before age 79 in the highest consumption group. The convergence of cancer death rates at very advanced ages implies that the cancer-preventive effects of green tea may be demonstrated, specifically for those who do not reach the average lifespan. Cigarette smoking is the most potent cancer cause in our environment, and it was associated with earlier onset of cancer: mean age at cancer onset was 71.3 ± 1.5 (48 cases) and 67.9 ± 0.7 (220 cases) years old for male non-smokers and smokers, respectively. Since drinking green tea was closely associated with cigarette smoking in lifestyle factors, we needed to determine the effects of green tea by smoking status. (Adjustment for cigarette smoking in relative risk estimation may not be sufficient.) We found a delay of cancer onset or death in both non-smokers and smokers consuming over 10 cups of green tea a day (Table 1), although the result in non-smokers did not reach statistical significance due to the small number of subjects for analysis. 3.2. Age at cardiovascular disease death Serum levels of total cholesterol, triglycerides, and atherogenic index are established biomarkers for predicting the risk of cardiovascular disease, and these increase with age. The lowering effects of drinking green tea on these markers have been observed in the
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Fig. 1. Age-specific cancer death rates among women by daily consumption of green tea on the basis of follow-up data in 1986–1999.
same cohort (Imai and Nakachi, 1995); a further follow-up study showed decreased risk of cardiovascular disease (Nakachi et al., 2000): men consuming over 10 cups a day showed a significantly decreased risk of 0.58 (0.34–0.99), compared with those consuming below three cups; women showed a decreased risk of 0.82 (0.49–1.38); both the sexes had a risk of 0.72 (0.50–1.04). We analyzed the association between age at cardiovascular death and consumption of green tea, using up-dated death data in 1986–1999. Mean age ± S.D. at cardiovascular death was 74.9 ± 2.0 (35 deaths), 76.2 ± 1.3 (77), and 76.8 ± 2.3 (25) for ≤3 cups, 4–9 cups, and ≥10 cups a day among men, respectively; 79.5 ± 1.5 (34), 80.6 ± 1.1 (79), and 80.9 ± 1.6 (31) for ≤3 cups, 4–9 cups, and ≥10 cups a day among women, respectively. Those consuming the largest amounts consistently showed later ages at cardiovascular death in all age groups. 3.3. Age at death from all causes Death from cancer and cardiovascular disease account for 51% of death from all causes, on the basis of follow-up data from our cohort in 1986–1999. We, therefore, examined the influence of drinking large amounts of green tea on age at death from all causes (Table 2). Mean age at death among men or women consuming over 10 cups a day was 4.3 and 3.8 years higher, respectively, than those consuming under three cups a day. The association between increased consumption of green tea and higher ages at death was more clearly observed in ages below 79 among both men and women.
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Table 2 Mean age (±S.E., years) at death from all causes by daily consumption of green tea, on the basis of follow-up data in 1986–1999 Daily consumption of green tea ≤3 cups
4–9 cups
≥10 cups
P for trend
Men Age ≤ 79 Age ≥ 80 All ages
64.8 ± 0.9 (135)a 85.2 ± 0.4 (60) 71.1 ± 0.9 (195)
67.6 ± 0.6 (246) 85.4 ± 0.3 (123) 73.5 ± 0.6 (369)
68.5 ± 0.7 (123) 85.3 ± 0.4 (86) 75.4 ± 0.7 (209)
0.001 0.9 <0.001
Non-smokersb Age ≤ 79 Age ≥ 80 All ages
65.6 ± 2.6 (21) 84.9 ± 0.9 (19) 74.8 ± 2.1 (40)
71.4 ± 1.5 (38) 85.7 ± 0.7 (32) 77.9 ± 1.2 (70)
69.3 ± 2.6 (9) 87.0 ± 1.4 (12) 79.4 ± 2.4 (21)
0.1 0.2 0.1
Current smokers Age ≤ 79 Age ≥ 80 All ages
62.9 ± 1.1 (81) 84.9 ± 0.7 (23) 67.7 ± 1.2 (104)
65.9 ± 0.8 (140) 85.5 ± 0.4 (63) 72.0 ± 0.9 (203)
68.9 ± 0.8 (93) 85.0 ± 0.4 (60) 75.2 ± 0.8 (153)
<0.001 0.8 <0.001
Women Age ≤ 79 Age ≥ 80 All ages
68.4 ± 0.9 (108) 86.7 ± 0.5 (78) 76.1 ± 0.9 (186)
69.2 ± 0.6 (172) 86.5 ± 0.3 (185) 78.2 ± 0.6 (357)
71.8 ± 1.0 (52) 87.3 ± 0.5 (74) 80.9 ± 0.8 (126)
0.03 0.4 <0.001
a b
In parentheses, number of deaths. Ex-smokers were excluded from the table, due to the small number of subjects.
Ages at death among male smokers were lower than those among non-smokers, indicating that cigarette smoking is a potent lifetime-limiting factor probably due to increased risk of cancer and other lifestyle-related diseases, specifically for younger ages: in fact, ages at death by smoking status did not differ at ages over 80. On the other hand, increased consumption of green tea was associated with higher ages at death among both non-smokers and smokers, resulting in the largest difference of over 10 years in mean age at death: 79.4 and 67.7 years for non-smokers drinking over 10 cups a day and smokers drinking less than three cups a day. This result demonstrates the impact of combined prevention against early death based on more green tea and no tobacco. Interestingly, mean age (75.2 years) at death among smokers consuming over 10 cups of green tea a day was almost the same as that (74.8) among non-smokers consuming less than three cups a day, implying the possible prevention of early death among smokers using green tea. 3.4. Cumulative survival Consumption of large amounts of green tea was associated with higher ages at death from all causes, specifically in ages under 80. We next confirmed the effect of green tea on lifetime among women in terms of cumulative survival as a function of age, based on life-table analysis of cohort data (Fig. 2). Our cohort members were aged over 40 at baseline, and hence cumulative survival was estimated starting from age 40. Women consuming over 10 cups a day showed improved survival over other groups consuming smaller amounts; surviving proportion ± S.E. at age 80, for instance, was 74 ± 2, 80 ± 1, or 82 ± 2% for
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Fig. 2. Cumulative proportion surviving (cumulative survival) among women calculated by consumption levels of green tea, using life-tables obtained from follow-up data in 1986–1999.
groups consuming below 3 cups, 4–9 cups or over 10 cups a day, respectively. After age 80, the differences in cumulative survival by consumption levels of green tea decreased. Compared with these differences in cumulative surviving proportion, age-differences for given cumulative survival were relatively small: the difference in ages from 70 to 85 was about 3 years between groups consuming below three cups and over 10 cups a day, with the gap decreasing in more advanced ages. The median survival time (equivalent to average lifespan of women who have already lived to age 40) was 87.1, 88.2 or 89.0 years old for groups consuming below 3 cups, 4–9 cups, and over 10 cups a day, respectively, indicating about two years longer lifetime associated with large consumption of green tea. On the other hand, cumulative survival among men did not show such clear differences by consumption of green tea as were seen in women (data not shown). This is in part due to the deleterious effects of cigarette smoking, which apparently disturbs the beneficial effects of green tea. In fact, when we divided men by smoking status, the life-table analysis among non-smokers showed a similar result to that in Fig. 2: current smokers consuming over 10 cups a day showed the highest survival in ages before 70, and there were no substantial differences in cumulative survival in ages after 70 between the groups consuming over 10 cups and 4–9 cups a day, although smokers consuming below three cups had a much lower survival.
4. Discussion Lifestyle-related diseases, including cancer and cardiovascular disease, are characterized as aging-related diseases, where aging may be the most potent causal factor. In the light of this, the target for prevention of lifestyle-related diseases is the aging process. The average
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lifespan of Japanese is 79 years, one of the highest in the world. Therefore, the Japanese population can serve as a model for the reduction of age-related diseases; using green tea may reduce disease risk among those below (middle to advanced age) or above (very advanced age) the average lifespan, where age-related diseases may be avoidable or unavoidable, respectively. In this paper, we demonstrated the impact of drinking large amounts of green tea on the prevention of cancer and death, on the basis of a prospective cohort study among a Japanese general population. We found an apparent delay of cancer onset/death and all deaths associated with increased consumption of green tea, specifically in ages before 79. This is consistent with age-specific cancer death rates (Fig. 1) and cumulative survival (Fig. 2) by consumption of green tea, indicating a significant slowdown of the increase in cancer death and all deaths along with aging, at least before the average lifespan is reached. These results indicate that daily, large consumption of green tea is beneficial for the avoidance of such pre-mature deaths from cancer and other diseases. In the analyses of prospective cohort studies, we often use relative risk as an index for judging the magnitude of risk enhancement or reduction: a major reason is that relative risk can reveal the influence of confounding factors such as cigarette smoking and alcohol consumption. One of the most popular models for relative risk estimation assumes proportional hazard as functions of follow-up years. However, the longer the follow-up continues, the older the cohort members are. In such cases, appropriate evaluation of green tea as cancer preventive may be difficult since the response to green tea seems to vary by age: aging overcomes environmental influences in very advanced ages beyond the average lifespan, as shown in Fig. 1. Another issue to be considered in the analysis may be the fundamental question of whether the influence of a potent confounder, cigarette smoking, on the effects of green tea can be fully and properly estimated by “adjustment” in multivariate analyses. Our experience revealed that the relative risk of cancer by consumption of green tea estimated among men was vague even after adjusting for smoking, and that other approaches, separating smokers and non-smokers, should be used to evaluate the effects of green tea, along with relative risk estimation. In this paper, we attempted to introduce several approaches along these lines. Our conclusion is that daily large consumption of green tea, specifically 10 cups and over a day, will add a little lifetime to those who have already lived the average lifespan of about 80 years, but it will help to prolong the lifetime of those aged below the average lifespan by avoiding pre-mature death, specifically that caused by cancer. Our final target of prevention is not a specific disease, but a category of diseases, such as all cancer, all lifestyle-related diseases, and all death, since we are not sure which disease will shorten our lifetime or reduce life activity in the future. In the light of this, studies of green tea showed a future of holistic prevention, which aims to realize not perennial youth or disease-free life in very advanced ages, but to delay the aging process and avoid pre-mature death.
Acknowledgements This work was supported in part by Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant from the Smoking Research Foundation.
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