Archives of Gerontology and Geriatrics 60 (2015) 178182

Contents lists available at ScienceDirect

Archives of Gerontology and Geriatrics

journal homepage: www.elsevier.com/locate/archger

Aging and chronic disease as independent causative factors for death

and a programmed onset for chronic disease
Liu Hui *
Department of Clinical Immunology, Dalian Medical University, Dalian 116044, China

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 1 June 2014
Received in revised form 27 September 2014
Accepted 5 November 2014
Available online 13 November 2014

To explore the relationship between occurrence of chronic diseases and the aging process, the role of age
in death from disease was assessed by receiver operating curve (ROC) analysis, to quantify differences in
the age compositions between death and survival groups using data for various diseases and from
regions of different socioeconomic status in China. Results showed that the contribution of age to
different diseases was varied. Increase in life expectancy was associated with relatively old age at the
time of death for ve of seven diseases. For cancer and diseases of the circulatory system, increase in life
expectancy was associated with relatively younger age at the time of death. These ndings indicate that
chronic diseases may occur independently of aging and may have a programmed onset pattern.
2014 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Chronic disease
Aging
Programmed onset

1. Introduction
Aging is a complex natural phenomenon, characterized by
decline in structure and function and diminished adaptability and
resistance, ending in death. Diseases are dened as abnormalities in
structure and function of the body caused by extrinsic or intrinsic
factors. Chronic diseases are dened as long-term conditions that
usually have a latent onset; the pathogenesis of several chronic
diseases is yet to be fully understood. Currently, chronic diseases are
rapidly becoming the leading cause of mortality worldwide (Asaria
et al., 2010; Geneau, Legowski, & Stachenko, 2009; Driver, Yung,
Gaziano, & Kurth, 2010), and there is a clear lack of evidence on the
causes of several chronic conditions.
Chronic diseases are considered to be related to aging, because
of their high incidence in the elderly. However, it is not clear
whether aging is a cause or result of chronic disease, since chronic
diseases found in the elderly are also found in young and middleaged individuals. Another belief is that chronic disease develops
independent of aging and only incidentally occurs alongside aging.
A better understanding of this relationship would be benecial in
developing the theoretical basis of strategies for the prevention
and control of chronic diseases.
Both chronic disease and aging could exist as independent
lethal factors. Chronic diseases are manifested by interactions
between genetic factors and external environmental factors
(Hackett et al., 2011; Sugimura et al., 2011; Nobili et al., 2011).

* Tel.: +86 411 86110383; fax: +86 41186110392.

E-mail addresses: liuhui60@sina.com, immunology@dlmedu.edu.cn
http://dx.doi.org/10.1016/j.archger.2014.11.002
0167-4943/ 2014 Elsevier Ireland Ltd. All rights reserved.

Genetic phenotypes may take a long time to be expressed and may

more commonly be expressed in the elderly although it is possible
that in the absence of chronic disease, aging would result in death.
Thus, natural death in the elderly is as likely to originate from a
chronic disease as it is from aging.
With the development of society, the life expectancy at birth
has increased (Ministry of Health, 2011a). Under this condition, if a
disease was a cause for aging and the lifetime for the disease was
prolonged, aging would also be delayed accordingly and the roles
of age in deaths from disease (RAD) should be unchanged.
However, if aging was a cause of the disease, with the prolongation
of age, the lifetime of the disease would also be prolonged and the
RAD for the disease would also be unchanged.
Moreover, if both disease and aging were independent lethal
factors, there would be more deaths from disease alone with
increasing age. This would imply that increase in life expectancy
was associated with relatively younger age at the time of death for
some diseases and relatively old age at the time of death for other
diseases. With the development of medicine, effective treatments
and society would increase the duration of the disease and delay
time of aging. When the prolonged survival time of a disease is
more than or less than the delayed time of aging, the age at death
from this disease would increase or decrease relatively.
Thus, we felt the need to explore the possibility of a denite
relationship between chronic disease and aging based on RAD. In
the present study, we used data on mortality in all age groups from
the census data of mainland China for different years and
established methods to calculate the RADs for different diseases.
China has a rather simple ethnic composition and a wide land
area, but because of an unbalanced economy, there is a large gap

L. Hui / Archives of Gerontology and Geriatrics 60 (2015) 178182

179

Table 1
The age-stratied number of deaths from non-infectious diseases and survival in the monitored population in developed urban areas in 2010 (Chinese Center for Disease,
2012).
Age

0
1
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
>85

Number of deaths

Survivors

8
28
18
28
28
43
95
118
305
520
1061
1489
2227
2214
2283
3068
3520
2647
1678

0
0
0
0
0
1
3
0
3
3
10
16
17
17
21
42
41
47
38

1
1
0
1
0
2
2
7
9
15
46
97
130
134
177
316
435
423
293

7
5
4
4
4
5
5
3
4
4
7
8
10
16
19
15
25
25
26

13
9
3
7
9
8
18
13
23
35
41
43
59
50
56
102
183
225
350

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

4
8
6
6
25
40
64
92
181
422
722
1000
1407
1652
2105
3764
5965
6657
8143

1
5
3
1
5
7
9
10
8
16
44
100
148
215
317
720
1387
1820
2582

6
1
0
2
1
2
7
12
28
71
96
137
128
128
140
187
276
332
377

1
0
0
3
2
7
7
11
16
14
37
38
57
55
79
99
143
145
145

0
0
0
0
1
0
0
1
1
1
0
1
0
2
5
4
12
23
68

0
0
0
2
0
5
4
0
4
4
14
17
13
9
20
20
26
32
47

158
24
5
8
9
11
6
6
6
6
9
7
7
2
3
2
3
3
1

1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

142,183
577,793
720,791
774,441
842,350
970,953
1,123,559
924,455
1,160,999
1,180,697
1,259,161
1,297,986
1,114,317
662,024
467,607
429,114
326,635
175,358
56,223

A: neoplasms; B: benign neoplasms; C: diabetes mellitus; D: endocrine and blood diseases and certain immune system disorders; E: nervous system and mental disorders; F:
diseases of the sense organs; G: diseases of the circulatory system; H: diseases of the respiratory system; I: diseases of the digestive system; J: diseases of the genitourinary
system; K: skin diseases; L: diseases of the musculoskeletal system and connective tissue; M: congenital disease; N: oral disease.

published by the Military Medical Science Press in 2012 (Chinese

Center for Disease, 2012) and the data set of the national disease
mortality surveillance system, 2005, which was edited by the
Chinese Center for Disease Control and Prevention and published
by the Military Medical Science Press in 2009 (Chinese Center for
Disease, 2009). The data in this book were obtained from over
73 million people living in the most developed city and the most
undeveloped rural area of China. The age-stratied number of
survival and deaths that occurred between 1980 and 1989 was
obtained from the previously published literature in Chinese
scientic journals (Ning, Li, & Zhang, 1992; Zhang, 1990; Shao,
1988; Fang, Fu, Xue, & Feng, 1991; Huang, 1993; Tian, Wang,
Zhang, Tang, Huang, & 1984). The underlying causes of death were

among regions that is a result of 30 years of rapid development.

Therefore, this country is ideal for assessing the relationship
between chronic diseases and aging based on socioeconomic status.
Based on the ndings, it was hypothesized that chronic disease
develops independent of aging and has a programmed onset.
2. Methods
2.1. Original data
The raw data were obtained from the data set of the national
disease mortality surveillance system, 2010, which was edited by
the Chinese Center for Disease Control and Prevention and

Table 2
The age-stratied number of deaths from non-infectious diseases and survival in the monitored population in mainland China in 2005 (Chinese Center for Disease, 2009).
Age

0
1
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
>85

Number of deaths

Survivors

54
175
169
222
419
398
567
1266
2458
3679
5659
8404
9570
10,844
13,384
15,222
12,378
7971
4409

13
14
6
12
20
8
20
23
46
64
92
103
101
127
139
163
115
103
58

2
1
2
4
7
17
27
54
97
185
230
456
517
690
1027
1278
1194
801
523

30
32
16
20
27
25
17
27
35
41
50
72
60
45
72
84
81
54
64

54
67
55
57
105
95
128
187
229
215
204
268
231
198
302
517
693
768
886

0
0
0
0
2
0
0
1
0
0
0
0
0
0
3
2
2
7
9

59
37
34
48
144
242
395
757
1557
2673
4153
6834
8754
11,718
18,184
26,689
29,327
28,610
25,590

22
5
5
5
21
38
65
132
241
376
631
1174
1956
3362
6171
10,612
12,861
13,137
11,996

183
93
18
21
42
66
98
212
363
489
633
850
891
956
1240
1643
1518
1398
1194

6
14
19
32
79
87
139
201
309
292
291
395
435
457
619
723
817
630
582

3
2
0
0
10
3
10
11
14
12
14
10
13
9
20
44
37
56
97

2
1
2
12
20
22
15
24
28
53
36
73
68
78
120
156
177
134
111

1399
294
93
99
108
80
48
58
37
35
22
18
10
7
7
17
10
7
10

22
2
0
0
0
1
0
1
2
1
1
2
1
3
1
1
0
0
2

716,241
3,048,289
4,616,341
6,436,211
5,943,307
5,495,536
6,351,590
6,966,702
6,351,777
5,235,550
5,076,470
4,099,566
3,099,462
2,507,405
2,119,081
1,609,793
1,031,507
553,188
319,261

A: neoplasms; B: benign neoplasms; C: diabetes mellitus; D: endocrine and blood diseases and certain immune system disorders; E: nervous system and mental disorders; F:
diseases of the sense organs; G: diseases of the circulatory system; H: diseases of the respiratory system; I: diseases of the digestive system; J: diseases of the genitourinary
system; K: skin diseases; L: diseases of the musculoskeletal system and connective tissue; M: congenital disease; N: oral disease.

L. Hui / Archives of Gerontology and Geriatrics 60 (2015) 178182

180

Table 3
The age-stratied number of deaths from non-infectious diseases and survival in the monitored population in mainland China during 19801989.
Age group

09
1019
2029
3039
4049
5059
6069
7079
>80

Number of deaths

Survivors

Cancer (Ning et al., 1992;

Zhang, 1990; Shao, 1988;
Fang et al., 1991;
Huang, 1993)

HD (Huang, 1993;
Tian et al., 1984)

CVD
(Huang, 1993;
Tian et al., 1984)

463
797
1525
4090
7370
17,710
22,452
14,714
3801

0
0
1
23
87
262
682
1063
735

0
0
12
56
190
815
1788
2503
1327

1,932,594
2,418,681
1,924,891
1,552,163
972,288
838,664
545,949
261,948
64,179

HD: heart disease; CVD: cerebrovascular disease.

classied according to the International Classication of Diseases

(ICD)-10 codes (WHO, 1992) in order to determine the mortality
statistics. The raw data are presented in Tables 13.
According to the data we collected, the life expectancy at birth
in developed urban populations was 79.4 years in 2010; the life
expectancy at birth in mainland China was 73.0 years in 2005 and
68.3 years in 1986. Nutritional deciencies accounted for 0.74 of
0.1 million deaths (standardized rate) in the developed urban
population in 2010 and for 1.49 of 0.1 million deaths (standardized
rate) in mainland China in 2005 (Ministry of Health, 2011a;
Chinese Center for Disease, 2012, 2009).
2.2. Assessment of the role of age in deaths caused by chronic diseases
The age-stratied number of deaths from non-infectious
diseases (death group) and number of survivors (survival group)
in the monitored population were collected (Tables 13).
Receiver operating characteristic (ROC) analysis (Florkowski,
2008) was used to quantify differences in age compositions
between the death and survival groups for each disease
(neoplasms, diseases of the circulatory system, diseases of the
respiratory system, diseases of the digestive system, diseases of the
genitourinary system, diabetes mellitus, nervous system and
mental disorders).
Assuming an age as a cutoff value, ages above the cutoff value
were considered to be positive while ages below that were
considered to be negative; the positive value in death group was
considered as true positive while that in survival group was
considered as false positive. The difference between true positive
rate (sensitivity) and false positive rate (1-specicity) could be
considered as RAD in a certain age; the sum of difference between
true positive rate and false positive rate in each age group could be
considered as RAD in all age groups. The area under the curve
(AUC) from ROC analysis was considered to indicate RAD.
AUC was not used as a quantitative indicator of RAD. The RAD
value was calculated using the following formula:

age who died (true positive rate, sensitivity). An AUC value of

0.5 meant that age had no effect on death; an AUC value above
0.5 meant that age had a greater effect on death than cancer.
Congenital malformation, which is mainly caused by genetic
factors, is not a typical chronic disease; therefore, it was not
analyzed in this study. Benign neoplasms, endocrine and blood
diseases and certain immune system disorders, sensory diseases,
skin diseases, diseases of the musculoskeletal system and
connective tissue, and oral disorders, which caused less than
500 deaths in the monitored population, were also not analyzed
because of the small number of cases. A total of 7 types of common
chronic diseases that cause the death of the patient were analyzed
in this study.
The signicance of the differences was determined by
independent-sample t-tests. Data were considered to be signicant
if the probability of a type I error was <0.05. The calculation was
performed using the Windows version of SPSS (Statistical Package
for Social Sciences) 13.0.
3. Results
The changes in RAD during different years are summarized in
Tables 4 and 5. The contributions of age to different diseases were
varied; the RAD value for the seven diseases studied ranged from
0.658 to 0.928. The differences of RAD values were relatively small
for the same chronic disease irrespective of the time period and

RAD ROC area  0:5  2:

In this way, the RAD value always ranged from zero to one. A
positive RAD value meant that age had an effect on death from
chronic disease, and the larger the value, the stronger was the
effect.
ROC analysis was used to calculate the contribution of age to
death caused by tumors in 2005 for example, and the ndings are
shown in Fig. 1. The X-axis represents the rate of individuals with
over cutoff age who survived (false positive rate, 1-specicity),
while the Y-axis represents the rate of individuals with over cutoff

Fig. 1. ROC analysis of the contribution of age to deaths caused by tumors in 2005.

L. Hui / Archives of Gerontology and Geriatrics 60 (2015) 178182

Table 4
Changes in the contribution of age to different diseases during different periods.
Diseases

RAD value

2005

2010

Neoplasms
Diabetes mellitus
Nervous system and
mental disorders
Diseases of the
circulatory
system
Diseases of the
respiratory system
Diseases of the digestive
system
Diseases of the genitourinary
system

0.77  0.001
0.83  0.001
0.66  0.003

0.75  0.001
0.85  0.002
0.75  0.006

20
10
15

<0.0001
<0.0001
<0.0001

0.88  0.001

0.87  0.001

10

<0.0001

0.92  0.001

0.93  0.001

10

<0.0001

0.74  0.002

0.78  0.004

10

<0.0001

0.70  0.002

0.78  0.006

13

<0.0001

social environment factors. That RAD value tended to decrease

with the development of society was observed in the case of
ischemic heart disease, cerebrovascular disease and cancer;
however, a reverse trend was observed in other diseases.
4. Discussion
We studied differences in age compositions of the death and
survival groups. The RAD values obtained from the ROC analysis
eliminated the effect of young age composition on survival;
moreover, the overall number of deaths had no inuence on RAD.
Therefore, RAD was suitable for comparisons between different
years, different areas, and different diseases. The more the number
of deaths in the older age group for a certain disease, the larger was
the RAD value, indicating a relatively older age at death as a result
of the disease. Relatively older age at the time of death from certain
diseases could imply that prolonged survival time for this disease
was more than the delayed time of aging; conversely, relative
younger age at death from certain diseases could imply that the
prolonged survival time for the disease was less than the delayed
time of aging.
Our results show that although the differences of RAD values
were relatively small for the same chronic disease irrespective of
the time period and social environmental factors, the age at the
time death increased with the development of society for ve of
seven diseases (nervous system and mental disorders, diseases of
the genitourinary system, diseases of the digestive system,
diabetes mellitus, and diseases of the respiratory system). The
RAD values for neoplasms and circulatory system diseases became
relatively lower. These results suggest that chronic disease is an
independent factor that is not related to aging.
To further prove our hypothesis, we focused on the demographics for cancer, heart disease and cerebrovascular disease,
because the RAD values for these three diseases were almost
constant under differing socioeconomic conditions and they
account for more than 60% of the deaths in China (Ministry of
Health, 2011b). By comparing data over a long period, from 1986 to
2010, we clearly saw a tendency toward reduced RAD with the
development of society. Accordingly, we speculated that, with the
development of society and the increase in the average life
Table 5
Changes in the contribution of age to three diseases during different periods.
Diseases

RAD value
1985

2010

Heart disease
Cerebrovascular disease
Cancer

0.92  0.001
0.91  0.001
0.77  0.001

0.88  0.001
0.87  0.001
0.75  0.001

40
40
20

<0.0001
<0.0001
<0.0001

181

expectancy, aging would be further delayed. For diseases with

relatively less control measures, e.g. cancer, age at death would be
relatively lesser and RAD would be further reduced. For diseases
with relatively more control measures, with the development of
society and the advances in medical technology, age at death
would be relatively greater and RAD would further be increased.
Chronic disease was found to be independent of aging; it therefore
follows that the incidence of many chronic diseases would increase
with prolonged life span.
It was generally believed that related-aging inammation
(inammaging) could contribute to age-associated diseases
(Campisi & Robert, 2014; Franceschi & Campisi, 2014; Davalos
et al., 2013); in this case, the RAD for a chronic disease would be
unchanged with the development of society and prolongation of
life expectancy. Unexpectedly, RAD value tended to decrease with
the development of society for the major chronic diseases
(Table 5). Based on this nding, we propose that chronic diseases
have programmed onset. Genetic phenotypes of chronic disease
would be expressed during the course of life or a certain years,
possibly midway through lifetime, and all genetic phenotypes may
not be expressed in the course of an individuals life. Increased life
expectancy with the development of society means delayed aging
and longer survival time; thus, the occurrence of diseases whose
genetic phenotypes are expressed relatively late in lifetime would
increase and appearance of relative older age at the time of death
from these diseases, while the occurrence of other diseases whose
genetic phenotypes are expressed relative early in lifetime would
remain the same and appearance of relative younger age at the
time of death from these diseases because of delayed aging and
longer survival time. It is now clear that cellular senescence is an
essential tumor-suppressive mechanism (Velarde, Demaria, &
Campisi, 2013; Freund, Laberge, Demaria, & Campisi, 2012;
Laberge et al., 2012); our nding that RAD for cancers decreased
with delay of aging also supported this opinion.
Based on our hypothesis, we think that effective measures
should include controlling disease and delaying aging. At present,
aging may still be the main reason for the death of chronic disease
since that relative old ages at death were found for 5 among
7 diseases with the development of society; therefore, increasing
the basal health status might be a principal measure to prolong
survival time. In addition, advances in medical technology are
important for improving the survival period for patients with
cancer and circulatory system diseases.
Conict of interest
None declared.
References
Asaria, P., Beaglehole, R., Chisholm, D., Gaziano, T. A., Horton, R., Leeder, S., et al. (2010).
Chronic disease prevention: The importance of calls to action. International Journal
of Epidemiology, 39(1), 309310.
Campisi, J., & Robert, L. (2014). Cell senescence: Role in aging and age-related diseases.
Interdisciplinary Topics in Gerontology, 39, 4561.
Chinese Center for Disease Control and Prevention (2009). Data set of the national
disease mortality surveillance system, 2005. China: Military Medical Science Press.
Chinese Center for Disease Control and Prevention (2012). Data set of the national
disease mortality surveillance system, 2010. China: Military Medical Science Press.
Davalos, A. R., Kawahara, M., Malhotra, G. K., Schaum, N., Huang, J., Ved, U., et al. (2013).
p53-Dependent release of Alarmin HMGB1 is a central mediator of senescent
phenotypes. The Journal of Cell Biology, 201(4), 613629.
Driver, J. A., Yung, R., Gaziano, J. M., & Kurth, T. (2010). Chronic disease in men with
newly diagnosed cancer: A nested case-control study. American Journal of Epidemiology, 172(3), 299308.
Fang, T., Fu, J., Xue, Z., & Feng, W. (1991). Analysis on the mortality of malignant tumors
in Xiacheng district of Hangzhou. Zhejiang Journal of Preventive Medicine, 1, 1921.
Florkowski, C. M. (2008). Sensitivity, specicity, receiver-operating characteristic
(ROC) curves and likelihood ratios: Communicating the performance of diagnostic
tests. The Clinical Biochemist Reviews, 29(Suppl. 1), S83S87.

182

L. Hui / Archives of Gerontology and Geriatrics 60 (2015) 178182

Franceschi, C., & Campisi, J. (2014). Chronic inammation (inammaging) and its
potential contribution to age-associated diseases. The Journals of Gerontology. Series
A, Biological Sciences and Medical Sciences, 69(Suppl. 1), S4S9.
Freund, A., Laberge, R. M., Demaria, M., & Campisi, J. (2012). Lamin B1 loss is
a senescence-associated biomarker. Molecular Biology of the Cell, 23(11),
20662075.
Geneau, R., Legowski, B., & Stachenko, S. (2009). An intersectoral network for chronic
disease prevention: The case of the Alberta healthy living network. Chronic Diseases
and Injuries in Canada, 29(4), 153161.
Hackett, T. L., Stefanowicz, D., Aminuddin, F., Sin, D. D., Connett, J. E., Anthonisen, N. R.,
et al. (2011). Effect of gene environment interactions on lung function and
cardiovascular disease in COPD. International Journal of Chronic Obstructive Pulmonary Disease, 6, 277287.
Huang, S. (1993). Analysis on the mortality of malignant tumors, heart disease and
cerebrovascular disease in Xicheng district of Chengdu from 1986 to 1990. Journal
of Preventive Medicine, (1), 6263.
Laberge, R. M., Zhou, L., Sarantos, M. R., Rodier, F., Freund, A., de Keizer, P. L., et al.
(2012). Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell, 11(4), 569578.
Ministry of Health of the Peoples Republic of China (2011a). Year book of public health in
the Peoples Republic of China in 2011. China: Peking Union Medical College Press.

Ministry of Health of the Peoples Republic of China (2011b). Year book of public health
in the Peoples Republic of China in 2011. China: Peking Union Medical College Press.
Ning, G., Li, Y., & Zhang, M. (1992). Analysis on the mortality of malignant tumors
within a two-decade in Jilin province. Journal of Practical Oncology, (1), 6468.
Nobili, S., Bruno, L., Landini, I., Napoli, C., Bechi, P., Tonelli, F., et al. (2011). Genomic and
genetic alterations inuence the progression of gastric cancer. World Journal of
Gastroenterology, 17(3), 290299.
Shao, S. C. (1988). Analysis on the mortality of malignant tumors within a decade in Yin
county. Journal of Oncology, 3, 2933.
Sugimura, H., Tao, H., Suzuki, M., Mori, H., Tsuboi, M., Matsuura, S., et al. (2011).
Genetic susceptibility to lung cancer. Frontiers in Bioscience, 3, 14631477.
Tian, Z., Wang, W., Zhang, L., Tang, W., & Huang, F. (1984). Analysis on the mortality in
Tianjin residents from 19761982. Chinese Journal of Health Statistics, 1(1), 1922.
Velarde, M. C., Demaria, M., & Campisi, J. (2013). Senescent cells and their secretory
phenotype as targets for cancer therapy. Interdisciplinary Topics in Gerontology, 38,
1727.
World Health Organization (1992). International statistical classication of diseases
and related health problems, tenth Revision. Geneva, Switzerland: World Health
Organization.
Zhang, Y. (1990). Analysis on the mortality of malignant tumors in 1988 in Xianju
county. Journal of Oncology, (3), 811.