Debate
Received: March 4, 2002
Accepted: April 29, 2002
Gerontology 2002;48:401–407
DOI: 10.1159/000065507
Ageing and Longevity Are Related to
Growth Hormone/Insulin-Like Growth
Factor-1 Secretion
Antonio Ruiz-Torres Marcia Soares de Melo Kirzner
University Research Institute of Gerontology and Metabolism, University Autónoma of Madrid, Madrid, Spain
Key Words
Ageing W Parameters W Longevity W Insulin-like growth
factor-1 W Testosterone W Lean body mass
Abstract
Background: It is known that the growth process is related to an individual’s life-span, but the role of growth hormone (GH) secretion in human ageing remains unknown. Objectives: This study has focussed on the
influence of GH on ageing parameters and on its relationship with human longevity. Methods: To deal with
the first issue, we compared ageing parameters of young
(up to 39) and old (over 70) individuals having similar
insulin-like growth factor-1 (IGF-1) blood levels. For the
second one, the decline in IGF-1 levels was studied comparing its behaviour in the first half with that in the second half of adult life. The latter represents the period of
life in which mortality progressively increases. Two
hundred and five healthy individuals were chosen as
subjects, well distributed by gender and age (between 19
and 93 years). Results: Old males with IGF-1 levels similar to young ones do not show the age-dependent
decrease in serum testosterone and lean body mass, nor
the increase in fat body mass. Other hormone-metabolic
and nutritional parameters do not reveal any change
compared with the results of all individuals. In females,
the results do not allow to assume any IGF-1 influence.
ABC
Fax + 41 61 306 12 34
E-Mail [email protected]
www.karger.com
© 2002 S. Karger AG, Basel
0304–324X/02/0486–0401$18.50/0
Accessible online at:
www.karger.com/journals/ger
The behaviour of the linear regression in the second half
of adult life of males, which becomes flat because old
men having low IGF-1 blood levels die earlier, is consistent with these results. This effect, which is supported by
predictive analysis, is not observed in females, i.e. the
IGF-1 level declines in the second half of the women’s
adult life are only a little flatter than in the first half. Finally, extrapolating the regressions obtained in the first half
of adulthood, the age at which the curve crosses the xaxis is 110 years for males and 132 for females. Conclusion: The presented study of IGF-1 levels suggests that
the GH secretion in adulthood plays a determinant role
not only for some regressive manifestations, but also for
life potential.
Copyright © 2002 S. Karger AG, Basel
Introduction
Human adulthood begins once the biological optimum
has been reached, after the completion of the growth and
differentiation process [1]. The next step is a continuous
organic regression until death. Therefore, if ageing is the
process of structural and functional regression, the process of growth and differentiation would constitute the
opposite. The relationship between life potential and
growing time is well known not only for mammalians. For
example, molluscs or plants live as long as they grow [2].
Prof. A. Ruiz-Torres
Instituto Universitario de Investigación Gerontológica
Diego de León 63
E–28006 Madrid (Spain)
Fax +34 91 520 2292/+34 91 633 1449, E-Mail [email protected]
Moreover, with an increasing growth period, there is also
an increase in life-span, as observed in salmons after castration [3].
The blood levels of insulin-like growth factor-1 (IGF1), which – as is well known – reflect the growth hormone
(GH) secretion, behave similarly to the biological development of the human organism: rising up to a maximum
and then declining continuously as adult age advances [4–
7]. Moreover, a deficiency in GH or IGF-1 seems to be
related to a reduced life expectancy [8, 9], and the experimental administration of GH/IGF-1 increases the lifespan [10]. This relationship between one’s biological state
and GH/IGF-1 secretion has justified its administration
in the elderly [11–13].
In this study, we investigated the role of IGF-1 as a
determinant of the ageing process. On the basis of data
collected from a healthy adult population, we first aimed
to detect the influence of IGF-1 on parameters which
are normally age dependent. Secondly, we investigated
whether IGF-1 levels were related to longevity.
Young
Old
36–46
27–36
20–25
15–20
18–27
10–15
Fig. 1. Scheme of the procedure used to study the influence of IGF-1
secretion on biological parameters. Young (19–39 years) and old (70–
90 years) individuals grouped in similar size samples (pie charts)
were split into thirds each showing a different range of IGF-1 blood
concentration (nmol/l) from high (white slice) to low (dark). Parameters from the third of young individuals having IGF-1 levels within
the lowest range (here represented for males) of 18–27 nmol/l (dark
slice of left pie chart) were compared with those of the third of old
subjects with the highest levels (20–25 nmol/l; white slice, on the
right). Therefore, both groups have similar IGF-1 levels in spite of a
great age difference.
Material and Methods
Material
Laboratory and nutritional data were collected from a welldefined healthy population of 204 persons aged between 19 and 92
years, homogeneously distributed by age and gender (more details on
this population in ref. [14]).
Analytical Procedures
(1) Parameters of a sample of individuals aged between 19 and 39
years grouped by gender were first compared with those of persons
over 70. Then, each sample was split into three homogeneous subgroups according to the different range of IGF-1 levels. The same was
done in the group with the old subjects. The parameters of the young
third showing the lowest IGF-1 levels were compared with those of
the old third having the highest IGF-1 blood concentrations. Figure 1
represents this procedure pointing out the three different IGF-1
ranges of each sample.
(2) After obtaining the age-dependent curve of IGF-1 levels as y =
e(a–bx) for males and females separately, these two population samples
were split into two similar parts according to age, considering that the
cut-off point of 56 years for males and 55 for females was close to the
inflexion point of the original curve. Linear regressions have then
been calculated and the corresponding statistical significance confirmed. The mathematical function obtained for the youngest half
was then used to predict the age-dependent individual evolution of
the measured IGF-1 concentration.
Laboratory and Nutritional Methods
IGF-1 serum determinations were performed by RIA using the
commercially available kit Incstar after extraction through columns
of octadecasilyl-silica. The cross-reaction of the IGF-1 antibody with
IGF-2, GH, TGF and PGF was ! 1%; the coefficient of variation
402
Gerontology 2002;48:401–407
(CV) of the interassay was 10.3%. Total testosterone serum concentration was also obtained by RIA (CV 12.3%). This was also true for
the other determinations whose methodology was mainly based on
standardised techniques for commercial kits. Finally, we measured
the serum concentration of the amino-terminal peptide of procollagen type III (PIIIP) (RIA-gnost Behringwerke, Marburg, Germany),
which in the adulthood behaves as a marker of arterial wall ageing
(see ‘Discussion’). Among other well-known anthropometric measurements, we mainly used the lean body mass (LBM) according to
Forbes and Bruining [15], expressed per metre of body height. The
fat body mass (FBM) was estimated according to Durnin and Womersley [16] on the basis of the mean skinfold thickness over the triceps
and scapula. The individuals’ ages were obtained from their birth
date to the exact moment of the determination time.
Statistic and Demographic Background
The above-mentioned methodological procedures were chosen
after a previous data analysis. Multiple and partial correlations, as
well as discriminatory studies using stepwise multiple regression
were done. The statistical analysis was performed with the help of
the programmes Statgraphics® Version 5.0 and S-Plus® 2000
(Springer). The normal distribution of the results was confirmed by
means of the Kolmogorov-Smirnov test; the data were expressed as
the mean with the standard deviation (SD). The homogeneity
between independent samples was estimated using the t test or
Mann-Whitney U test. All regressions shown here are statistically significant, setting the significance at p ! 0.05. The difference between
regression slopes was calculated according to Armitage and Berry
[17]. We extrapolated mortality data which could be basically
applied to the Spanish population from mortality tables [18] containing data for the last 15 years. The rate of mortality was given as percent of the total number of deaths for all ages.
Ruiz-Torres/Soares de Melo Kirzner
120
NS
NS
NS
NS
NS
NS
100
Percent of values of young subjects
NS
NS
NS
NS
NS
NS
*
****
NS
80
****
****
**
****
***
****
****
****
60
****
40
20
0
R
0
a
0
IGF-1
R
R
0
Testosterone
LBM
R
0
0
Caloric intake
R
R
0
Protein intake
Triiodothyronine
180
**
160
****
**
**
Percent of values of subjects
140
***
**
120
*
**
**
*
*
NS
**
NS
****
*
100
80
60
40
20
0
b
R
0
FBM
R
0
Apo B
R
0
Glucose
R
0
PIIIP
Fig. 2. a Age-dependent parameters which normally show a decreasing behaviour. Results of old individuals (70–92
years old) expressed as percent of the value of the young group (19–39 years old). First column (white = male; whitepointed = female) in reference to the total samples; second column (grey = male; dark = female) when comparing old
individuals with the highest IGF-1 blood concentrations with the young subjects having the lowest levels. Statistical
significance of the difference between the group with the young and the group with the old subjects: * p ! 0.05; ** p !
0.01; *** p ! 0.001; **** p ! 0.0001, NS = not significant. b The same as in a, but for parameters which show an
age-dependent rising behaviour.
Insulin-Like Growth Factor-1,
Ageing and Longevity
Gerontology 2002;48:401–407
403
35
(1) 0
IGF-1 (nmol/l)
30
Fig. 3. Linear regression of IGF-1 levels
with age in males (1) between 19 and 56
years (1a) y = 39.6 – 0.36x (p ! 0.0001) and
between 56 and 92 years (1b) y = 28.06 –
0.12x (p ! 0.05). The same for the female
subjects (2) in the age range from 20 to 55
years (2a) y = 36.97 – 0.28x (p ! 0.005) and
from 55 to 90 years (2b) y = 33.04 – 0.23x
(p ! 0.001). x-Axis crossing point: 110 years
for males and 132 for females.
a
50
25
(1b) 0 Regression 56–92 years
20
(1a)
Extrapolated regression
0 19–56 years
15
10
P–0.05
5
45
40
40
35
35
30
30
25
25
20
20
15
15
10
10
5
5
0
20
IGF-1 levels at age 20
33.3
29.4
8.3
Percent of IGF-1
levels < 35 nmol/l age 20
Fig. 4. The values are obtained from individuals from the following
age ranges: 56–69, 70–79, and 1 80 years. a Theoretic values at the
age of 20 calculated from IGF-1 blood concentrations of males in
their second half of adult life. Mean B SD were related to the age
range of the individual, showing that the higher IGF-1 levels in
youth, the longer the life-span. b In contrast, the percentage of relatively low IGF-1 concentrations (! 35 nmol/l) which those male individuals now in their second half of adulthood should have had in
their youth. However, the frequency drastically decreases in those
persons who reached the highest life-span (1 80).
Results
Compared with young adults, males over 70 clearly
show different values for 9 of the 10 investigated parameters. Nevertheless, as shown in figure 2, these differences
with respect to testosterone, LBM, and FBM practically
disappear when the IGF-1 levels are similar, indicating
that this parameter rather than age is a determinant. No
404
55–90 years
40
60
80
100
120
140
Age (years)
0
0
R Regression
(2a)
0
50
45
(2b)
Extrapolated
regression
R 20–55 years
b
P–0.001
P–0.05
(2) R
Gerontology 2002;48:401–407
influence has been observed for the other parameters with
the exception of apolipoprotein B (apo B) where the loss
of age-dependent differences seems to be due to higher
apo B concentrations in young individuals with low IGF1 levels. In contrast to males, the results in females are not
conclusive. Old females having higher IGF-1 levels do not
show a parameter influence like males. Here, the differences between young and old in testosterone levels and
LBM disappear; but this is related to changes in the young
group itself, as figure 2 for females shows.
In males, the decline in IGF-1 levels with advancing
age is exponential (r = 0.53, r2 = 28%, p ! 0.0001), showing a progressively lower slope from around age 55
onwards. The linear regression obtained for IGF-1 levels
of individuals in their first half of adult life shows a slope
clearly higher than in the case of the second half (fig. 3).
These regressions are statistically significantly different.
In females, the exponential behaviour of the curve is also
clear (r = 0.7, r2 = 70%, p ! 0.0001), but the slope change
is not so drastic, as the linearized regression of both components shows. Furthermore, the regression obtained for
the young population crosses the x-axis at the age of 110
years in males, whereas it does so 12 years later in females
(fig. 3).
Figure 4 represents the longitudinal extrapolation –
back to the age of 20 – of the IGF-1 levels in males of the
last three decades of life. Applying the regression formula
of the first half of adulthood, as mentioned in the methodology, there is an increase in mean values with the age of
measurement. 33.3% of 56- to 69-year-old individuals,
but only 8.3% of over 80-year olds, should have had IGF1 levels bellow 35 nmol/l when they were young.
Comparing the highest with the lowest blood values
measured in males, the age-dependent decline shows dif-
Ruiz-Torres/Soares de Melo Kirzner
Fig. 5. Comparison between the measured highest (r = –0.91, r2 = 83.5 %) and lowest IGF-1 levels at several ages with
the predicted values in males. Stars = Predicted values for the highest concentration measured in youth at several ages;
dark squares = predicted values for the lowest concentration measured in youth.
ferent curves. Figure 5 represents these differences in relation to the progression of mortality. While the age-dependent decrease in the measured highest blood concentration behaves as a linear regression, that of the lowest levels
mimics a power function whose slope factor progressively
diminishes with advancing age. Around age 55 onwards –
when the mortality rate increases – the curve is so flat that
the lowest measured values in older ages remain almost
similar. As figure 5 also shows, when considering the highest IGF-1 concentration measured in several decades of
the second half of adult life, the age-dependent regression
is similar to that obtained from predicted values for young
males with the highest levels. On the contrary, the followup of the lowest value measured in several decades of life
shows no significant decline, but the predicted regression
for the lowest IGF-1 concentration measured in young
individuals declines, reaching the zero point at a relatively early age.
Discussion
The comparison between the gender of the decline in
IGF-1 levels in the whole age range of the studied population between the gender indicates that, as already re-
Insulin-Like Growth Factor-1,
Ageing and Longevity
ported in ref. [19], women show a higher slope than men
(fig. 3). In fact, there are two types of regressions with age:
one corresponding to the first half of adulthood and one to
the second half. The latter is clearly flat in males but not in
females. Our results show that IGF-1 levels in old females
are slightly higher than expected when considering the
slope of decline during the first half of adult life. Furthermore, a dependence of the ageing parameters LBM, FBM
and testosterone on IGF-1 levels is not observed in
females either, in contrast to males. The older these individuals are, the lesser is the decline. The age-dependent
IGF-1 level curve becomes flat, obviously because old
males having low IGF-1 levels die earlier. For this reason,
the evolution of the measured lowest blood concentrations of IGF-1 do not cross a limit. IGF-1 levels influence
the result of the mentioned biomarkers in such a manner
that age seems to lose its determinant character. In this
context, it has to be stressed that LBM, FBM and testosterone levels are related to GH secretion [6, 20]. This
agrees with reports which claim that GH/IGF-1 protects
against ageing manifestations [8, 21–23]. In any case,
especially in males, the decline in GH/IGF-1 secretion
seems to represent the first step within the regression by
ageing.
Gerontology 2002;48:401–407
405
It is known that cross-sectional studies have to take
into account that mortality may affect the result, when
investigating the age dependence of a specific parameter.
For instance, total cholesterol levels increase as age advances, but from around the sixties onwards, a decline
begins due to the fact that persons with higher values die
earlier. The opposite behaviour is observed in those
parameters which decrease with ageing. In both cases, one
assumes that the regression curve has been artificially
modified by mortality. For this reason, we would like to
stress that, since it is very difficult to perform a longitudinal study for the whole adult human life, only that age
range in which mortality does not become important can
be used to estimate the age dependence of cross-sectionally obtained results. This involves the age range from
youth up to mid-adult age. Understandably, the regression curve should be statistically significant to allow a valid extrapolation. We used this method to predict IGF-1
values at later ages. The comparison with corresponding
measured levels shows a consistence in males when considering high concentrations, but not in the case of low
levels. As mentioned above, the lowest IGF-1 levels measured in old males are clearly over those predicted,
obviously because they are selected by mortality.
The differences between males and females could indicate that the latter are less dependent on IGF-1 levels to
survive because the decline in the second part of adult life
has a slope which is only a little flatter than that of the first
half. Nevertheless, the decline measured in the young half
is a little slower in females than in males. In fact, the
extrapolated curve crosses the x-axis (no GH/IGF-1 secretion should exists at this point) at the age of around 110
for males and 132 for females. This crossing point could
indicate the maximal life potential expected in the studied
sample, which is not far from that reported by other
authors [24, 25], where – compared with males – the year
difference in longevity of females is a little over of that
known from demographic studies [26–29].
A clear influence of IGF-1 levels on ageing parameters
has not been detected in females in contrast to males. This
may be due to a less important role of IGF-1 in females’
survival, as discussed above. But on the basis of the results
in males, there are parameters whose behaviour is doubtless IGF-1-independent, as apo B and glucose levels. On
the contrary, these parameters, as total cholesterol and
LDL (not shown), could be related to increasing insulin
resistance, which in some manner is age dependent [30,
31]. Regarding triiodothyronine levels, it is known that
they decrease with age [32–34], but so slightly that, when
comparing two age groups as done in our work, the differ-
406
Gerontology 2002;48:401–407
ences do not reach statistical significance, without showing any relationship with IGF-1 levels. The results remain
unaltered when comparing old with young subjects having similar IGF-1 levels. With respect to the total caloric
and protein intake, the results might be somehow related
to IGF-1 levels in males in contrast to females, but we
were not able to demonstrate this. Many factors are probably involved here.
There are no data on the role of GH/IGF-1 secretion in
collagen III deposition in adulthood, but in the growth
period [35]. On the other hand, blood levels of PIIIP are a
good marker to detect the effect of GH/IGF-1 treatments
[36, 37]. As our results do not show any relationship of
IGF-1 levels with those of PIIIP, we believe that in both
males and females, the increase in PIIIP as adult age
advances is independent of GH secretion. On the contrary, it seems that increasing PIIIP levels during adulthood are related to a parallel enhancement of the insulin
secretion [38].
Concluding, the presented study of IGF-1 levels points
out that the GH secretion in adulthood may play a role as
a determinant of some regressive manifestations and of
life potential and thus seems to be related to longevity.
The results in females, which indicate a lower dependence
on GH than those in males in the ageing process, could
explain why women live longer.
Acknowledgement
This research has been supported by a grant from the Fondo de
Investigaciones Sanitarias (98/0177), Spanish Ministry of Health.
Ruiz-Torres/Soares de Melo Kirzner
References
1 Beier W: Vitalitätskonzept und biologischer Index nach Ries. Z Gerontol 1985;18:357.
2 Jones DS: Sclerochronology: Reading the record of molluscan shell. Am Sci 1983;71:384–
391.
3 Robertson OH: Prolongation of the life span of
kokanee salmon (Oncorhynchus nerka kennerlyi) by castration before beginning gonad development. Proc Natl Acad Sci USA 1961;47:
609–621.
4 Florini JR, Prinz P, Vitiello MV, Hintz RL:
Somatomedin-C levels in healthy young and
old men: Relationship to peak and 24 h integrated levels of growth hormone. J Gerontol
1985;40:2–7.
5 Iranmanesh A, Lizarralde G, Veldehuis JD:
Age and relative adiposity are specific negative
determinants of the frequency and amplitude
of growth hormone (GH) secretory bursts and
half-life of endogenous GH in healthy men. J
Clin Endocrinol Metab 1991;73:1081–1088.
6 Veldhuis JD, Liem AY, South S, Weltman A,
Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson M, Pincus S, Straume M, Iranmanesh A: Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as
assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab 1995;80:
3209–3222.
7 Corpas E, Harman SM, Blackman MR: Human growth hormone and human aging. Endocr Rev 1993;14:20–39.
8 Markussis V, Beshyah SA, Fisher C, Sharp P,
Nicolaides AN, Johnston DG: Detection of
premature atherosclerosis by high-resolution
ultrasonography in symptom-free hypopituitary adults. Lancet 1992;340:1188–1192.
9 Rosén T, Bengtsson BA: Premature mortality
due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285–288.
10 Khansari DN, Gustad T: Effects of long-term,
low-dose growth hormone therapy on immune
function and life expectancy of mice. Mech
Ageing Dev 1991;57:87–100.
11 Rudman D, Kutner MH, Rogers CM, Lubin
M, Fleming GA, Bain RP: Impaired growth
hormone secretion in the adult population: Relation to age and adiposity. J Clin Invest 1981;
67:1361–1369.
12 Rudman D, Feller AG, Nagraj HS, Gergans
GA, Lalitha PY, Goldberg AF, Schlenker RA,
Cohn L, Rudman IW, Mattson DE: Effects of
human growth hormone in men over 60 years
old. N Engl J Med 1990;323:1–6.
Insulin-Like Growth Factor-1,
Ageing and Longevity
13 Marcus R, Butterfield G, Holloway L, Gilliland
L, Baylink DJ, Hintz RL, Sherman BM: Effects
of short-term administration of recombinant
human growth hormone to elderly people. J
Clin Endocrinol Metab 1990;70:519–527.
14 Ruiz-Torres A, Vicent D, Sánchez de Paco G,
Muñoz FJ, Gimeno A, Carraro R: Increase in
insulin secretion with age: Its clinical importance in evaluating abnormal secretions focused on diabetes type II and obesity. Arch
Gerontol Geriatr 1996;22:39–47.
15 Forbes GB, Bruining GJ: Urinary creatinine
excretion and lean body mass. Am J Clin Nutr
1976;29:1359–1366.
16 Durnin VGA, Womersley J: Body fat assessment from total body density and its estimation from skinfold thickness measurements of
481 men and women aged from 16 to 72 years.
Brit J Nutr 1974;32:77–97.
17 Armitage P, Berry G: Statistical Methods in
Medical Research. Oxford, Blackwell Scientific
Publications, 1990.
18 Consejerı́a de Salud (ed): Estadı́sticas del movimiento natural de la población de la Comunidad de Madrid. Madrid, 1991.
19 Landin-Wilhelmsen K, Wilhelmsen L, Lappas
G, Rosén T, Lindstedt G, Lundberg P-A,
Bengtsson B-A: Serum insulin-like growth factor I in a random population sample of men
and women: Relation to age, sex, smoking habits, coffee consumption and physical activity,
blood pressure and concentrations of plasma
lipids, fibrinogen, parathyroid hormones and
osteocalcin. Clin Endocrinol (Oxf) 1994;41:
351–357.
20 Benbassat CA, Maki KC, Unterman TG: Circulating levels of insulin-like growth factor
(IGF) binding protein-1 and -3 in ageing men:
Relationship to insulin, glucose, IGF and dehydroepiandrosterone sulfate levels and anthropometric measures. J Clin Endocrinol Metab
1997;82:1484–1491.
21 Cuneo RC, Salomon F, McGauley GA, Sonksen PH: The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf) 1992;
37:387–397.
22 Salomon F, Cuneo RC, Hesp R, Sonksen PH:
The effects of treatment with recombinant human growth hormone on body composition
and metabolism in adults with growth hormone deficiency. N Engl J Med 1989;321:
1797–1803.
23 Rudman D: Growth hormone, body composition and ageing. J Am Geriatr Soc 1985;33:
800–807.
24 Rosén T, Larsson G, Wilhelmsen L, Bengtssom
BA: Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta
Endocrinol 1993;129:195–200.
25 Hayflick L: Origins of longevity; in Warner
HR, et al (eds): Modern Biological Theories of
Ageing. New York, Raven, 1987, pp 21–34.
26 Allard M, Lébre V, Robine J: Jeanne Calment:
From Van Gogh’s time to ours. New York, WH
Freeman, 1998.
27 Instituto Nacional de Estadistica: Anuario estadı́stico 1981–1997, Madrid.
28 United Nations Demographic Yearbook 1997.
29 Wilmoth JR, Deegan LJ, Lundström H, Horiuchi S: Increase of maximum life-span in Sweden, 1861–1999. Science 2000;289:2366–
2368.
30 Boden G: Pathogenesis of type 2 diabetes. Insulin resistance. Endocrinol Metab Clin North
Am 2001;30:801–815.
31 Larkin LM, Reynolds TH, Supiano MA, Kahn
BB, Halter JB: Effect of aging and obesity on
insulin responsiveness and glut-4 glucose transporter content in skeletal muscle of Fischer 344
x Brown Norway rats. J Gerontol A Biol Sci
Med Sci 2001;56:B486–B492.
32 Gregerman RL, Gaffney GW, Shock NW: Thyroxine turnover in euthyroid man with special
reference to changes in age. J Clin Invest 1962:
41:2065–2074.
33 Dilman CM, Dean W: The Neuroendocrine
Theory of Aging and Degenerative Disease.
Pensacola Center for Bio-Gerontology, 1992,
pp 61–62.
34 Lamberts SWJ, van den Beld AW, van der Lely
A-J: The endocrinology of aging. Science 1997;
278:419–424.
35 Kajantie E, Dunkel L, Risteli J, Pohjavouri M,
Andersson S: Markers of type I and III collagen
turnover as indicators of growth velocity in
very low birth weight infants. J Clin Endocrinol
Metab 2001;86:4299–4306.
36 Longobardi S, Keay N, Ehmborg C, Cittadini
A, Rosen T, Dall R, Boroujerdi MA, Basset EE,
Healy ML, Pentecost C, Wallace JD, Powrie J,
Jorgensen JO, Sacca L: Growth hormone (GH)
effects on bone and collagen turnover in
healthy adults and its potential as a marker of
GH abuse in sports: A double blind, placebocontrolled study. The GH-2000 Study Group.
Clin Endocrinol Metab 2000;85:1505–1512.
37 Guida HJ: How do we best measure growth
hormone action? Horm Res 1997;48(suppl
5):1–10.
38 Ruiz-Torres A: The role of IGF-1 and insulin in
ageing and atherosclerosis; in Veldhuis J (ed):
Endocrine Facets of Ageing in the Human and
Experimental Animal. London, Wiley 2002, pp
143–160.
Gerontology 2002;48:401–407
407