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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 499-502
Copyright © 1998 by The Endocrine Society

Original Studies

The Insulin-Like Growth Factor Axis and Plasma Lipid Levels in the Elderly1

Gian Paolo Ceda, Elisabetta Dall’Aglio, Andrea Magnacavallo, Nicola Vargas, Vittorio Fontana, Marcello Maggio, Giorgio Valenti, Phillip D. K. Lee, Raymond L. Hintz and Andrew R. Hoffman

Cattedra di Geriatria (G.P.C., A.M., N.V., V.F., M.M., G.V.) e Cattedra di Scienza dell’Alimentazione (E.D.), Università di Parma, Parma, Italy; Diagnostic Systems Laboratories, Inc. (P.D.K.L.), Webster, Texas 77598; the Departments of Pediatrics (R.L.H.) and Medicine (A.R.H.), Stanford University, Stanford, California 94305; and Geriatric Research, Education, and Clinical Center, Veterans Administration Palo Alto Health Care System (A.R.H.), Palo Alto, California 94304

Address all correspondence and requests for reprints to: Dr. Gian Paolo Ceda, Cattedra di Geriatria, Università di Parma, Ospedale G. Stuard, Via Don Bosco 2, 43100 Parma, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The activity of the hypothalamic-GH-insulin-like growth factor (IGF) network declines with age. It has recently been shown that increased cardiovascular mortality occurs in adults with GH deficiency. As hypercholesterolemia is common in GH-deficient adults, and because there is experimental evidence that GH may play a role in regulating plasma cholesterol, we decided to investigate the activity of the GH-IGF axis in an elderly population by measuring serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and to study their relationship with blood lipid levels. One hundred and thirty-two elderly subjects, 52 men and 80 women, were studied (age range, 60–91 yr). Men had significantly lower levels of IGFBP-3, high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) compared to the women, whereas IGF-I and IGF-II were only slightly lower. Using linear regression analysis, we observed an inverse relationship of age with IGF-I (r = -0.35; P < 0.001), IGF-II (r = 0.40; P < 0.001), IGFBP-3 (r = 0.52; P < 0.001), body mass index, and lipid levels. Univariate regression analysis showed a strong and positive correlation of both IGF-I and IGFBP-3 with HDL-C and ApoA1. Partial correlation analysis, after adjustment for age and body mass index, showed that IGFBP-3 and IGF-II were still significantly and positively related to HDL-C and ApoA1. Furthermore, a strong association was documented among IGF-I, IGF-II, and IGFBP-3. These data demonstrate that even in an elderly population, further aging is accompanied by a progressive decline in circulating IGF-I, IGF-II, and IGFBP-3, suggesting a continuing diminution of the GH-IGF axis throughout aging. Moreover, the strong correlation between HDL-C and an index of GH secretion, such as IGFBP-3, suggests that GH might play an important role in lipid metabolism in healthy elderly subjects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH SECRETION declines dramatically with advancing age (1, 2). The reduced activity of the GH-insulin-like growth factor (GH-IGF) axis leads to a condition known as the somatopause (3), which is characterized by a decrease in lean body mass and an increase in adipose mass, osteopenia, muscle atrophy, reduced exercise tolerance, and changes in the plasma lipoprotein profile. These alterations are similar to those observed in younger adult patients with GH deficiency (4). In these subjects there are signs and symptoms that define a GH deficiency syndrome, including central adiposity, an increased waist/hip ratio, and decreased muscle strength and exercise performance. Furthermore, in these patients hypercholesterolemia and increased low density lipoprotein cholesterol (LDL-C) levels have frequently been observed (5, 6, 7). GH deficiency has been associated with an increased risk of death due to cardiovascular disorders (8), an observation that might indicate a role for GH in the control of lipoprotein metabolism.

GH therapy has been shown to lower plasma cholesterol in patients with hypercholesterolemia (7, 9). Plasma IGF-I has been shown to correlate inversely with LDL-C in women with mildly elevated cholesterol levels, hypothyroid women, and normal elderly individuals (10, 11, 12), whereas IGF-binding protein-1 (IGFBP-1) has been found to be correlated with LDL (13). In the rat, GH has effects on serum levels of total cholesterol, LDL-C, apolipoprotein B (ApoB), and ApoE as well as on hepatic secretion of triglycerides (TG), ApoB48, ApoB100, and ApoE (14, 15, 16, 17, 18). Furthermore, GH and IGF-I increase macrophage uptake and degradation of LDL (19), and GH plays a role in the regulation of hepatic LDL receptors (20).

Therefore, we decided to investigate the activity of the GH-IGF axis in a cohort of normal elderly subjects by correlating IGF-I, IGF-II, and IGFBP-3 levels with plasma lipid levels.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
One hundred and thirty-two healthy elderly subjects (52 men and 80 women), 60–91 yr of age, were examined. The subjects were out-patients living at home with their families, who were referred for minor physical problems, such as mild disease of the respiratory system, borderline systolic hypertension, or degenerative joint diseases. All subjects had normal renal and liver function, as documented by a normal physical examination, electrocardiogram, and blood chemistry panel. Each subject was within 20% of ideal body weight. No subject was known to have consumed excessive alcohol, and none was taking any medication known to influence central nervous system and pituitary function or to alter plasma lipid levels, such as ß-blockers, diuretics, or lipid-lowering drugs. All patients had normal thyroid function tests, and none of the women was currently taking estrogen replacement therapy for the menopause.

All subjects gave informed consent to the study, and the protocol was approved by the local ethics committee of the University of Parma. After an overnight fast, a blood sample was drawn between 0800–0900 h. Serum was separated and stored at -70 C.

IGF-I and IGF-II were assayed by RIA after acid chromatography of the samples to separate the IGF peptides from the IGFBPs (21). Serum (0.3–1 mL) was introduced into a 100 x 0.9-cm column of Sephadex G-50 and eluted with 0.25 mol/L formic acid at room temperature. The IGF fraction (Kd, 0.43–0.68) was lyophilized and reconstituted in the appropriate assay buffer. IGFBP-3 was measured by RIA using reagents provided by DSL (Webster, TX).

Total cholesterol, high density lipoprotein cholesterol (HDL-C; after precipitation of very low density lipoprotein and LDL with phosphotungstic acid and magnesium ions), and TG were assayed by enzymatic-colorimetric reactions with reagents provided by Boehringer Mannheim (Mannheim, Germany). LDL-C was calculated using the Friedwald formula. ApoAI and ApoB were determined with a turbidimetric method (Turbiquant, Istituto Behring, Scoppito, Italy).

Statistical analysis was performed using an SAS software package (SAS Institute, Cary, NC). Analytical methods included routine descriptive statistics, simple correlations, partial correlations, unpaired t test, and repeated measures ANOVA. Normality test was applied to all of the variables, and only body mass index (BMI), IGFBP-3, and ApoA were normally distributed. Spearman correlations were used to assess the crude associations between the variables without making assumptions about normality of the data. Pearson’s partial correlation coefficients were also performed on log-transformed values, which better approximate a normal distribution.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Although no difference in the mean age, BMI, cholesterol, and TG values between male and female subjects was observed, HDL-C and ApoA1 levels were significantly lower in the men, indicating that sex differences in lipid metabolism are maintained even in the elderly subjects. Men also showed significantly lower IGFBP-3 levels, and IGF-I and IGF-II levels were slightly, but not significantly, lower than those in the women (Table 1Go).


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  		Table 1. Mean ± SD of the examined parameters

 
The influence of age on the various parameters was investigated using linear regression analysis (Table 2Go). A strong negative correlation of age with IGF-I, IGF-II, and particularly IGFBP-3 was documented. There was also a negative correlation between age and BMI; this was due to significantly lower BMI values of the octogenarians (data not shown). Total cholesterol and HDL-C levels declined significantly with age, whereas LDL-C and ApoB were not significantly affected by aging.


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  		Table 2. Linear regression coefficients (r) and P values between age, BMI, and the other measured variables

 
When BMI was the dependent variable, and all of the other parameters were the independent covariates, as expected, a positive correlation with total cholesterol and TG, and a negative correlation with HDL-C were observed (Table 2Go). BMI was not correlated with any of the growth factors studied.

IGFBP-3 and, to a lesser extent, IGF-I were positively correlated with HDL-C (Fig. 1Go) and ApoA1, whereas IGF-II was positively associated with all lipid values, with the strongest correlations recorded again for HDL and ApoA1 (Table 3Go). Partial correlation analysis after adjustment for age and BMI (Table 4Go) showed that IGFBP-3 was still significantly and positively related to HDL-C and ApoA1, whereas the IGF-I correlation was lost. IGF-II, however, remained significantly correlated with total cholesterol, HDL, and LDL levels. Furthermore, a very strong association was documented among IGF-I, IGF-II, and IGFBP-3. Therefore, if IGFBP-3 is considered to be an index of GH secretion, the positive associations documented in this study with HDL-C suggest that GH as well as IGF-II might play a role in lipid metabolism during aging.



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  		Figure 1. Relationship between HDL-C and IGFBP-3 levels.

 

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  		Table 3. Linear regression coefficients (r) and P values between IGFBP-3, IGF-I, and IGF-II and the other measured variables

 

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  		Table 4. Partial correlation coefficients, after adjustment for age and BMI, between IGF-I, IGF-II, and IGFBP-3 and the other measured variables

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Previous cross-sectional studies in adult subjects have demonstrated that the levels of IGF-I decline with advancing age (1, 2, 22, 23, 24, 25), attaining values in the seventh decade 40–50% lower than those recorded in young subjects. We demonstrate that even in an old population, aging is accompanied by continuously declining levels of IGF-I. There is a parallel decline in the levels of IGFBP-3, a GH-dependent protein, which is the major IGFBP in the circulation (22). Previous studies have clearly demonstrated that aging is associated with a decrease in both the 24-h integrated GH values and the mean pulse amplitude and duration (26). Furthermore, an age-related decline in the responsivity to GHRH stimulation has been reported (27). Although these data seem to suggest a GH dependency of age-related declines in IGF-I and IGFBP-3, other hypotheses cannot be excluded. As the production of both IGF-I and IGFBP-3 is also nutritionally regulated (22), the presence of subtle nutritional and metabolic alterations in the very elderly might have played a causative role in the progressive decrease in IGF and IGFBP-3 levels. We also observed a slight decline in BMI in the octogenarians. The observation that the levels of IGF-II, which are far less GH dependent, decline continuously with aging does not contradict this interpretation. The reduction of IGF-II levels could be secondary to the reduction of IGFBP-3, which is the principal binding protein in the blood for both IGF-I and IGF-II. It is also possible that the age-related decline in IGF and IGFBP levels occurs independent of changes in the hypothalamic-somatotroph axis.

It is known that with aging there is a decline in both gonadal and thyroid function (28, 29). As both testosterone and thyroid hormones play an important role in IGF-I synthesis (30, 31), it is possible that the reduced levels of these hormones might also play some role in the declining activity of the GH-IGF axis with aging. In our subjects, thyroid hormone levels were normal, whereas testosterone levels were not assayed due to limitations of the volume of phlebotomy.

We then examined the relationships between plasma lipid levels and IGF-I, IGF-II, and IGFBP-3 levels. It has become increasingly evident that GH deficiency in the adult population is accompanied by hypercholesterolemia (4, 7, 32) and clinical evidence of premature vascular disease (33, 34). Furthermore, GH treatment in these patients has been shown to reduce lipid levels (7, 35, 36) and, in some studies, to increase HDL-C levels (9, 36). The mechanisms underlying the favorable effects of GH on lipid and lipoprotein metabolism in GH deficiency are not completely understood. GH stimulates LDL-C catabolism and influences lipoprotein lipase activity either directly (37) or through modulation of the activities of other hormones (9).

The demonstration in our study of a positive relationship of IGFBP-3 and IGF-I with HDL-C and ApoA1 levels would suggest a favorable effect of GH treatment on plasma lipid levels even in the old subjects. In fact, when the confounding effects of age and BMI were corrected, both IGFBP-3 and IGF-II showed positive correlations with HDL-C, suggesting that during aging, higher levels of IGFs are accompanied by a less atherogenic plasma lipid profile. This hypothesis is supported by the observation that adult patients with GH deficiency have lower HDL-C levels and higher TG levels than age-matched controls (38).

In conclusion, the present study demonstrates that even in an elderly population, further aging is accompanied by a progressive decline in circulating IGF-I, IGF-II, and IGFBP-3, suggesting a continuing diminution of GH secretion throughout aging. This decrease has been previously reported for IGF-I and IGFBP-3, but not for IGF-II, and the role of IGF-II in lipid metabolism deserves further investigation. Moreover, the strong correlation between HDL-C and an index of GH secretion, such as IGFBP-3, suggests that GH might play an important role in lipid metabolism in healthy elderly subjects. It will be important to examine lipoprotein and lipid metabolism, therefore, in elderly subjects who receive long term GH therapy for treatment of the somatopause.


   Acknowledgments
 
The authors thank Ms. M. Calinosi for her excellent secretarial assistance, and Dr. F. Ablondi for his excellent technical assistance.


   Footnotes
 
1 This work was supported in part by NIH Grant AG-10999 and the Research Service of the Department of Veterans Affairs. Back

Received March 25, 1997.

Revised September 15, 1997.

Accepted October 9, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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