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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M79-M82 (2001)
© 2001 The Gerontological Society of America

Serum Insulin-like Growth Factor-1 in Centenarians

Implications of IGF-1 as a Rapid Turnover Protein

Yasumichi Araia, Nobuyoshi Hirosea, Ken Yamamuraa, Ken-ichirou Shimizua, Michiyo Takayamaa, Yoshinori Ebiharaa and Yasunori Osonob

a Department of Geriatric Medicine, Keio University School of Medicine, Tokyo, Japan
b School of Law, Aoyama Gakuin University, Tokyo, Japan

Yasumichi Arai, Department of Geriatric Medicine, Keio University School of Medicine, P.O. Box 160-8582, 35 Shinanomachi, Shinjyuku-ku, Tokyo, Japan E-mail: yasumich{at}tka.att.ne.jp.

Decision Editor: John E. Morley, MB, BCh


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. It is well documented that serum insulin-like growth factor 1 (IGF-1) levels as well as growth hormone secretion decline with advancing age. Low levels of IGF-1 are shown to be associated with low activity of growth hormone, low lean mass, and high body fat mass; however, in the elderly, the relationship has not been confirmed.

Methods. We studied serum IGF-1 levels in 49 centenarians, who are at the ultimate stage of physiological senescence, and investigated the possible relationship between IGF-1 and body mass index, lipid parameters, nutritional indices, physical and cognitive function, and frequency of hip fracture. As nutritional indices, serum levels of albumin, prealbumin, transferrin, and retinol binding protein were measured. Cognitive function of the centenarians was assessed by clinical dementia rating.

Results. In the centenarians, the mean levels of IGF-1 were relatively low, indicating that there is an age-associated decline in IGF-1 even in the extremely old age. We demonstrated a strong association of IGF-1 with prealbumin and retinol binding protein (r 2 = .192, .195, respectively); however, there was no association with albumin, transferrin, or body mass index. Interestingly, centenarians with lower IGF-1 levels had a higher prevalence of definitive dementia.

Conclusions. These data suggest that serum IGF-1 levels in the centenarians appeared to reflect their short-term nutritional status as a rapid turnover protein. It is also suggested that low levels of serum IGF-1 may be involved in the progression of dementia in the oldest old.

MECHANISMS underlying age-associated change in body composition such as an increase in body fat and a decrease in bone mass are not fully understood. Decrease in growth hormone (GH) secretion and serum insulin-like growth factor-1 (IGF-1) levels with aging may have some impact on these processes. IGF-1 is predominantly synthesized in the liver, and serum levels of IGF-1 are tightly regulated by GH release (1) and are indicated to reflect the integrated 24-hour secretion of GH (2). From results of epidemiological studies and interventional trials using recombinant human GH, serum IGF-1 levels have shown a positive association with muscle strength, lean body mass (3)(4), and physical activity (5), and they have shown a negative correlation with body mass index (BMI) and the body fat index (6)(7). However, in elderly population, serum IGF-1 levels have been reported to have no association with BMI, body fat, or lean body mass, but they have been significantly correlated with nutritional parameters and liver function (8). Moreover, recent epidemiologic studies demonstrated that low serum IGF-1 levels may be associated with increased cardiovascular risk (9) and cognitive impairment (10) in the elderly population. These data suggest that IGF-1 values in elderly persons may not represent their GH activities and determinants of serum IGF-1 levels may differ from middle-aged individuals.

In this study, we examined serum IGF-1 levels of centenarians who have reached extremely old age and who are considered to be natural models for physiological senescence (11). We also determined the relationship between IGF-1 and BMI, nutritional indices, lipid parameters, and physical and cognitive function to clarify a clinical implication of IGF-1 in the oldest old.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
The subjects were 49 centenarians living in Tokyo (14 men and 35 women with a mean age of 100.4 ± 1.1 years). They included 13 patients with hypertension, eight with a history of or treatment for ischemic heart disease, two with a history of cerebrovascular disease, four with malignant tumors (colorectal cancer and prostate cancer in two each), and seven with a history of hip fracture. None were diabetic or used lipid-lowering drugs. Informed consent was obtained from each subject or from close relatives.

Methods
Serum IGF-1 concentrations were determined by radioimmunoassay (RIA). Factors assessed for the influence on serum IGF-1 were BMI, liver function (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and gamma-glutamyl transpeptidase), serum lipids, nutritional indices, and C-reactive protein (CRP). BMI was calculated by dividing the weight (in kilograms) by the square of the height (in square meters). The concentrations of total cholesterol (TC) and triglyceride (TG) were determined by automated enzymatic procedures. The concentrations of high-density lipoprotein cholesterol (HDL-C) were determined by a precipitation method. The concentrations of apolipoprotein A1 (apo A1) and apolipoprotein B (apo B) were determined by turbidimetric immunoassay (TIA). As nutritional indices, the serum albumin, prealbumin, transferrin, and retinol binding protein (RBP) concentrations were determined by standard methods. The activities of daily living (ADL) of the centenarians were assessed with a modified Lawton Scale (12) in terms of six parameters, including walking, eating, dressing, toiletting, bathing, and transferring. A normal status (complete independence) scored 19 points, and zero points meant a bed-ridden status requiring complete assistance. Cognitive function was assessed according to the clinical dementia rating (CDR) scale (13) as follows: 0, no dementia; 0.5, dementia suspected; 1, mild dementia; 2, moderate dementia; and 3, severe dementia. A CDR score of 0 or 0.5 was taken to represent the absence of definitive dementia in the centenarians and a score of 1, 2, or 3 indicated the presence of dementia. The prevalence of dementia was determined from the CDR data.

Statistical Analysis
All results are expressed as mean ± SD. For assessment of the correlations between serum IGF-1 and BMI, liver function, serum lipids, or nutritional indices, simple correlation coefficients were calculated. Based on the use of the median IGF-1 level, the centenarians were divided into high and low IGF-1 groups; parameters obtained were compared between the two groups by using Student's t test or the Mann-Whitney U test as needed. For a comparison of the difference in frequency between the groups, the chi-square test was performed. A p value less than .05 was taken to indicate a significant difference.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Table 1 shows the baseline characteristics of the centenarians. Their BMIs were a low 19.4 ± 3.6, and the serum levels of albumin, prealbumin, transferrin, and RBP were all lower than the normal range, indicating that centenarians in this study were undernourished. However, liver function of the centenarians was within normal range. The mean serum IGF-1 level in the centenarians was 64.4 ± 28.4 ng/ml (68.8 ± 32.5 ng/ml in men and 62.7 ± 26.9 ng/ml in women), showing no sex-related difference. Because sex-related differences were noted for only BMI, the following analyses were performed on the total number of centenarians.


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  		Table 1. Characteristics of Centenarians

 
The centenarians were divided into a high IGF-1 group (n = 25, mean IGF-1 = 83.2 ± 28.2 ng/ml) and a low IGF-1 group (n = 24, mean IGF-1 = 44.9 ± 8.8 ng/ml), based on the median value of serum IGF-1, and the parameters obtained were compared between these two groups (Table 2 ). The two groups did not differ with respect to BMI, serum lipids, liver function, albumin, and transferrin, but the prealbumin and RBP levels were significantly lower in the low IGF-1 group. The ADL score did not differ between the two groups. Prevalence of hip fractures and incidence of dementia were compared between the two groups (Table 3 ). There was no significant difference in the frequency of hip fractures, which may be a consequence of age-associated osteopenia. However, significantly more of the subjects had dementia in the low IGF-1 group ({chi}2 = 4.02, p = .049).


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  		Table 2. Comparison of BMI, Lipid Parameters, Liver Function, Nutritional Indices, CRP, and ADL Score Between Low and High IGF-1 Groups

 

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  		Table 3. Frequencies of Hip Fracture and Dementia According to IGF-1 Level

 
Table 4 shows the simple correlation coefficients (r2) for the serum IGF-1 level versus variables including the serum lipids, liver function, nutritional indices, log-transformed CRP, and the ADL score. No significant correlation was found between the IGF-1 level and BMI in the centenarians. Their serum IGF-1 level was not correlated with any of the lipid parameters or with liver function. Contrary to our prediction, serum IGF-1 levels showed no significant correlation with the levels of serum albumin or transferrin; however, they showed a significant correlation with the levels of prealbumin and RBP (r2 = 0.192, p = .0047; r2 = .195, p = .0043, respectively), which have a relatively short half-life in the blood.


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  		Table 4. Correlations of Body Mass Index, Lipid Parameters, and Nutritional Indices with IGF-1 in Centenarians

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
A number of studies have demonstrated that serum IGF-1 levels as well as GH secretion decline with advancing age; however, only limited data have indicated this in centenarians (14). Compared with the reference value of serum IGF-1 reported by Shimazu and colleagues (15), the serum IGF-1 levels in the centenarians seem to be profoundly lower than those in any other age group, and they appeared to show an age-related decline in IGF-1 even in extremely old age. In this regard, centenarians are considered not to be exceptional individuals, but to be on the extended line of physiological senescence. Paolisso and colleagues (14) examined serum IGF-1 levels of 19 centenarians, and their results that centenarians had a similar IGF-1 level and higher IGF-1/IGFBP-3 molar ratio (IGFBP stands for IGF-binding protein) as compared to aged subjects were not compatible with our results. The reason for the discrepancy is not clear; however, at least partially, it is due to the small sample size of both studies, and to a difference in selection and nutritional status of centenarians.

Together with GH, IGF-1 is an essential factor for human growth, especially for bone growth. IGF-1 also plays a major role in nitrogen balance and muscular metabolism. It has been previously speculated that a decrease in IGF-1 is related to decreased muscle volume, increased body fat (16), decreased bone mineral content (17), and reduced physical activity (4) in the elderly; however, no consistent results have been reported. Harris and colleagues (8) reported from the Framingham study that an age-associated decline in IGF-1 was not related to a change in body composition, but was strongly associated with poor nutritional status. A significant association between IGF-1 and bone mineral density in postmenopausal women has been demonstrated by Langlois and colleagues (17), whereas Collins and colleagues (18) failed to find significant association of these variables. Our data, which showed no association of IGF-1 with BMI, prevalence of hip fracture, or ADL score, did not support the hypothesis that a decline in IGF-1 could contribute to age-associated changes in body composition and physical function. Biological significance of IGF-1 may be altered in the oldest old.

In this study, we emphasize that the serum IGF-1 levels of the centenarians are strongly correlated with the levels of serum prealbumin and RBP, but not with albumin or transferrin. The serum half-life of albumin is approximately 3 weeks, and that of transferrin is 7–10 days, whereas it is 3 days for prealbumin and 12–16 hours for RBP. The serum half-life of IGF-1 is relatively short; however, it is greatly influenced by IGFBPs, mainly IGFBP-3. Although we did not examine any IGFBPs, these data suggested a possible indication of IGF-1 as a marker of acute nutritional deficit, rather than as a marker of chronic undernutrition in the oldest old. The clinical implications of a decreased serum IGF-1 in the very old may be better understood by performing further longitudinal studies that involve IGFBPs and GH secretion.

The present study found a higher prevalence of dementia in the centenarians with lower serum IGF-1 levels. Several investigators reported the positive association between serum IGF-1 level and cognitive function (9)(19). Both IGF-1 and its receptor, the type 1 receptor (IGF-1R), are present in the brain (20)(21) and are involved in brain development (22). IGF-1 is also recognized as a neuronal rescue agent after hypoxic injury (23)(24). Central administration of IGF-1 to adult rats after exposure to transient ischemia reduces neuronal loss (25). As well as apolipoprotein E4, which is a potent risk factor for late onset Alzheimer's disease and may be related to impaired neural repair function, IGF-1 deficit may contribute to neural cell loss later in life. This may also be an interesting theme for future research.

In conclusion, our study demonstrated an age-associated decline in serum IGF-1 levels even in extremely old age. A lower IGF-1 level was not associated with lower BMI, hypoalbuminemia, or poor functional status, but it was highly correlated with a decline in nutritional indices with a short half-life. It may not be relevant to use the serum IGF-1 level as an indicator of GH release in centenarians, but instead the IGF-1 level appeared to reflect its short-term nutritional status as a rapid turnover protein. Further longitudinal studies, including assessment of IGF-1 binding proteins such as IGFBP-3 and the association of IGF-1 with dementia, should be conducted in the future.


   Acknowledgments
 
This study was partially supported by a grant for the Ministry of Health and Welfare for the Scientific Research Project for Longevity and by a grant for a research panel for the sociomedical background of centenarians (Chief, Hisashi Tauchi); aid for research was also provided by the Keio Health Consultation Center.

Received May 25, 2000

Accepted June 14, 2000


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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