| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 80 === Aging is a deteriorating physiological change accompanied with multiple metabolic dysfunctions. The aberration of lipid metabolism further deterioates with the advance of age and aggregates a number of systemic diseases including atherosclerosis, diabetes mellitus, and cancer, In the study of age-related aberration of lipid metabo-lism, it is crucial to clarify the causes of high prevalence of the above-mentioned diseases in aging.
Adipose tissue plays a critical role in whole body lipid meta-bolism. Recent studies have shown that it is not merely a reservoir of triacylglycerols (TG) .Adipocytes are active in carbohydrate and lipid metabolism and these metabolic events are regulated avidly by hormones. The homeostasis of adipose TG is dependent on three dyna-mio-metabolic events, namely lipogenesis, lipolysis, and re-esteri-fication. plasma free fatty acids (FFA), which are re-esteri-fication. plasma free fatty acids (FFA), which are released from the adipose tissue as lipolytic products or from chylomicron and very low density lipoprotein (VLDL) by the action of lipoprotein lipase, play an important role in lipid mobilization and metabolism. In adult ani-mals, plasma FFA are the major source of fatty acids in TG for the assembly of VLDL in the liver. In this current thesis, the aging eff-ects on lipid metabolim in the rat adipocytes and human plasma FFA metabolim will be investigated.
Adipocytes isolated from young (Y) (8 - wk - old) and aged (A) (81 - wk - old) male Sprague - Dowley rats were chosen to elucidate the aging effect on lipid metabolism. Lipogenesis was measured and compared by the ncorporation of radiolabeled glucose and acetate into TG. Lipolysis was measured by the release of FFA or glycerol after a 30 - minincubation whereas re - esterification was measured by the incorporation of radiolabeled oleic acid into TG. Results showed that lipogenesis was drastically reduced in the aged animals (A, 0.67 ± 0.13; Y, 1.18 ± 0.45%, p < 0.01). Lioplysis was still functioning in adipocytes of aged rats. However, the respective anti - lipolytic and lipolytic responses to maximal insulin (50 nM) (A, 85% of basal; Y, 18% of basal) and isoproterenol (a β- agonist) (10μM) (A, 343 ± 17; Y, 554 ± 35 nmoles / μl cell / 30 min, p < 0.01) were reduced in a differential manner in aoipocytes from aged rats. Re - esterification was not significantly influenced by aging or by insulin. For the route leading to assembly of adipocyte TG, de novo synthesis of saturated fatty acids deteriorated more severely than the acyl elongation and desaturation. The fatty acid (FA) compositions of adipocyte TG and dietary lipids were determined by reversed phase HPLC method. Results showed that the FA composition of adipocyte TG of aged rats, but not from young rats, was very similar to that of dietary lipids. In comparison with young rats, the adipocyte TG of aged rats had lower molar percentage of saturated FA (palmitic acid: A, 15.2 ± 2.0; Y 25.3 ± 4.1%, p < 0.05) and higher molar percentage of polyunsaturated FA (linoleic acid: A, 46.0 ± 3.9; Y, 24.9 ± 4.6%, p < 0.005).
In order to elucidate the aging effects on the plasma FFA metabolism in humans, 12 young (22.5 ± 0.8 yr) and 12 aged (60.9 ± 2.3 yr) normal male volunteers were recruited for the following four studies: (Ⅰ) Insulin suppression test at high (1 mu / kg / min) and low doses (0.4 mu / kg / min) of insulin infusion (Ia and Ib). (Ⅱ) standard meal test. (Ⅲ) Euglycemic clamp study. (Ⅳ) Glucagon test. The results were: (Ⅰ) The steady state plasma glucose (sspG) were significantly higher in the aged subjects (study Ia: A, 157.6 ± 3.7; Y, 122.2 ± 4.2 mg / dl, p < 0.05. study 1b: A, 94.3 ± 3.5; Y, 79.0 ± 6.8 mg / dl, p < 0.05), whereas the suppression rate of steady state serum FFA (SSFFA) were similar between the aged and young groups in study Ia and Ib. (Ⅱ) As compared with the young group during the 8 - hour standard meal test, the aged group''s serum FFA profiles started with a higher fasting FFA level (A, 487 ± 170; Y, 422 ± 114 μM, P < 0.05). followed by suppression to a comparable degree during the initial two hours after the meal, and gradually rose to a higher level throughot the rest four hours. (Ⅲ) The serum FFA levels rose in both groups during the entire euglycemic pancreatic clamp period but the manitude was smaller in the aged group (A, 45%; Y, 98% above basal levels, p < 0.01). (Ⅳ) There was no significant difference in the rate of stimulation of steady state serum FFA between the aged and young groups after glucagon infusion (0.5ng / kg / min).
Based on the observations in animal and human studies, it was concluded: (1). Lipogenesis was drastically imparied, which made reesterification play an increasingly important role in the adipocytes of aged animals. This trend rendered the aged animals to rely on exogenous sources of fatty acids in adipocyte TG assembly. (2) The lower fasting plasma FFA level in aged animals suggested that the resistance to β - adrenergic stimulation on lipolysis may outweigh insulin resistance on anti - lipolysis. (3) In human, the fasting FFA level of the aged group was higher than the young group. It implies that aged people showed impairment of anti - lipolytic effect at the insulin level below ~ 10 μU / ml. However, the anti - lipolytic effect of insulin in aged human subjects remained as sensitive as that in the young group when insulin level is higher than ~ 30 μU / ml. Hyperinsulinemia is evidently the common way in humans and other animals to correct thd impairment of insulin action due to aging.
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