Regulation of Serum Cholesterol Level in Middle-Aged and Elderly Men. Relation of Cholesterol Absorption and Synthesis to Lipoprotein Metabolism

Transcription

1 694 Regulatin f Serum Chlesterl Level in Middle-Aged and Elderly Men Relatin f Chlesterl Absrptin and Synthesis t Lipprtein Metablism Helena Gylling, Tim Strandberg, Reij Tilvis, Tatu A. Miettinen Abstract The aim f the present study was t investigate chlesterl absrptin and chlesterl and bile acid synthesis and relate these values t kinetics f lw-density lipprtein (LDL) apprtein (ap) B in 50- and 75-year-ld men t find ut why and by which mechanism serum chlesterl level decreases with advancing age under nrmal hme-living cnditins. The daily calrie, fat, and chlesterl intakes were lwer in the 75-year-ld men because the physilgical requirements f daily energy are reduced in ld age. Hwever, abslute bdy weight was identical in the tw grups, indicating iscalric energy intake. Serum levels f ttal and LDL chlesterl were insignificantly lwer but thse f LDL ap B significantly lwer, s that the LDL chlesterl/ap B rati was higher in the elderly men. The mean reductin f LDL ap B by 26% (P<.05) in the ld men was assciated with a 30% (P<.05) decrease in transprt rate (TR) and a 3% (P=NS) decrease in remval (FCR) fr LDL ap B. Hwever, at the cmparable ap B levels, bth TR and FCR fr ap B were significantly lwer in the ld than in the yunger men. In ppulatin-based epidemilgical studies, serum ttal and lw-density lipprtein (LDL) chlesterl increases in males up t 64 years f age, fllwed by a decline fr unknwn reasns. 15 In the Finnish male ppulatin the values tend t decrease after as early as 50 years f age. 6 The effect f aging n LDL metablism has been evaluated in kinetic studies 478 including yung, middle-aged (55±8 years, mean±sd), 7 and ld (68±2 years) 8 men. In these studies fractinal catablic rate (FCR) f LDL apprtein (ap) B was diminished by age. Hwever, LDL chlesterl was significantly higher in the elderly; accrdingly, these results did nt slve the mechanism f age-assciated decline in LDL chlesterl. Because f the well-knwn assciatin f LDL chlesterl with crnary artery disease and the high prevalence f crnary artery disease in the aged, 9 it was imprtant t expand the metablic studies f LDL t include the elderly. Received December 31, 1993; revisin accepted February 22, Frm the Secnd Department f Medicine, University f Helsinki (Finland). Presented in part at the 65th Scientific Sessins f the American Heart Assciatin, New Orleans, La, and published in abstract frm in Circulatin. 1992;86(suppl I):I-404. Crrespndence t Prf Tatu A. Miettinen, MD, Secnd Department f Medicine, University f Helsinki, FIN Helsinki, Finland. Chlesterl absrptin efficiency, bile acid synthesis, fecal neutral and ttal sterl excretin, and chlesterl turnver but nt synthesis were reduced in the elderly men. Chlesterl absrptin efficiency was psitively crrelated with LDL chlesterl and ap B, TR fr LDL ap B, and dietary fat, chlesterl, and energy intakes and inversely with chlesterl synthesis, s that at the cmparable absrptin efficiency and lw abslute absrptin, chlesterl synthesis was surprisingly lw in the lder men, lwer than in the yunger men. Thus, lw LDL level in the ld men is cntributed by reduced chlesterl absrptin, which insufficiently stimulates chlesterl synthesis, and is related t lw LDL ap B transprt and t lw but iscalric fd intake. LDL level is mainly influenced by reduced LDL ap B transprt rate, the cntributin f decreased remval rate being less cnsistent. (Arteriscler Thrmb. 1994;14: ) Key Wrds chlesterl LDL turnver elderly chlesterl absrptin chlesterl synthesis Aging affects the cncentratin and metablism f chlesterl in the whle bdy. Age-assciated athersclertic lesins are rich in chlesterl. In additin, in several tissues, eg, muscles, adipse tissue, skin, and tendns, the cncentratin f chlesterl is markedly increased by age. 10 These findings suggest impaired eliminatin f chlesterl frm the bdy. Thus, agerelated changes in the frmatin and cmpsitin f bile are imprtant because bile is the majr excretry pathway f bdy chlesterl. The prprtin f chlesterl in bile is elevated by age, resulting in increased lithgenicity and risk f stne frmatin. 11 ' 12 Supersaturatin f bile in the aged may reflect an increased abslute r relative rate f hepatic secretin f chlesterl 12 r a decreased rate f bile acid synthesis. In fact, bth nrmal and decreased bile acid turnver and synthesis have been bserved in aged human subjects, 1112 but daily biliary bile acid r chlesterl secretin and fecal eliminatin, absrptin, and synthesis f chlesterl have nt been measured. In previus studies chlesterl absrptin efficiency was invlved in the regulatin f chlesterl hmestasis and LDL chlesterl cncentratin and metablism in middle-aged men In these studies chlesterl absrptin efficiency was psitively related t LDL chlesterl levels and inversely t FCR fr LDL ap B and t verall chlesterl synthesis. At the mment it is nt knwn whether chlesterl absrptin efficiency is related t chlesterl metablism r kinetics f LDL

2 TABLE 1. Characteristics f the Study Grup Weight, kg Height, m Bdy mass index, kg/m 2 Ap E phentype 75-Year-Old Men(n=11) 79.2± ± ± Year-Old Men (n=34) 82.0± ± ±0.6 3/3 4/3 Dietary calries, kcal kg" 1 d" 1 Fat intake, g kg" 1 d~ 1 Fat intake, % f calries P/S rati in dietary fat Dietary chlesterl, mg kg" 1 d" ±1.1* 0.9±0.1* 36.3± ± ±0.2* ± ± ± ± ±0.3 Ap indicates apprtein; P/S, plyunsaturated t saturated. Values are mean±sem. ap B in elderly subjects. Thus, ur first aim was t study chlesterl absrptin efficiency, the whle-bdy chlesterl metablism, and bile acid synthesis in 50- and 75-year-ld men t find ut the effect f age n these functins and whether these variables are related t decreases f serum chlesterl with advancing age. Secnd, we investigated LDL kinetics t find ut whether chlesterl absrptin and metablism are similarly related t lipprtein metablism in these tw grups and whether the lipprtein kinetics is related t a mechanism by which age regulates serum chlesterl level. S, in additin t serum lipids, lipprteins, and chlesterl absrptin, we measured fecal eliminatin f chlesterl as bile acids and neutral sterls, chlesterl synthesis by the sterl balance technique, and FCR and transprt rate (TR) f LDL ap B in the tw grups f men n their nrmal hme diet. Methds Study Ppulatin The 75-year-ld men (n=ll) were selected frm a brn randm ppulatin-based age chrt f the inhabitants f Helsinki. Only ambulatry men living at hme with a general health that allwed them t visit the Lipid Clinic f ur hspital were included. Thus, men with pr general health; manifest heart failure; malignancy; thyrid, renal, liver, r gastrintestinal diseases; r degenerative brain disease were excluded. The 50-year-ld men (n=34) were recruited frm a randm ppulatin-based age chrt f the inhabitants f Helsinki. 17 ' 18 The inclusin criteria were similar t thse fr the 75-year-ld men. In additin, t avid the pssible cnfunding effect f different ap E phentype distributin, thse 50-year-ld men with the el allele r hmzygsity fr the e4 allele were excluded (Table 1). Accrdingly, ap E phentype distributin was nt different in the tw grups. The studies were carried ut n an utpatient basis with subjects eating their nrmal hme diet. The subjects were encuraged t cntinue their habitual diet, and the cnsumptin f dietary cnstituents was calculated frm 7-day fd recrds. 19 The cmpletin f dietary recrds was clsely mnitred by experienced labratry persnnel. All subjects vlunteered t participate in the study, which had been apprved by the Ethics Cmmittee f ur hspital. Gylling et al Chlesterl Metablism in Elderly Men 695 Prcedures Fasting serum samples were btained fur times fr lipid, lipprtein, and apprtein analyses. Ttal and lipprtein chlesterl and triglycerides were measured with cmmercial kits (Behringer Diagnstica). Ap B was quantified immunturbidimetrically with anti-human antiserum with a cmmercial kit (Orin Diagnstica). The crrelatin cefficient between immunturbidimetric assessment and ap B value determined after selective precipitatin with isprpanl was (P<.001). Lipprteins were separated by ultracentrifugatin mainly as presented in Lipid Research Clinic Methds fr Labratry Prgrams. 20 High-density lipprtein (HDL) was separated int subgrups HDL 2 and HDL3 by ultracentrifugatin. Ap E phentyping was perfrmed frm serum by immunelectrphresis and electrfcusing. 21 Chlesterl absrptin was studied with the perral dubleistpe methd. 22 Chlesterl and bile acid synthesis and sterl excretin in feces were analyzed by the sterl balance technique. 23 ' 24 Fr fecal sterid and chlesterl absrptin measurements, during the 7-day dietary recrding all subjects cnsumed a capsule cntaining [ 14 C]chlesterl, [ 3 H]sitsterl, and chrmic xide (Cr 2 O 3 ) with each f the three majr meals. A three-day stl cllectin was perfrmed during the last 3 days f the week. The fecal flw was crrected with the recvery f CTJO^. 25 Fractinal absrptin fr chlesterl was measured with the change in the rati f the tw istpes. 22 Fecal sterids, bile acids, and neutral sterls were quantified with gas-liquid chrmatgraphy n a capillary clumn. 26 The fllwing calculatins were made: Ttal intestinal chlesterl flux=fecal neutral sterls/(l -chlesterl absrptin efficiency); biliary chlesterl flux=ttal chlesterl flux dietary chlesterl; dietary chlesterl absrbed=chlesterl absrptin efficiency x dietary chlesterl; ttal chlesterl absrbed=chlesterl absrptin efficiency x ttal chlesterl flux; chlesterl turnver r transprt=fecal endgenus neutral sterls+fecal bile acids; chlesterl synthesis=(fecal neutral sterls+bile acids)-dietary chlesterl. Fr the turnver studies autlgus LDL frm hydrated densities t g/ml was cllected, resuspended, and ultracentrifuged t remve cntaminating prteins. Apprximately 1.0 t 1.5 mg f LDL was labeled with 125 I by the idine mnchlride methd Ninety-eight percent f the label in LDL was recvered in LDL ap B. The labeled LDL was mixed with 5% human serum albumin, filtered thrugh pyrgen-free 0.22-/j,m Millipre filters, and injected intravenusly int the subjects. After the injectin, 10-mL bld samples were cllected and cunted fr radiactivities ver a 14-day perid. The die-away curves were cnstructed in whle plasma fr the radiactivities, f which FCRs were determined by use f a tw-pl mdel. 29 The TR fr LDL ap B was calculated by multiplying the pl sizes f crrespnding apprteins by the FCR. Pl size was calculated frm a plasma pl f 4.5% f bdy weight. The data are presented as mean±sem. The significance f differences was analyzed with tw-tailed Student's t test and Fisher's exact x 2 test. Crrelatins were tested by calculating the Pearsn's crrelatin cefficient. Regressin lines were cnstructed fr cmparisn f kinetic and metablic data, and regressin cefficients were estimated. A value f P<.05 was cnsidered statistically significant. Results Dietary Intakes Fat intake ( % versus 39.2±1.1% f calries) and the rati f plyunsaturated t saturated fatty acids (0.32±0.07 versus 0.33±0.03) were similar in the 75- and 50-year-ld men, while the intakes f chlesterl (273±22 versus 480±26 mg/d), fat (71±5 versus 105±5 g/d), and energy (33±2 versus 23±1 kcal/kg) were significantly higher in the yunger than in the lder men

3 696 Arterisclersis and Thrmbsis Vl 14, N 5 May 1994 TABLE 2., mml/l Serum Lipids and Lipprteins 75-Year-Old Men (n=11) 50-Year-Old Men (n=34) Serum chlesterl VLDL chlesterl IDL chlesterl LDL chlesterl HDL chlesterl HDL 2 chlesterl HDL 3 chlesterl Serum triglycerides VLDL triglycerides IDL triglycerides LDL triglycerides HDL triglycerides 5.43± ± ± ± ± ±0.02* ±0.15* 0.09± * 0.14± ± ± ± ± ± ± ±0.01 VLDL indicates very-lw-density lipprtein; IDL, intermediatedensity lipprtein; LDL, lw-density lipprtein; and HDL, highdensity lipprtein. Values are mean+sem. (Table 1). Hwever, the similar bdy weight, height, and bdy mass index indicated that bth grups were eucalric and in a steady state during the metablic studies. Serum Lipids Table 2 shws that serum ttal and lipprtein chlesterl and triglyceride levels were therwise similar in the 75- and 50-year-ld men except that HDL3 chlesterl and LDL triglycerides were significantly lwer and very-lw-density lipprtein triglycerides higher in the lder men. Intermediate-density lipprtein tended t be decreased in the aged. LDL ap B was lwer (Table 3) and the LDL chlesterl/ap B rati was higher in the elderly, suggesting that the LDL particle was less dense. Turnver Studies LDL ap B cncentratin was significantly lwer in the elderly because f a lwer TR f LDL ap B (Table 3) and insignificantly decreased FCR fr LDL ap B. In the lder men LDL ap B was 26%, TR 30%, and FCR nly 3% lwer than in the yunger men. In the elderly men LDL chlesterl and ap B cntents were related t TR (Fig 1, lwer panels) but nt t FCR (Fig 1, upper panels). In the yunger men LDL ap B was regulated TABLE 3. Kinetics LDL ap B, mg/dl Lw-Density Lipprtein Apprtein B LDL chlesterl/ap B FCR LDL ap B, pls/d TR LDL ap B, mg kg" 1 75-Year-Old Men(n=11) * 2.51 ±0.05* 0.304± ±0.46* 50-Year-Old Men (n=34) 76.99± ± ± ±0.34 LDL indicates lw-density lipprtein; ap, apprtein; FCR, fractinal catablic rate; and TR, transprt rate. Values are mean±sem. by its catablism and TR, whereas the LDL chlesterl level was related nly t FCR (Fig 1, upper panel). The mean FCR and TR fr the similar LDL ap B cncentratins were lwer and the crrespnding LDL chlesterl/ap B values were higher in the elderly than in the yunger men (Fig 1 and Table 4). Thus, the 21% lwer TR and 10% lwer remval rate f LDL ap B in the ld men kept the LDL chlesterl and ap B levels similar t thse in the yunger men. The LDL chlesterl/ap B rati was insignificantly related t FCR but significantly (r=-.5o6) t TR fr LDL ap B. Intestinal Chlesterl Fluxes and Bile Acid and Chlesterl Synthesis Chlesterl absrptin efficiency, bile acid synthesis, and fecal neutral and ttal sterid excretin were significantly reduced in the elderly men (Table 5). Calculatins shwed further that biliary and ttal chlesterl fluxes int the intestine, abslute ttal and dietary chlesterl absrptin, and chlesterl turnver but nt synthesis were als lwer in the lder men. It is interesting t nte that despite markedly reduced relative and abslute absrptin f chlesterl, chlesterl synthesis tends even t be reduced in the lder men. Fig 2 shws that the crrelatin between chlesterl absrptin and synthesis was significant in bth grups but that at the cmparable absrptin efficiency chlesterl synthesis was lwer in the lder than yunger men. The amunt f dietary chlesterl and fat and energy intake were nt related t any variables f chlesterl metablism separately in the tw grups. In the cmbined grups (n=45) chlesterl absrptin efficiency was significantly related t the daily intakes f energy (r=.332), dietary fat (r=.322), and chlesterl (r=.318) (Table 6). Dietary calries and chlesterl but nt fat were als weakly related t bile acid (but nt chlesterl) synthesis (r=.337 and.327, respectively). Lipprteins and Chlesterl Metablism In the cmbined grups the LDL chlesterl and ap B levels were significantly related t FCR (r= and -.417) and TR (r=.369 and.787) fr LDL ap B (Fig 1) and t chlesterl absrptin (Table 6). Chlesterl synthesis, in turn, was psitively crrelated with FCR fr LDL ap B (r=.348). Dietary fat intake was significantly related t LDL ap B cncentratin and TR fr LDL ap B. Virtually similar assciatins were fund separately in the tw age grups as in Table 6 except that chlesterl synthesis and transprt were psitively related t TR fr LDL ap B (r=.717 and.682) nly in the elderly men and t FCR fr LDL ap B in the middle-aged men (r=.342 and r=.356, respectively). Discussin The present study evaluating the age-related lwering f serum chlesterl investigated chlesterl absrptin and metablism and simultaneusly LDL ap B kinetics fr the first time in a ppulatin-based study f men at 50 and 75 years f age. Since the lipid levels are determined t sme extent by the dietary cnditins the subjects have been used t at hme all their lives, the present studies were perfrmed under hme cnditins with unchanged dietary habits. Therefre, the dietary cnditins represent a steady-state situatin and, despite the utpatient basis, had a fairly similar cmpsi-

4 Gylling et al Chlesterl Metablism in Elderly Men m* g. 0.3 a >' m 0 % D '^ 0 c? 0 r = r = P- 0 r = r = O m 0 r = r = a * 6~--... " - 0 ' Ojf r = r = p I 5 a fe FIG 1. Scatterplts shwing (upper panels) crrelatins between fractinal catablic rate (FCR) fr lw-density lipprtein (LDL) apprtein (ap) B and LDL ap B and chlesterl (LDL-C) cncentratins and (lwer panels) crrelatins between transprt rate (TR) fr LDL ap B and LDL ap B and chlesterl cncentratins. indicates 75-year-ld men;, 50-year-ld men LDL apb, mg/dl LDL-C, mml/l tin in the tw grups. The lwer calrie intake in the ld men, 23 versus 33 kcal ct 1 kg bdy wt" 1 in the yunger men, was physilgical, hwever, since the requirements f daily energy are reduced in ld age by abut 1% per year f age. 30 Despite the lw calrie intake f the lder men, the relative and abslute bdy weights were identical in the tw grups, indicating iscalric energy intake. The amunts f daily dietary fat and chlesterl intakes were lwer in the elderly, yet the relative dietary fat intake, type f fat, and plant sterl cnsumptin were identical. Accrding t earlier absrptin studies, the lw chlesterl intake shuld nt explain the reduced absrptin efficiency f chlesterl in the lder men because, in cntrast t the psitive crrelatin between absrptin and intake (Table 6), additin f chlesterl t the diet is usually cnsidered t reduce absrptin efficiency Hwever, the psitive crrelatin f chlesterl absrptin with dietary fat intake, bserved als in a nrmal ppulatin, 15 might indicate that the lw abslute fat intake f the ld men reduced chlesterl absrptin efficiency. A reductin f dietary fat and chlesterl intake in yunger men reduced chlesterl absrptin efficiency. 15 In additin, the lw bile acid synthesis may have decreased intestinal micellar frmatin and subsequent absrptin thrugh reduced intestinal bile acid cncentratin in the elderly men. Dietary plant sterls, which in amunts present in nrmal diets als inhibit chlesterl absrptin, 14 were similar in the tw grups. The reduced calrie intake f the elderly men, althugh iscalric t the bdy requirements, may have decreased chlesterl absrptin because the latter was psitively crrelated with the energy intake. On the ther hand, lw energy and fd intake may reduce intestinal mass and diminish gut mtility, a factr knwn, in fact, t increase chlesterl absrptin. 34 Finally, it is pssible that an age-dependent impairment f intestinal mucsal functin culd be a cntributry factr, even thugh the nrmal fecal fat indicates that the general absrptive functin is impaired nly t a limited degree, if at all. The lw chlesterl absrptin in the elderly men mdifies chlesterl and lipprtein metablism and may actually be a majr factr fr the age-related decrease in serum chlesterl. TABLE 4. Relative Lipprtein and Kinetic Values in Old and Middle-Aged Men With Similar and Higher Lw-Density Lipprtein Apprtein B Levels 50-Year-Old Men LDL ap B, mg/dl LDL chlesterl, mg/dl LDL chlesterl/ap B FCR LDL ap B, pls/d TR LDL ap B, mg kg" 1 d"' 75-Year-Old Men (n=11) 100±7 100±6 100± ±6 Lw Ap B* (n=16) 109±5 93± ±4* 126±3* High Ap Bf (n=18) 158±2t 124+5* 79 ±5* 97±4 155 ±4* Ap indicates apprtein; LDL, lw-density lipprtein; FCR, fractinal catablic rate; and TR, transprt rate. Mean values f 75-year-ld men in Table 3 were cnverted t 100, t which the respective mean values f 50-year-ld men were related. *Represents values f the men with less than r equal t the highest (81 mg/dl) LDL ap B level fr 75-year-ld men in Fig 1. trepresents values f the men with greater than the highest (81 mg/dl) LDL ap B level fr 75-year-ld men in Fig 1. tp<.05 frm lder men.

5 698 Arterisclersis and Thrmbsis Vl 14, N 5 May 1994 TABLE 5. Chlesterl Absrptin, Fecal Sterls, and Chlesterl Metablism Chlesterl absrptin, % Fecal bile acids, mg kg" 1 d"' Neutral sterls, mg kg"' d" 1 Ttal sterls, mg kg"' d" 1 Plant sterls, mg kg"' d" 1 Dietary chlesterl, mg kg~' d" 1 Ttal chlesterl flux, mg kg"' d" 1 Biliary chlesterl flux, mg kg"' d"' Dietary chlesterl absrbed, mg kg"' d"' Ttal chlesterl absrbed, mg kg"' d"' Chlesterl synthesis, mg kg" 1 d"' Chlesterl transprt, mg kg"' d"' 75-Year-Old Men(n=11) 34.4±2.9* * 8.1 ±0.6* 12.5±0.9* 3.5± ±0.2* * 8.8±0.6* 50-Year-Old Men (n=34) 45.9± ± ± ± ± ± ± ± ±0.1* 2.7± ±0.4* 9.1± ±0.9* 8.5± ± ±0.6 Fecal fat, g/d 3.7± ±0.2 Ttal chlesterl flux=fecal neutral sterls/(1-chlesterl absrptin efficiency); biliary chlesterl flux=ttal chlesterl flux-dietary chlesterl; dietary chlesterl absrbed=chlesterl absrptin efficiencyxdietary chlesterl; ttal chlesterl absrbed=chlesterl absrptin efficiencyxttal chlesterl flux; chlesterl transprt=fecal endgenus neutral sterls+fecal bile acids; and chlesterl synthesis= (fecal neutral sterls+bile acids)-dietary chlesterl. Values are mean+sem. Chlesterl absrptin efficiency was psitively crrelated with LDL chlesterl and ap B levels and negatively with chlesterl synthesis, indicating that chlesterl absrptin regulated chlesterl metablism independently f age. Similar results have been attained in yung men Hwever, reduced return f intestinal chlesterl t the liver apparently weakly stimulated chlesterl synthesis in the ld men because, fr instance, at a 40% absrptin in Fig 2, chlesterl synthesis was 6 mg kg~' d" 1 in the ld men and abut 14 mg kg" 1 d" 1 in the yunger men. Under these cnditins hepatic sterl balance is maintained by reduced utput f chlesterl as bile acids and biliary chlesterl, but LDL ap B receptr activity als plays a cntributry rle by taking up LDL, which was rich in chlesterl in the elderly subjects. Chlesterl absrptin efficiency was insignificantly negatively assciated with FCR but significantly psitively assciated with TR fr LDL ap B and inversely with chlesterl synthesis and turnver, which, in turn, were psitively related t FCR fr LDL ap B. Accrdingly, chlesterl absrptin efficiency and chlesterl synthesis interrelate with LDL ap B kinetics in the regulatin f serum chlesterl levels. What, then, is the rle f receptr activity fr LDL ap B in age-dependent regulatin f LDL chlesterl? A lw chlesterl absrptin nrmally enhances chlesterl synthesis and activates receptr activity fr LDL ap B 15 s that the regulatins f these tw are linked with each ther. In the elderly men the tw variables were lw-nrmal, but they were bth lw in relatin t the lw entry f intestinal chlesterl t the liver. CHOL2rEROl. ABSOFIPTION, % ' 0 ru-0.488, p»0.004, y -1.04x+66.2 rs-0.674, p=0.023, ys-1.94xts2.0 O O O Q ^^v^ v CHOLESTEROL SYNTHESIS, mg/kg/day FIG 2. Scatterplt shwing crrelatin between chlesterl absrptin efficiency and chlesterl synthesis. indicates 75-year-ld men;, 50-year-ld men. Advancing age increased the LDL chlesterl/ap B rati, which culd be explained by the lw TR and insignificantly diminished FCR fr LDL ap B s that the LDL particles becme chlesterl rich. These particles culd bring sufficient chlesterl t the liver even at a limited receptr activity. A lw TR fr LDL ap B has been suggested t indicate enhanced receptr activity when effective receptr-mediated remval f remnant particles lwers LDL ap B transprt. 7 Hwever, when the tw grups were selected t have similar LDL ap B levels, bth the remval and transprt f LDL ap B were significantly reduced in the elderly, indicating that receptr activity was lw but sufficiently effective fr chlesterl-rich LDL particles t keep LDL chlesterl unchanged at lw LDL ap B transprt. It can be expected that with mre advanced age the transprt rate is even mre reduced, resulting finally in significantly decreased LDL chlesterl levels as well. It is interesting t nte that, similar t ur results, unaltered ttal and LDL chlesterl levels were bserved in ctgenarians. 3S - 36 The age-related decrease in serum chlesterl appears t be slw, as shwn in a 12-year fllw-up study f 65-year-ld subjects, in whm serum chlesterl was actually fairly cnstant up t 75 years f age, after which it declined nnsignificantly by 6%. 5 In mst previus LDL kinetic studies the ldest subjects studied were less than 65 years f age, 4 ' and in nly ne study, 8 fur subjects were mre than 70 years f age. In the large review by Miller, 4 there was nly a small difference in the individual FCR values between age grups frm 40 t 49 t 60 t 69 years, and, in fact, 40 years f age seemed t be a clear-cut cutpint fr FCR values, which were definitely higher befre than after this age. Our present results shw reduced LDL receptr activity in the elderly at LDL ap B levels similar t thse f the yunger men. In in vitr studies, LDL receptr activity is unaffected by age in lymphcytes and fibrblasts. 8 ' 38 In additin t lw chlesterl absrptin efficiency, bile acid synthesis was decreased by age in agreement with sme but nt all 11 previus studies. Since bile acid synthesis is psitively related t transprt (/"=.761; f<.001) and synthesis (r=.634;/ > <.001) f chlesterl, the mre r less cnsistent decrease f the tw latter variables culd have cntributed t the reduced bile acid synthesis in the elderly. Lw bile acid synthesis may als character- 20

6 Gylling et al Chlesterl Metablism in Elderly Men 699 TABLE 6. Crrelatins Between Lw-Density Lipprtein and Metablic in the Whle Study Ppulatin (n=45) Chlesterl absrptin, % Fecal bile acids, mg-kg-'-d" 1 Chlesterl synthesis, mg kg- 1 d" 1 Chlesterl transprt, mg kg- 1 d~ 1 Dietary fat, g kg" 1 d~ 1 LDL Chlesterl, mml/l 0.315* LDL ApB, mg/dl 0.439* * FCR LDL ApB, pls/d * 0.348* 0.359* TRLDL ApB, mg kg" 1 d * Dietary chlesterl, g-kg- 1 -d- 1 Energy, kcal d" 1 kg" * 0.332* LDL indicates lw-density lipprtein; ap, apprtein; FCR, fractinal catablic rate; and TR, transprt rate * 0.338* Chlesterl Absrptin, % * * Fecal Bile Acids, mg kg- 1 d * 0.761* * 0.337* ize the aging liver, a factr related t the weak psitive assciatin f bile acid synthesis with lw calrie and chlesterl intakes. The findings indicate that, even thugh chlesterl synthesis data suggested that 3-hydrxy-3-methylglutaryl cenzyme A (HMG-CA) reductase activity was incnsistently decreased, bile acid synthesis was clearly decreased in the ld men. This might indicate that cnsumptin f hepatic hydrxysterls, knwn t regulate HMG-CA and ap B receptr activities 40 " 42 t bile acids, is als decreased, enhancing their cntent in the liver. A clinical cnsequence f the lw bile acid utput may be cnstipatin, a general cmplaint f the elderly, knwn t be wrsened by lw bile acid utput. 43 The present findings shw that the ld age-related decrease in LDL chlesterl is assciated with reduced relative and abslute absrptin f chlesterl, lw chlesterl synthesis and turnver, a lw FCR fr LDL ap B in relatin t the LDL ap B and chlesterl levels, a markedly reduced TR fr LDL ap B, lw bile acid synthesis, and a reduced biliary chlesterl secretin. 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