Aging and plasma triglyceride metabolism
2020; Elsevier BV; Volume: 61; Issue: 8 Linguagem: Inglês
10.1194/jlr.r120000922
ISSN1539-7262
AutoresKathryn M. Spitler, Brandon S.J. Davies,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoThe risk for metabolic disease, including metabolic syndrome, insulin resistance, and diabetes, increases with age. Altered plasma TG metabolism and changes in fatty acid partitioning are also major contributors to metabolic disease. Plasma TG metabolism itself is altered by age in humans and rodents. As discussed in this review, the age-induced changes in human TG metabolism include increased plasma TG levels, reduced postprandial plasma TG clearance rates, reduced postheparin LPL activity, decreased adipose tissue lipolysis, and elevated ectopic fat deposition, all of which could potentially contribute to age-associated metabolic diseases. Similar observations have been made in aged rats. We highlight the limitations of currently available data and propose that mechanistic studies are needed to understand the extent to which age-induced alterations in TG metabolism contribute to metabolic disease. Such mechanistic insights could aid in therapeutic strategies for preventing or managing metabolic disease in older individuals. The risk for metabolic disease, including metabolic syndrome, insulin resistance, and diabetes, increases with age. Altered plasma TG metabolism and changes in fatty acid partitioning are also major contributors to metabolic disease. Plasma TG metabolism itself is altered by age in humans and rodents. As discussed in this review, the age-induced changes in human TG metabolism include increased plasma TG levels, reduced postprandial plasma TG clearance rates, reduced postheparin LPL activity, decreased adipose tissue lipolysis, and elevated ectopic fat deposition, all of which could potentially contribute to age-associated metabolic diseases. Similar observations have been made in aged rats. We highlight the limitations of currently available data and propose that mechanistic studies are needed to understand the extent to which age-induced alterations in TG metabolism contribute to metabolic disease. Such mechanistic insights could aid in therapeutic strategies for preventing or managing metabolic disease in older individuals. Age is a significant risk factor for metabolic syndrome and T2D. The percentage of individuals with metabolic syndrome significantly increases with age (1Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5762) Google Scholar, 2Hildrum B. Mykletun A. Hole T. Midthjell K. Dahl A.A. Age-specific prevalence of the metabolic syndrome defined by the International Diabetes Federation and the National Cholesterol Education Program: the Norwegian HUNT 2 study.BMC Public Health. 2007; 7: 220Crossref PubMed Scopus (262) Google Scholar). In the United States, over one-quarter of adults over 65 have diabetes, and simply being older than 45 years old is considered a risk factor for T2D (niddk.nih.gov; cdc.gov/diabetes/data/). Although age is clearly a risk factor for metabolic disease, the mechanisms that contribute to this age-related risk have not been fully elucidated. One major contributing factor to metabolic disease is aberrant TG metabolism and fat partitioning (3Unger R.H. Clark G.O. Scherer P.E. Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome.Biochim. Biophys. Acta. 2010; 1801: 209-214Crossref PubMed Scopus (444) Google Scholar). Excessive delivery of fatty acids to tissues such as heart, skeletal muscle, and liver can lead to insulin resistance, cardiac lipotoxicity, and fatty liver disease (4Kim J.K. Fillmore J.J. Chen Y. Yu C. Moore I.K. Pypaert M. Lutz E.P. Kako Y. Velez-Carrasco W. Goldberg I.J. et al.Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.Proc. Natl. Acad. Sci. USA. 2001; 98: 7522-7527Crossref PubMed Scopus (589) Google Scholar, 5Wende A.R. Symons J.D. Abel E.D. Mechanisms of lipotoxicity in the cardiovascular system.Curr. Hypertens. Rep. 2012; 14: 517-531Crossref PubMed Scopus (84) Google Scholar, 6Girousse A. Virtue S. Hart D. Vidal-Puig A. Murgatroyd P.R. Mouisel E. Sengenès C. Savage D.B. Surplus fat rapidly increases fat oxidation and insulin resistance in lipodystrophic mice.Mol. Metab. 2018; 13: 24-29Crossref PubMed Scopus (15) Google Scholar). This ectopic lipid deposition often results from adipose dysfunction, wherein white adipose tissue no longer efficiently stores fat (7Kusminski C.M. Bickel P.E. Scherer P.E. Targeting adipose tissue in the treatment of obesity-associated diabetes.Nat. Rev. Drug Discov. 2016; 15: 639-660Crossref PubMed Scopus (414) Google Scholar). Ectopic lipid deposition is associated with metabolic syndrome and T2D, and humans with metabolic syndrome or T2D have increased TG content in heart and liver (3Unger R.H. Clark G.O. Scherer P.E. Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome.Biochim. Biophys. Acta. 2010; 1801: 209-214Crossref PubMed Scopus (444) Google Scholar). Surprisingly, although age and aberrant TG metabolism are both associated with increased risk of metabolic disease, the two are rarely studied in combination. In this review, we examine what is currently known about how age effects plasma TG clearance, adipose tissue lipolysis, and the partitioning of fat. We review how the activity of LPL, the enzyme primarily responsible for plasma TG clearance, is altered by age. Aging in rodent models and how well these models reflect the human condition are also discussed. Finally, we consider the deficiencies in our current understanding of age-associated changes in TG metabolism and suggest how some of these deficiencies might be addressed. Plasma TGs levels are higher in older adults versus younger adults (8Herzstein J. Wang C-I. Adlersberg D. Fat-loading studies in relation to age.AMA Arch. Intern. Med. 1953; 92: 265-272Crossref PubMed Scopus (3) Google Scholar, 9Cohn J.S. McNamara J.R. Cohn S.D. Ordovas J.M. Schaefer E.J. Postprandial plasma lipoprotein changes in human subjects of different ages.J. Lipid Res. 1988; 29: 469-479Abstract Full Text PDF PubMed Google Scholar, 10Cassader M. Gambino R. Ruiu G. Marena S. Bodoni P. Pagano G. Postprandial triglyceride-rich lipoprotein changes in elderly and young subjects.Aging (Milano). 1996; 8: 421-428PubMed Google Scholar). At least some of this increase in plasma TG levels can be attributed to delayed postprandial TG clearance. In 1949, Becker, Meyer, and Necheles (11Becker G.H. Meyer J. Necheles H. Fat absorption and atherosclerosis.Science. 1949; 110: 529-530Crossref PubMed Scopus (6) Google Scholar) gave a high-fat meal to 30 younger (average age 18) and 30 older (average age 76) fasted subjects and then measured serum chylomicrons over time. They found that in younger subjects, serum chylomicrons peaked at around 3 h and were cleared to fasting levels within 6 h. However, in older subjects, serum chylomicrons peaked later (∼9 h) and at a much higher level. Moreover, in older subjects, clearance of chylomicrons to fasted levels took nearly 24 h (11Becker G.H. Meyer J. Necheles H. Fat absorption and atherosclerosis.Science. 1949; 110: 529-530Crossref PubMed Scopus (6) Google Scholar). In 1953, Herzstein, Wang, and Adlersberg (8Herzstein J. Wang C-I. Adlersberg D. Fat-loading studies in relation to age.AMA Arch. Intern. Med. 1953; 92: 265-272Crossref PubMed Scopus (3) Google Scholar) similarly found that clearance of total serum lipids was delayed in older (ages 51–71) compared with younger (ages 17–34) subjects after a fat-loaded meal. A more recent study by Vinagre et al. (12Vinagre C.G. Freitas F.R. de Mesquita C.H. Vinagre J.C. Mariani A.C. Kalil-Filho R. Maranhão R.C. Removal of chylomicron remnants from the bloodstream is delayed in aged subjects.Aging Dis. 2018; 9: 748-754Crossref PubMed Scopus (7) Google Scholar) suggested that the delayed TG clearance in older subjects is due, at least in part, to delayed clearance of remnant particles in the liver. In this study the authors used TG emulsions labeled with both 3H-TGs and 14C-cholesterol esters to distinguish fractional clearance through lipolysis (TGs only) from fractional clearance through remnant uptake (clearance of both TGs and cholesterol esters). They found that clearance through lipolysis was similar between healthy young ( 60 years) subjects, but that remnant clearance was delayed in older subjects (12Vinagre C.G. Freitas F.R. de Mesquita C.H. Vinagre J.C. Mariani A.C. Kalil-Filho R. Maranhão R.C. Removal of chylomicron remnants from the bloodstream is delayed in aged subjects.Aging Dis. 2018; 9: 748-754Crossref PubMed Scopus (7) Google Scholar). However, it is important to note that these experiments were carried out in fasting (12 h) individuals and that clearance of TG emulsions may not reflect the behavior of endogenous lipoproteins. Interestingly, although the authors did not find a difference in lipolysis-driven clearance in older subjects, they did find that older individuals had lower postheparin LPL activity (12Vinagre C.G. Freitas F.R. de Mesquita C.H. Vinagre J.C. Mariani A.C. Kalil-Filho R. Maranhão R.C. Removal of chylomicron remnants from the bloodstream is delayed in aged subjects.Aging Dis. 2018; 9: 748-754Crossref PubMed Scopus (7) Google Scholar). The possible role of LPL in aging-induced changes in plasma TG metabolism is discussed below. Rodent models are often used in aging studies due to their dramatically shorter lifespans. How well do rodent aging-models reflect the changes in TG metabolism observed in humans? Several studies have found that older male and female rats have elevated plasma TG levels compared with younger rats (13Reaven G.M. Effect of age and sex on triglyceride metabolism in the rat.J. Gerontol. 1978; 33: 368-371Crossref PubMed Scopus (27) Google Scholar, 14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar, 15Chen Y-D.I. Reaven G.M. Relationship between plasma triglyceride concentration and adipose tissue lipoprotein lipase activity in rats of different ages.J. Gerontol. 1981; 36: 3-6Crossref PubMed Scopus (11) Google Scholar, 16Carlile S.I. Lacko A.G. Age-related changes in plasma lipid levels and tissue lipoprotein lipase activities of Fischer-344 rats.Arch. Gerontol. Geriatr. 1985; 4: 133-140Crossref PubMed Scopus (19) Google Scholar), though the degree of elevation appears to be strain dependent (14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar). Early studies also suggested that older rats, both male and female, have slower TG clearance rates than younger rats (13Reaven G.M. Effect of age and sex on triglyceride metabolism in the rat.J. Gerontol. 1978; 33: 368-371Crossref PubMed Scopus (27) Google Scholar). Interestingly, older mice appear to have slightly lower plasma TGs than younger mice (17Houtkooper R.H. Argmann C. Houten S.M. Cantó C. Jeninga E.H. Andreux P.A. Thomas C. Doenlen R. Schoonjans K. Auwerx J. The metabolic footprint of aging in mice.Sci. Rep. 2011; 1: 134Crossref PubMed Scopus (354) Google Scholar, 18Calligaris S.D. Lecanda M. Solis F. Ezquer M. Gutiérrez J. Brandan E. Leiva A. Sobrevia L. Conget P. Mice long-term high-fat diet feeding recapitulates human cardiovascular alterations: an animal model to study the early phases of diabetic cardiomyopathy.PLoS One. 2013; 8: e60931Crossref PubMed Scopus (106) Google Scholar). We are unaware of any study examining postprandial TG clearance in aged mice. LPL is critical for the proper clearance of plasma TGs. LPL bound to the vascular lumen hydrolyzes the TGs of TG-rich lipoproteins, releasing fatty acids for uptake by tissues. The delayed clearance of plasma TGs in older humans suggests that LPL activity may be altered with age. Although a survey of tissue-specific LPL activity in younger and older humans is lacking, several studies have examined the levels of LPL activity released into the bloodstream by an injection of heparin (12Vinagre C.G. Freitas F.R. de Mesquita C.H. Vinagre J.C. Mariani A.C. Kalil-Filho R. Maranhão R.C. Removal of chylomicron remnants from the bloodstream is delayed in aged subjects.Aging Dis. 2018; 9: 748-754Crossref PubMed Scopus (7) Google Scholar, 19Niemi T. Nikkila E.A. Effect of age on the lipemia clearing activity of serum after administration of heparin to human subjects.J. Gerontol. 1957; 12: 44-47Crossref PubMed Scopus (12) Google Scholar, 20Brodows R.G. Campbell R.G. Effect of age on post-heparin lipase.N. Engl. J. Med. 1972; 287: 969-970Crossref PubMed Scopus (26) Google Scholar). In each of these studies older subjects had significantly less postheparin LPL activity than younger subjects, suggesting that LPL activity does indeed decrease with age (12Vinagre C.G. Freitas F.R. de Mesquita C.H. Vinagre J.C. Mariani A.C. Kalil-Filho R. Maranhão R.C. Removal of chylomicron remnants from the bloodstream is delayed in aged subjects.Aging Dis. 2018; 9: 748-754Crossref PubMed Scopus (7) Google Scholar, 19Niemi T. Nikkila E.A. Effect of age on the lipemia clearing activity of serum after administration of heparin to human subjects.J. Gerontol. 1957; 12: 44-47Crossref PubMed Scopus (12) Google Scholar, 20Brodows R.G. Campbell R.G. Effect of age on post-heparin lipase.N. Engl. J. Med. 1972; 287: 969-970Crossref PubMed Scopus (26) Google Scholar). There are caveats to these observations. First, two of the studies did not report the gender of subjects and so it is not clear whether both males and females were included (19Niemi T. Nikkila E.A. Effect of age on the lipemia clearing activity of serum after administration of heparin to human subjects.J. Gerontol. 1957; 12: 44-47Crossref PubMed Scopus (12) Google Scholar, 20Brodows R.G. Campbell R.G. Effect of age on post-heparin lipase.N. Engl. J. Med. 1972; 287: 969-970Crossref PubMed Scopus (26) Google Scholar). The final study did include males and females but gender-separated data were not reported (12Vinagre C.G. Freitas F.R. de Mesquita C.H. Vinagre J.C. Mariani A.C. Kalil-Filho R. Maranhão R.C. Removal of chylomicron remnants from the bloodstream is delayed in aged subjects.Aging Dis. 2018; 9: 748-754Crossref PubMed Scopus (7) Google Scholar). Second, although heparin releases LPL into the circulation, there is scant evidence that heparin releases all vascular LPL or that LPL is released from all vascular beds with similar efficiency. There is also some evidence that heparin can release nonvascular LPL, LPL that would not normally participate in TG clearance (21Weinstein M.M. Yin L. Beigneux A.P. Davies B.S.J. Gin P. Estrada K. Melford K. Bishop J.R. Esko J.D. Dallinga-Thie G.M. et al.Abnormal patterns of lipoprotein lipase release into the plasma in GPIHBP1-deficient mice.J. Biol. Chem. 2008; 283: 34511-34518Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Therefore, although these studies suggest that LPL activity is altered in older humans, which tissues and pathways contribute to the change remain unclear. More detailed studies of age-induced changes in tissue-specific LPL activity have been performed in rats. Unfortunately, observations in rats have not been consistent, in part due to the use of different rat strains and different feeding conditions (Table 1). Chen and Reaven (15Chen Y-D.I. Reaven G.M. Relationship between plasma triglyceride concentration and adipose tissue lipoprotein lipase activity in rats of different ages.J. Gerontol. 1981; 36: 3-6Crossref PubMed Scopus (11) Google Scholar) found no difference in fasted LPL activity between 40-day-old, 100-day-old, and 1-year-old Sprague-Dawley rats, but found that when the rats were fed, LPL activity was significantly lower in the 100-day-old rats compared with the 40-day-old rats. Interestingly, there was no further decrease in LPL activity in 1-year-old rats. A contemporaneous study looked at both Sprague-Dawley and Fischer-344 rats aged out to 2 years. In this study, fasting LPL activity in adipose tissue increased with age in the Sprague-Dawley rats, but decreased in the Fischer-344 rats (14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar). The same study found that LPL activity in heart did not change significantly with age in either rat strain, but that activity in the diaphragm muscle decreased with age in the Sprague-Dawley rats (14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar). Four years later, the same authors reported a more extensive study of LPL activity in aging male Fisher-344 rats, measuring fasting lipase activity at 6, 12, 15, 18, 21, and 24 months of age. In this study, they found a highly significant age-dependent decrease in LPL activity in white adipose tissue, diaphragm muscle, and cardiac muscle (16Carlile S.I. Lacko A.G. Age-related changes in plasma lipid levels and tissue lipoprotein lipase activities of Fischer-344 rats.Arch. Gerontol. Geriatr. 1985; 4: 133-140Crossref PubMed Scopus (19) Google Scholar). Ursini et al. (22Ursini F. Vugman M. Fernandes L.C. Curi C.M.O.N. Curi R. Metabolic changes of several adipose depots as caused by aging.Physiol. Behav. 1991; 50: 317-321Crossref PubMed Scopus (17) Google Scholar) found that in Wistar rats, fed LPL activity was significantly higher in adipose tissue at 15 months compared with 3 months. Bey et al. (23Bey L. Areiqat E. Sano A. Hamilton M.T. Reduced lipoprotein lipase activity in postural skeletal muscle during aging.J. Appl. Physiol. 2001; 91: 687-692Crossref PubMed Scopus (33) Google Scholar) looked at LPL activity specifically in skeletal muscle. In both Fischer-344 rats and the F1 progeny of a Fischer-344, Brown Norway cross, they found that LPL activity was reduced in the soleus muscle of older rats, but not in the tibialis anterior muscle. Although it is not clear why LPL activity observations vary so widely from study to study, undoubtedly differences in rat strain and age, sampling conditions, testing methods, and the highly dynamic regulation of LPL activity contributed to these discrepancies. In fact, there is evidence that feeding state regulation of LPL changes with age. Bergö, Olivecrona, and Olivecrona (24Bergö M. Olivecrona G. Olivecrona T. Regulation of adipose tissue lipoprotein lipase in young and old rats.Int. J. Obes. Relat. Metab. Disord. 1997; 21: 980-986Crossref PubMed Scopus (19) Google Scholar) found that in young rats (29 days), fasting results in a dramatic decrease in LPL activity in white adipose tissue, but a dramatic increase in activity in the soleus muscle. By eight months of age, these fasting-induced changes in activity had virtually disappeared (24Bergö M. Olivecrona G. Olivecrona T. Regulation of adipose tissue lipoprotein lipase in young and old rats.Int. J. Obes. Relat. Metab. Disord. 1997; 21: 980-986Crossref PubMed Scopus (19) Google Scholar). The mechanism behind this change has not been uncovered.TABLE 1Effects of age on LPL activity in ratsTissueStrainRelevant ObservationReferenceAdipose tissueSprague-DawleyIncreasing fasted LPL activity with age (2, 12, 24 months)(14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar)No differences in fasted LPL activity at 40 days, 100 days, and 1 year of age(15Chen Y-D.I. Reaven G.M. Relationship between plasma triglyceride concentration and adipose tissue lipoprotein lipase activity in rats of different ages.J. Gerontol. 1981; 36: 3-6Crossref PubMed Scopus (11) Google Scholar)Increased fed LPL activity (compared with fasting) at 40 days of age, but no difference between fasting and fed activity at 100 days or 1 year(15Chen Y-D.I. Reaven G.M. Relationship between plasma triglyceride concentration and adipose tissue lipoprotein lipase activity in rats of different ages.J. Gerontol. 1981; 36: 3-6Crossref PubMed Scopus (11) Google Scholar)Fisher-344Decreasing fasted LPL activity with age (2, 12, 24 months)(14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar)Decreasing fasted LPL activity with age (6, 12, 15, 18, 21, and 24 months)(16Carlile S.I. Lacko A.G. Age-related changes in plasma lipid levels and tissue lipoprotein lipase activities of Fischer-344 rats.Arch. Gerontol. Geriatr. 1985; 4: 133-140Crossref PubMed Scopus (19) Google Scholar)WistarIncreased LPL activity at 15 months compared with 3 months (feeding state not specified)(22Ursini F. Vugman M. Fernandes L.C. Curi C.M.O.N. Curi R. Metabolic changes of several adipose depots as caused by aging.Physiol. Behav. 1991; 50: 317-321Crossref PubMed Scopus (17) Google Scholar)Cardiac tissueSprague-DawleyNo change in LPL activity with age(14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar)Fisher-344No change in LPL activity with age(14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar)Decreasing fasted LPL activity with age (6, 12, 15, 18, 21, and 24 months)(16Carlile S.I. Lacko A.G. Age-related changes in plasma lipid levels and tissue lipoprotein lipase activities of Fischer-344 rats.Arch. Gerontol. Geriatr. 1985; 4: 133-140Crossref PubMed Scopus (19) Google Scholar)Diaphragm muscleSprague-DawleyDecreased fasted LPL activity in 12- and 24-month-old rats compared with 2-month-old animals(14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar)Fisher-344No change in LPL activity with age(14Carlile S.I. Lacko A.G. Strain differences in the age related changes of rat lipoprotein metabolism.Comp. Biochem. Phys. B. 1981; 70: 753-758Crossref Scopus (14) Google Scholar)Decreasing fasted LPL activity with age (6, 12, 15, 18, 21, and 24 months)(16Carlile S.I. Lacko A.G. Age-related changes in plasma lipid levels and tissue lipoprotein lipase activities of Fischer-344 rats.Arch. Gerontol. Geriatr. 1985; 4: 133-140Crossref PubMed Scopus (19) Google Scholar)Skeletal muscleFisher-344Decreased LPL activity in 24-month-old rats compare with 2-month-old animals in soleus but not tibialis anterior muscles (feeding state not specified)(23Bey L. Areiqat E. Sano A. Hamilton M.T. Reduced lipoprotein lipase activity in postural skeletal muscle during aging.J. Appl. Physiol. 2001; 91: 687-692Crossref PubMed Scopus (33) Google Scholar)Fisher-344 × Brown NorwayDecreased LPL activity in 31-month-old rats compare with 18-month-old animals in soleus but not tibialis anterior muscles (feeding state not specified)(23Bey L. Areiqat E. Sano A. Hamilton M.T. Reduced lipoprotein lipase activity in postural skeletal muscle during aging.J. Appl. Physiol. 2001; 91: 687-692Crossref PubMed Scopus (33) Google Scholar) Open table in a new tab Although mice have been used extensively to study the regulation of LPL activity, to our knowledge no systematic profiling of LPL activity in older mice has been performed. Tissue-specific changes in LPL activity could lead to changes in lipid partitioning, altering the distribution of fat in the body. The location of TG storage has important metabolic consequences. Ectopic deposition of fat to tissues such as liver and skeletal muscle can lead to metabolic disease [reviewed in (3Unger R.H. Clark G.O. Scherer P.E. Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome.Biochim. Biophys. Acta. 2010; 1801: 209-214Crossref PubMed Scopus (444) Google Scholar)]. The distribution of fat between adipose depots is also important. Both the Framingham Heart Study and the Jackson Heart Study found that excess visceral fat, independent of total or subcutaneous fat levels, is correlated with cardiovascular pathologies (25Liu J. Fox C.S. DeMarc H. Aurelian B. Jeffery C.J. Taylor H.A. Fatty liver, abdominal visceral fat, and cardiometabolic risk factors.Arterioscler. Thromb. Vasc. Biol. 2011; 31: 2715-2722Crossref PubMed Scopus (90) Google Scholar, 26Preis S.R. Massaro J.M. Robins S.J. Hoffmann U. Vasan R.S. Irlbeck T. Meigs J.B. Sutherland P. D'Agostino R.B. O'Donnell C.J. et al.Abdominal subcutaneous and visceral adipose tissue and insulin resistance in the Framingham Heart Study.Obesity (Silver Spring). 2010; 18: 2191-2198Crossref PubMed Scopus (286) Google Scholar). 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Couillard C. Tchernof A. Bergeron J. et al.Age-related increase in visceral adipose tissue and body fat and the metabolic risk profile of premenopausal women.Diabetes Care. 1999; 22: 1471-1478Crossref PubMed Scopus (143) Google Scholar). Ectopic lipid deposition also increases with age. Using magnetic resonance spectroscopy, Cree et al. (33Cree M.G. Newcomer B.R. Katsanos C.S. Sheffield-Moore M. Chinkes D. Aarsland A. Urban R. Wolfe R.R. Intramuscular and liver triglycerides are increased in the elderly.J. Clin. Endocrinol. Metab. 2004; 89: 3864-3871Crossref PubMed Scopus (204) Google Scholar) found that liver fat increased over 3-fold in elderly subjects (ages 65–74 years) compared with younger (ages 20–32 years) subjects. Intramyocellular lipids were also increased by ∼50% in the older subjects (33Cree M.G. Newcomer B.R. Katsanos C.S. Sheffield-Moore M. Chinkes D. Aarsland A. Urban R. Wolfe R.R. Intramuscular and liver triglycerides are increased in the elderly.J. Clin. Endocrinol. 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