The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:39-43 (2005)
© 2005 The Gerontological Society of America
Accumulation of Dolichol in Older Tissues Satisfies the Proposed Criteria To Be Qualified a Biomarker of Aging
Ilaria Parentini,
Gabriella Cavallini,
Alessio Donati,
Zina Gori and
Ettore Bergamini
Centro Interdipartimentale di Ricerca di Biologia e Patologia dell'Invecchiamento dell'Università degli Studi di Pisa, Scuola Medica, Pisa, Italy.
Address correspondence to Ettore Bergamini, MD, PhD, Professor, Centro di Ricerca di Biologia e Patologia dell'Invecchiamento, Via Roma 55–Scuola Medica, 56126 Pisa, Italy. E-mail: ebergami{at}med.unipi.it
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Abstract
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Criteria for defining biomarkers have been suggested. Accumulation of dolichol in tissues of older animals meets the following criteria: (a) levels of dolichol exhibit a quantitative correlation with age in all tissues and are not altered by several age-dependent diseases in the same direction as that of aging; (b) accumulation is not secondary to metabolic changes of aging and is altered appropriately by factors that modulate the aging rate like caloric restriction and physical exercise; (c) biomarker is applicable to different tissues across mammalian species, including humans, and to trisomy 21 and its hypothalamic digoxin-mediated model. Reliable changes in tissue dolichol levels are seen in relatively short intervals of time compared to over a life span, and levels can be tested on a small amount of tissue without causing death of the animal. In this article, we show applications to the study of host–graft interaction and detection of gender-related differences in biological age, and we discuss mechanism(s) of accumulation.
TO search for biological markers, or biomarkers, of aging has been the focus of biogerontological research for many decades (1). The National Institute on Aging (NIA) and the Italian Ministry of Universities and Research (MIUR) funded specific research proposals on this issue. It was stated that the importance of identifying biomarkers of aging cannot be overemphasized in view of their role in, among other things, understanding the various determinants of aging, standardizing gerontological studies, monitoring the impact of various interventions on the rate of aging, determining the biological age of an individual, and estimating life expectancy (2).
An age-related alteration in a biological parameter may not be a biomarker of aging. A set of primary and secondary criteria as well as desirable features was proposed to distinguish a true biomarker of aging from an alteration indirectly related to aging (2). In this article we review recent evidence that accumulation of dolichol in the tissues of older animals meets all of these criteria, show useful applications, and discuss relation(s) between dolichol accumulation and basic mechanism(s) of aging.
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DOLICHOL
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Dolichol is a polyisoprenic molecule ubiquitously present in the lipid fraction of animal and plant tissues (3,4), discovered 40 years ago during experiments on the biosynthesis of ubiquinone (5). The molecular structure of dolichol comprises a sequence of unsaturated isoprenic units bearing a primary terminal hydroxyl group. The length of dolichyl chains depends on the species of the organism from which they are isolated. Mammalian dolichol generally is made up of 16–23 unsaturated isoprene units (4,6,7), and the terminal hydroxyl group may exist either free or esterified with fatty acids, phosphoric acid, and pyrophosphoric acid. In biological membranes, this linear polyisoprenoid compound may be located between the two leaflets of the lipid bilayer, close to the free end of the phospholipid fatty acid molecules. Metabolism and function of dolichol were largely unknown until recently. Synthesis of dolichol by the mevalonate pathway was demonstrated in vitro and in vivo in many tissues (6). The isoprenoid pyrophosphate intermediates are shared by the cholesterol, dolichol, and ubiquinone pathways (8), and treatment with drugs that block hydroxymethyl glutaryl coenzyme A reductase may significantly decrease their plasma and tissue levels (9). In humans, there is no apparent positive correlation between serum dolichol and tissue dolichol and age (10,11). In view of the total content of the body, half-life of the total body dolichol, and dolichol content in the extracellular space, it was concluded that the dolichol in tissues probably derives from biosynthesis in those tissues and that relocation of dolichol via circulation cannot be prominent in vivo (6,12). The levels of dolichol in human serum have apparently no correlation to age or serum total cholesterol, and exhibit a linear correlation to high-density lipoprotein cholesterols which may reflect the fact that the dolichols are associated with the high-density lipoprotein fraction (11). No enzymic pathways for dolichol degradation were described, but no case of dolichol-storage disease was reported (13). Shrinkage of tissue because of increased lysosomal degradation in the process of atrophy does not affect the dolichol content and concentration increases (13). Small quantities of dolichol that may be excreted into the urine at least in part is derived from the lysosomes of the excretory organ (14), and serum dolichol levels may be elevated in chronic cholestatic liver diseases (15). Recent evidence shows that phagocytosis may cause the degradation and disposal of the engulfed dolichol (13), possibly because of nonenzymatic free radical–mediated decomposition (16). By means of a 1H-nuclear magnetic resonance (NMR) analytical method, the hypothesis was substantiated that dolichol may act as a free-radical scavenger in the cell membranes and protect polyunsaturated fatty acids from peroxidation, and that it may undergo decomposition in the process (17).
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DOLICHOL ACCUMULATES IN MAMMALIAN TISSUES WITH INCREASING AGE
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Dolichol can be assayed easily in plasma, urine, and tissues by the high-performance liquid chromatography procedure and by spectrophotometric or fluorometric detection (11,18). The contents of free dolichol, dolichyl fatty acid ester, and dolichyl phosphate in human serum do not correlate to age or serum total cholesterol [a linear correlation was found instead between dolichol and high-density lipoprotein (HDL) cholesterol (11)]. Studies in older humans (6,19,20) and mice (21,22) show that dolichol accumulates in tissues during aging. In rats, a significant age-related accumulation of dolichol was reported during growth (20,23) and at maturity (20,23,24) and older age (25,26). More recently, a quantitative correlation was found between accumulation of dolichol and chronological age in the tissues of several rats aged more than 6 months (27) (see Figure 1). Both dolichol content in the entire organ and dolichol concentration in the tissue are known to increase with increasing age (13). A reliable change in dolichol concentration in tissues was seen within a short interval of time compared to life span (Figure 1), which is a highly desirable feature in a biomarker of aging (1). The chain-length distribution of dolichol showed a significant aging-related tendency of shorter molecules to increase (and of longer molecules to decrease) which was statistically significant, irrespective of diet (28). Age-related increases in the level of dolichol in rat plasma (29) and red blood cell ghosts (30) were reported.
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Figure 1. Aging-related changes in dolichol concentration in the liver (A) and the soleum muscle (B) of male Sprague-Dawley rats fed ad libitum. Linear regression and 5% fiducial limits are depicted. Regression equations are: liver: y = 0.7 + 8.4x; soleum muscle: y = 1.8 + 0.6x. Dolichol was extracted and assayed as described in (25)
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LEVELS OF DOLICHOL ARE NOT ALTERED WITH DISEASE PROCESSES, OR ALTERATION WITH DISEASE IS NOT IN THE SAME DIRECTION AS THAT OF AGING
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Dolichol accumulation in older tissues also meets this second suggested primary criterion for identifying biomarkers of aging (1). Acute (16) or chronic (31,32) pathological conditions and life-long dietary deficiency of vitamin E and polyunsaturated fatty acids (unpublished data) associated with an increase in oxidative stress may cause a dramatic decrease in tissue dolichol levels. The effects of several age-dependent diseases on dolichol levels and metabolism were studied and found to be different than those of aging. For example, in various organs of a mouse model for Niemann-Pick's disease, dolichol content varied from a 50% decrease in the lung to a two-fold increase in kidney and heart, with most organs being unaffected (33). A drastic increase in dolichol content was observed in rat liver hyperplastic nodules, whereas human liver cirrhosis and hepatocarcinoma and highly differentiated hepatomas showed a marked decrease in dolichol (7,34).
In the latter case, the distribution pattern was also changed (7). During human aging, the brain shows a progressive increase in the levels of dolichol, a reduction in the levels of ubiquinone, and relatively unchanged concentrations of cholesterol and dolichyl phosphate; in the neurodegenerative age-associated Alzheimer's disease, the situation is reversed, with decreased levels of dolichol and increased levels of ubiquinone (35; see also 36). Atherosclerosis is a frequent human age-associated disease of the arteries. Human atherosclerotic plaques obtained at autopsy from patients ranging in age from 45 to 85 years were richer in cholesterol than in dolichol as compared with nonatherosclerotic aortic tissue, and the homologue pattern of dolichol in the atherosclerotic plaques differed from that in aorta and blood (37). Diabetes mellitus was said to be a premature aging syndrome (1,38), but changes in dolichol metabolism show that cholesterol and dolichol synthesis either from 1-14C-acetate or from 2-3H-mevalonate decrease significantly (39) and go in the opposite direction as those of aging (29).
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AGE-RELATED ALTERATION IN TISSUE LEVELS OF DOLICHOL IS NOT SECONDARY TO METABOLIC OR NUTRITIONAL CHANGES OF AGING
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This question was investigated by the use of organ transplantation (40). Dolichol-poor hearts donated by 3-month-old and dolichol-rich hearts by 22-month-old male Lewis rats were transplanted heterotopically into 3-month-old syngeneic recipients, whose peripheral tissues and liver were poor in dolichol. Native and transplanted hearts were taken 7 and 21 days after surgery. Native hearts of 3- and 22-month-old male Lewis rats served as controls. Dolichol content was higher in older than in younger native hearts, as expected. In the transplanted hearts, the quantity of dolichol was unchanged, irrespective of the age of the donor and of the time of transplantation. This is unlike the case of pentosidine, the levels of which were higher in older than in younger native hearts and, in older hearts transplanted into younger recipients, rapidly decreased the levels of younger hearts in less than 7 days (41).
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CALORIC RESTRICTION, WHICH MODULATES THE AGING RATE, APPROPRIATELY ALTERS LEVELS OF DOLICHOL IN LIVER TISSUE
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An age-dependent accumulation of dolichol was observed in the liver of the rats fed ad libitum but not in the liver of 24-month-old food-restricted rats, and accumulation of dolichol preceded the accumulation of altered liver proteins (25). To test the hypothesis that the aging-related alteration in membrane lipids might reflect the biological age of rodents, the levels of liver dolichol were assayed by high-performance liquid chromatography in male Sprague-Dawley rats aged 2, 6, 12, and 24 months fed ad libitum (Figure 1) and in 24-month-old rats on anti-aging food restrictions differing in duration and effects on longevity (Figures 2 and 3). Results showed that the effects on liver dolichol of food restriction initiated at 2, 6, and 12 months of age, or initiated at 2 and interrupted at 18 months of age, were significantly different, and reflected the differences in the effects of food restriction on life expectancy (the longer the expected residual life span the lower the content in liver dolichol (28). A similar study was performed with male Sprague-Dawley rats on a low-level dietary restriction. Once more, results showed that a low-level (10%) dietary restriction significantly reduced the accumulation of dolichol in the liver (42), which reflected the change in life expectancy (43). The conclusion was that assay of dolichol content in the liver tissue may be used as a marker of the biological age of an animal.
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Figure 2. Effects of duration of calorie restriction on the concentration of dolichol in the liver of 24-month-old male Sprague-Dawley rats. Rats were fed ad libitum every other day (food restriction was 35%) starting by different age (24, 18, 12, 6, and 2 months of age). Means ± SEM (standard error of mean) of at least 6 cases are given. Dolichol was extracted and assayed as described in (25)
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Figure 3. Effects of the level of calorie restriction on the dolichol concentration in the liver of 24-month-old male Sprague-Dawley rats. A 10% caloric restriction (24 hours of fasting every week) or a 35% caloric restriction (24 hours of fasting every other day) were started by age 2 months. Means ± SEM (standard error of mean) of at least 6 cases are given. Dolichol was extracted and assayed as described in (25)
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AS A BIOMARKER OF AGING, DOLICHOL IS APPLICABLE TO DIFFERENT TISSUES WITH SIMILAR REPLICATIVE CAPACITY AND IS GENERALIZABLE ACROSS MAMMALIAN SPECIES
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The effects of age on levels of dolichol were studied in different organs of the rat with different replicative capacity, involved (liver and kidney) or not involved (brain, sciatic nerve, heart, soleus, and extensor digitorum longus muscles) in dolichol excretion. Levels of dolichol were significantly different in different tissues and, in all tissues, increased dramatically with increasing age by a similar percent value (6-fold to 8-fold, between ages 2 and 24 months) (27). A three-fold increase in dolichol levels was observed in red blood membranes from 24-month-old rats as compared with 2-month-old rats (30). Anti-aging calorie restriction had significant preventive effects on dolichol accumulation in the excretory organs. The effect of calorie restriction was much bigger in the liver than in the kidney. With regard to rat brain, dolichol content increased continuously after a 10-day lag period, leading to a 10-fold elevation during the first 45 days of postnatal life, and continued in the individual regions of the brain prepared from older animals; elevation in these different regions varied: at 24 months of age, the dolichol content in the cerebral cortex, hippocampus, and striatum were 140, 100, and 75 µg/g, respectively, and the apparent increase from birth was higher than 100 times (44). Brain cholesterol and dolichol exhibit a low rate of turnover during aging, whereas ubiquinone is synthesized at a high rate and exhibits rapid turnover throughout the entire life span (45). In conclusion, these data show that the quantity of dolichol in the hepatic tissue might be used as a marker of the biological age of the animal.
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APPLICABILITY OF DOLICHOL TO SYNDROMES OF PREMATURE AGING
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Age changes in dolichol levels were studied in Down's syndrome, which is the most common human genetic disease associated with premature aging (46). Down's syndrome patients are mentally retarded, and those who survive past their mid-30s usually develop Alzheimer's disease and premature aging. Results were positive: the concentration of dolichol was elevated for age in the frontal cortex of Down's syndrome patients (36). The isoprenoid pathway-related cascade was also assessed in a hypothalamic digoxin-mediated model of trisomy 21 with positive results: researchers noticed an increase in dolichol levels, together with reduced levels of ubiquinone, reduced glutathione, and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide (47).
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APPLICATION OF THE BIOMARKER DOLICHOL TO AGING STUDIES
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It is conceivable that dolichol may be a determinant of aging and that assays may shed light on the basic mechanisms underlying the aging phenomenon. Serum may not be a useful sample for dolichol assay in studies on aging (see 10). Urinary dolichol reflects lysosomal degradation of epithelial cells and may be affected by several different clinical conditions (47). In conclusion, the biomarker dolichol may not be applicable to aging studies if tissue samples cannot be used for ethical reasons. At present, the assay of dolichol is used mostly in rodents to detect differences in the rate of aging of different tissues (19–27) and to monitor the impact of various anti-aging interventions on the rate of aging (25,27,28,42). Tissue dolichol was used to study the influence of a younger environment on organ transplantation from elderly donors (41,48,49). The assay of tissue dolichol may reveal a gender-related difference in the rate of aging (Figure 4).
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Figure 4. Effects of age on the concentration of dolichol in the liver of male (open squares) and female (closed squares) Sprague-Dawley rats. Means ± SEM (standard error of mean) of at least 6 cases are given. Dolichol was extracted and assayed as described in (25)
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MECHANISMS OF THE AGE-RELATED ACCUMULATION OF DOLICHOL
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The mechanisms of the age-related accumulation of dolichol in animal tissues have not been elucidated fully, but very recent evidence shows that they may be intimately bound to the mechanism of aging. The rate of mevalonate incorporation in cholesterol and dolichol and the activity of HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway, exhibit an age-related increase in ad libitum-fed (but not in food-restricted) rats (29). In addition, an age-related decrease in the susceptibility to degradation of HMG-CoA reductase has been reported. Both enzyme changes are compatible with an alteration in the lipophilic moiety of this bipartite enzyme (50). Similar changes in HMG-CoA reductase were observed in ultraviolet radiated isolated hepatocytes (51). Changes in the metabolism of free radicals (52) and in the concentrations of lipophilic antioxidants (53) have been observed in older cytomembranes. In conclusion, data are compatible with the hypothesis that an age-related misfunctioning of the antioxidant machinery of cell membranes is the primary event that alters HMG-CoA activity and initiates accumulation of dolichol (see 54).
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Footnotes
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Decision Editor: James R. Smith, PhD
Received June 22, 2004
Accepted July 25, 2004
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Abstract
Dolichol
