REJUVENATION RESEARCH Volume 15, Number 2, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/rej.2011.1286
Bile Acids, Chaperones, and Mammalian Longevity Jens Krøll
Abstract
Bile acids are detergent molecules derived from cholesterol in the liver that are important for the metabolism and absorption of lipids in the intestine. Bile acids are also steroid hormones activating specific nuclear receptors and G protein–coupled receptors. Conjugated bile acids are cytoprotective and anticarcinogenic. Bile acid synthesis and bile flow decreases markedly during aging. The housekeeping molecular chaperones are stress response proteins, important for the processes of folding, maintenance, and repair of proteins, RNA, and DNA, as well as for the structure and function of the steroid hormone receptors. The level of expression of the molecular chaperones correlates with mammalian longevity as well as with the life span of differentiated cells. The functions of the chaperone machinery are progressively impaired during aging, and the progressive age-related impairment of these housekeeping mechanisms probably contributes to the phenotype of aging. This review presents evidence that the bile acids are chemical chaperones, improving the general chaperone defense, and thus serve to support an epigenetic mechanism of possible significance for the evolution of mammalian longevity, as well as for the attainment of healthy aging.
Introduction
T
he life span in mammals varies from a few years in rodents to more than 100 years in humans. The mechanisms determining these differences in longevity are unknown. However, the rapid evolution of hominid longevity suggests the involvement of relatively few genes.1 Also the inherent immortality of embryonic stem cells in vitro suggests that replicative senescence, as possibly organismal aging, is an epigenetic phenomenon.2 Accordingly, an increasing body of evidence suggests a significant role of epigenetic factors in aging and longevity.3 Gene products of importance for the evolution of mammalian longevity could be expected to be expressed at relatively high levels in long-lived species. This criterion is met by the molecular chaperones,2 as well as by cortisol4 and dehydroepiandrosterone.5 Bile acids are detergent molecules derived from cholesterol in the liver and are important for the metabolism and absorption of lipids in the small intestine.6 In addition to their significance for intestinal lipid metabolism, the bile acids are steroid hormones that activate specific nuclear receptors and G protein–coupled receptors and interact with cell signaling pathways.7 In human serum, the bile acid concentration amounts to 2–5 lmol/L, i.e., a molar concentration about 5-fold higher than that of cortisol and resembling that of dehydroepiandrosterone.7 The fasting serum level of bile salts is about 5-fold higher in hominids then in
dogs and cats, suggesting a positive correlation with mammalian life span.8 Conjugated bile acids are cytoprotective and anticarcinogenic.9 Bile acid synthesis and bile flow decreases markedly during aging.10 The housekeeping molecular chaperones are stress response proteins essential for the processes of folding, translocation, maintenance, and repair of proteins, RNA, and DNA, as well as for the structure and function of the steroid hormone receptor complex. The significance of the DNA chaperones for longevity is evident from the role of defective WRN and BLM proteins for development of syndromes of premature aging.2,11 The importance of the molecular chaperones for the evolution of longevity could be supposed also from the observation that the chaperone-generating FOXO transcription factors are implicated as a convergence point for multiple longevity pathways.12 The effectiveness of the maintenance and repair mechanisms tends to decline with age. Thus, a progressive impairment of the chaperone machinery is observed,13–15 as exemplified also by the age-dependent decline of the chaperone-mediated autophagy.16 The progressive agerelated decline of these housekeeping mechanisms probably contributes to the phenotype of aging. This review presents evidence that the bile acids are chemical chaperones, improving the general chaperone defense, and thus they serve to support an epigenetic mechanism of possible significance for the evolution of mammalian longevity, as well as for the attainment of healthy aging.
Hafnia Unit of Biogerontology, Frederiksberg, Denmark.
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BILE ACIDS, CHAPERONES, AND LONGEVITY
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Bile Acids and Chaperones 17
Bile acids are ligands for the nuclear hormone receptors. Here the molecular chaperone machinery of heat shock protein 90 (Hsp90) is essential for the intracellular transport and function of the hormone receptor.18 The chaperone Hsp70 assists the bile acid transporters in driving the bile flow.19 The conjugated bile acid tauroursodeoxycholic acid (TUDCA) is a chemical chaperone. TUDCA is cytoprotective and has been shown to lower the respiratory quotient and normalize the impairment of the glucose tolerance associated with high fat feeding.20 Also, TUDCA has been observed to reduce endoplasmatic stress and act as a leptin-sensitizing agent, and so has been suggested for the treatment of obesity.21 In the case of acute liver damage, TUDCA counteracts inflammation, apoptosis, and necrosis and improves liver regeneration.22 After acute myocardial infarction, TUDCA reduces the stress response of other chaperones, reduces infarct size,23 and alleviates obesity-induced myocardial contractile dysfunction.24 The effect of TUDCA on myocardial dysfunction possibly relates to the digitalis-like structure of the bile salts.25 TUDCA also enhances the function of the pancreatic islets by reducing the effects of induced endoplasmatic reticulum stress.26 Bile Acids and Longevity Bile acids extend longevity in yeast beyond the effect of caloric restriction, an effect resulting from modulation of housekeeping longevity assurance pathways, leading to enhancement of the resistance to oxidative and thermal stresses.27 In Drosophila melanogaster, feeding with taurocholic acid results in increased life span and improves survival under stressful conditions.28 In Caenorhabditis elegans, the bile acid–like steroid dafachronic acid extends life span through nuclear receptor signaling.29 In the long-lived Ghrhr mutant mice, the inherent increased bile acid levels probably contribute to longevity by activation of the nuclear farnesoid X receptor.30 Contributing to longevity may also be the fact that bile acids are inhibitory to tumor promotion, as observed in a two-stage carcinogenesis model in mouse skin.9 An anticarcinogenic effect of the bile acids can be supposed also from the rare occurrence of cancer in the small intestine, where the intestinal epithelium is exposed to micellar bile acid concentrations. For the attainment of healthy aging, it should be noted that the bile acids alleviate constipation,31 are inhibitory to the formation of gallstones,32 and counteract the formation of amyloid.33 The observation that the bile acid serum level in hominids is 5-fold higher than in dogs and cats8 suggests a contribution of the bile acids in the evolution of mammalian longevity. Bile Acid Supplementation in Aging The progressive age-related reduction in bile acid synthesis, associated with impairment of the chaperone defense, can be counteracted by oral replacement therapy,34 preferably by use of the chemical chaperone TUDCA? Conclusions The evolution of mammalian longevity probably depends on an enforcement of housekeeping mechanisms, including
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Address correspondence to: Jens Krøll Hafnia Unit of Biogerontology Godtha˚bsvej 111,3 DK-2000, Frederiksberg Denmark E-mail:
[email protected]
