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Aging Cell (2013) 12, pp950–954 Doi: 10.1111/acel.



Liver diseases and aging: friends or foes?

Fareeba Sheedfar,1* Stefano Di Biase,2* Debby Koonen1 and human life expectancy (WHO, 2002). Longer life span, however, does
Manlio Vinciguerra3,4,5 not necessarily mean a prolonged healthspan, as indicated by the
Molecular Genetics, University of Groningen, University Medical Center
steep rise in the number of elderly individuals suffering from chronic
Groningen (UMCG), Groningen, The Netherlands diseases, including metabolic and cardiovascular disease. Although
Andrus Gerontology Center and Department of Biological Sciences, aging is not a disease, it is considered the leading risk factor for all
University of Southern California, Los Angeles, CA, USA chronic diseases, accounting for 60% of all deaths worldwide (WHO,
Division of Medicine, University College London (UCL) – Institute for Liver 2009). Aging refers to a multidimensional process of organism decline.
and Digestive Health, Royal Free Hospital, London, UK The liver is a vital organ with a wide range of functions, including
Euro-Mediterranean Institute for Science and Technology (IEMEST), Palermo,
detoxification, protein synthesis, and production of compounds nec-
Department of Medical Sciences, Division of Internal Medicine, IRCCS “Casa essary for digestion. Specific age-related hepatic changes have been
Sollievo della Sofferenza”, S. Giovanni Rotondo, Italy reported, such as increased hepatocyte size, increase in the number of
binucleated cells, and reduction in mitochondrial number (Premoli
Summary et al., 2009; Gan et al., 2011). These changes may significantly affect
The liver is the only internal human organ capable of natural liver morphology, physiology, and oxidative capacity. Also, in the
regeneration of lost tissue, as little as 25% of a liver can regenerate elderly population, there is a one-third loss of hepatic volume and
into a whole liver. The process of aging predisposes to hepatic perfusion between the ages of 30 and 100 years (Wynne et al., 1989),
functional and structural impairment and metabolic risk. There- a loss which has been reported to interfere with hepatic phase 1 drug
fore, understanding how aging could affect the molecular pathol- pharmacokinetics (Marchesini et al., 1988; Wynne et al., 1989;
ogy of liver diseases is particularly important, and few studies to Schmucker, 2005).
date have tackled this complex process. The most common liver At the level of single-cell populations, a sharp decline in hepatic
disease, affecting one-third of the overall population, is nonalco- regeneration following hepatectomy or chemical injury has been
holic fatty liver disease (NAFLD), characterized by an intrahepatic observed during aging (Bucher et al., 1964; Stocker & Heine, 1971;
accumulation of lipids. NAFLD can evolve into nonalcoholic Popper, 1986; Jin et al., 2009a). Indeed, in young rats, all hepatocytes
steatohepatitis (NASH) in the presence of oxidative stress and enter the cell cycle after 70% liver resection, whereas only one-third do
inflammation. NASH is a serious risk factor for disabling and deadly so in the aged liver (Stocker & Heine, 1971). The molecular basis for the
liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). loss of regenerative capacity of aged livers is just starting to be elucidated
Old age seems to favor NAFLD, NASH, and ultimately HCC, in and may involve CCAAT/enhancer-binding protein (C/EBP) family mem-
agreement with the inflamm-aging theory, according to which bers (a, b, c), GSK3b, HDAC1, and SIRT1 epigenetic and signaling
aging accrues inflammation. However, the incidence of HCC drops pathways (Gagliano et al., 2007; Jin et al., 2009a, 2011; Timchenko,
significantly in the very elderly (individuals aged more than 70) and 2009; Jiang et al., 2013). Interestingly, transgenic mice having under-
the relationship between the progression of NAFLD/NASH/HCC gone replacement of C/EBPalpha with C/EBPbeta, generating beta/beta
and very old age is obscure. In this review, we discuss the literature alleles, are long-lived (Chiu et al., 2004), and targeting GSK3b, HDAC1,
and we argue that there might be an age window in which the liver and SIRT1 enzymatic activities has been proposed to improve the course
becomes resistant to the development of injury; this needs to be of various age-related diseases (Lucas et al., 2001; Willis-Martinez et al.,
studied to understand fully the interaction between age and liver 2010; Guarente, 2011).
diseases from a therapeutic perspective. Worth noting is that aging is associated with a physiological increase
Key words: aging; cytokines; demography; injury; insulin/ in lipid accumulation in nonadipose tissues, including the liver (Petersen
IGF-1 signalling; reactive oxygen species; mouse models; et al., 2003; Slawik & Vidal-Puig, 2006). As with other organs,
NAFLD; NASH. accumulation of lipids in the liver may compromise their normal
functionality by promoting organ-specific toxic reactions, also known
as lipotoxicity (Slawik & Vidal-Puig, 2006). Aging markedly increases the
prevalence of the metabolic syndrome in the human population (Ford
Aging and liver function
et al., 2002). Accumulating evidence also points toward an increased
The aging of a vast majority of the population is a very recent prevalence of nonalcoholic fatty liver disease (NAFLD) with older age in
phenomenon that has emerged as a direct consequence of the rise in humans (Floreani, 2007). NAFLD includes a wide spectrum of liver
Aging Cell

pathologies ranging from benign hepatic lipid accumulation (steatosis) to
advanced nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and
ultimately hepatocellular cancer (HCC) (De Minicis et al., 2013). Aging
Manlio Vinciguerra, PhD, Division of Medicine, UCL Institute for Liver and Digestive
has also been reported to significantly enhance the progression to NASH
Health, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
and fibrosis, thus predisposing to increased mortality in elderly subjects
Tel.: +44 (0) 20 74332874; fax: +44 (0) 20 74332852;
e-mail: with NAFLD (Regev & Schiff, 2001; Frith et al., 2009). However, is the
higher prevalence of NAFLD seen in the elderly population a result of
*These authors contributed equally to this work.
physiological changes intrinsic to the aging process or may it reflect age-
Accepted for publication 21 June 2013 long compensation for lifestyle-associated factors, like obesity and

950 ª 2013 the Anatomical Society and John Wiley & Sons Ltd

T2D. which is an irreversible state of the disease characterized by scars on the liver tissue that can possibly lead to HCC (Podrini et al. Sheedfar et al. accumulation in the liver. 1993.. The incidence of liver diseases in humans increases with age up to 75 years.. GH.. and/ Insulin resistance. and HCC. While the disease is reversible in its early posed challenges such as viral hepatitis or alcohol consumption during stages. 951 nutritional oversupply? Is aging then an actual risk factor for liver NAFLD is a progressive disease characterized by hepatic fat diseases. Although it is much Aging and nonalcoholic fatty liver disease (NAFLD) debated whether insulin resistance is a cause of age-associated NAFLD is the most common chronic liver pathology in the United States. ER Stress. Insulin resistance is (Cohen et al. Consistent with this. decreased b-oxidation. F. metabolic disturbances or rather a protective adaptive mechanism affecting almost 40 million obese adults or 15% of the population. These mechanisms may include enhanced resistance and predisposes to type 2 diabetes and cardiovascular disease. IL-6.. Although NAFLD is a strong and independent predictor for the mediated lipid accumulation with age remain undefined (Ghosh et al. 1). EGF.. 2012). development of type 2 diabetes. 2002). NF-kB).6 million develop NASH as a result of multiple abnormalities of hepatic lipid metabolism. resulting in enhanced fat uptake by the tor (Sanguino et al. If not treated. Jin et al. IR Healthy liver Steatosis NASH Chronic inflammation. although the specific mechanisms underlying b-adrenergic- 2008). Obesity. 2004). NASH. a cluster of abnormalities that includes insulin are yet to be clearly defined. further driving NAFLD (Brown & Goldstein. advanced NASH (Fig. However. it is generally believed that age is a risk also the 4th most common reason for liver transplants. whether acquired or genetically determined. ª 2013 the Anatomical Society and John Wiley & Sons Ltd . About 30. 2011). nonalcoholic steatohepatitis (NASH). and HCC) and the respective molecular changes are represented on the right. MetS. or a bystander? This review discusses the evidence both accumulation (liver steatosis) in the early stages and hepatic inflam- supporting and confuting the interrelationship between aging and mation driving the transition from benign steatosis toward more NAFLD. thereby accelerating fatty acid synthesis and triglyceride induction of liver steatosis with aging (Katz et al. Scars. 2008). synthesis in the liver. insulin continues to activate important role for augmented hepatic-adrenergic signaling in the lipogenesis. TGF-β Hepatocyte proliferation 75-90 + Incidence of HCC drops HCC significantly in subjects of age 75 and older Fig. Fat may accumulate in the liver million obese adults contract liver steatosis and 8. (Angulo. Collagen deposition. ROS. the link between insulin resistance and 2012). Lipotoxicity. Liver diseases and aging. fat uptake. NASH may progress to cirrhosis. 2013. subjects aged more than 75 have a significantly reduced incidence of hepatocellular cancer (HCC) (left). Giant cell Necrosis Liver disease incidence < 75 Increases with age Growth factors IGF1.1 factor for increased hepatic steatosis. Cirrhosis JAK/STAT. Western diet. it was found that the p300-p-C/E Smoking. The different states of liver disease progression (NAFLD. In a hyperinsulinemic state. cirrhosis. 1). Sun & during aging causes the activation of 5 key genes that drive triglyceride Lazar. TNFα. recently provided a clear molecular NAFLD has not always been demonstrated and there are a number of mechanism for the age-associated development of steatosis by studies reporting dissociation of NAFLD from insulin resistance in genetic demonstrating that p300-dependent regulation of chromatin structure mouse models and in patients (Aparicio-Vergara et al.. its treatment becomes more complicated in the advanced state. NAFLD is regarded as the hepatic manifestation of the although the mechanisms that underlie this age-related liver steatosis metabolic syndrome. Apoptosis Fibrosis. Cytokines (IL-1β. 1 Schematic illustration of the pattern of liver disease progression during aging. aging. In addition. 2012). Sedentary life style.. Moreover. is found or decreased synthesis/secretion of very low-density lipoproteins in approximately 60% of all patients with NAFLD. reported to decline in livers with old age. 2013). 2013) (Fig. Ghosh et al. involving reduced hepatic there is a failure to suppress the flux of free fatty acid derived from the expression of nuclear receptor peroxisome proliferator-activated recep- expanding adipose tissue mass. b-oxidation has been believed to be the primary cause of NAFLD. It is (Barzilai & Ferrucci. increased de novo lipogenesis. We will not cover here the role of superim. See text for details. Other studies have highlighted an liver (Tilg & Moschen. Interestingly.

flies. Given that elderly patients have more severe biological background favoring susceptibility to age-related diseases/ liver disease as compared with nonelderly patients (Koehler et al. demonstrated that tissue (Smith & Pereira-Smith...5 and 5 months. 2011. However. Although aging has (Floreani. 2013). Detrimental factors that et al. and growth and C/EBP proteins are essential participants in hepatic steatosis with hormones age in both mice and humans (Jin et al. Honma et al.. 2012).. enrolling 2811 individuals. 2013). increased proinflammatory M1 macrophage manner (Wang et al. average the development of HCC (Wang et al. 2007). enrolling 735 nonelderly (18–64 years old. Noureddin et al. fat is redistributed outside 2012. this resolution of hepatic steatosis may IGF-1 levels observed in elderly individuals is a feature that. Only are cigarette smoking and a sedentary lifestyle (Breitling et al. liver-specific transgenic mouse model. the liver may take a long time for regenerating. Components of the IGF1 pathway such as PI3K/ been reported to increase lipid accumulation in the liver (Petersen AKT and GSK3beta (Jin et al. as well as other undergoing prolonged fasting or a diet based on 500 kcal day 1 features of severe liver disease (Noureddin et al. Chan et al.. and metabolic dysfunction (Rodriguez et al. fat depots resulting in ectopic lipid accumulation in nonadipose tissues ª 2013 the Anatomical Society and John Wiley & Sons Ltd . 2013). aging had an important role in strated to be crucial for the development of HCC in a C/EBPa-dependent inducing liver damage. 2009b) have been demonstrated to et al. Even if hepatic steatosis is considered intrinsic to disease development. Fontana et al. 2011). in a of participants aged 80–84 years (n = 495). the persistence of inflammatory stimuli over time represents the (Noureddin et al. 2012).6% of participants aged 70–74 (n = 809) the modification of the IGF1/AKT axis and C/EBPa. Remarkably. As previous studies in centenarians have shown (Tietz been suggested as contributing factors. activation of nuclear factor-kappa B (NF-jB) signaling the last 80 years. characterized by increased levels of inflammatory markers such as (van der Poorten et al. a clear trend of at a young age (Timchenko. 2013). 2004). 1996. Recent data also demonstrate gradual decline of growth hormone (GH) and insulin-like growth factor 1 a strong correlation between hepatocyte senescence markers and (IGF1). the inflammatory. the aging known as burnt-out NASH and may be related to a number of process is driven by an unbalanced stimulation/response of the immune proposed mechanisms including elevations in serum adiponectin levels system. In addition to <70 years (n = 455). advanced liver fibrosis in NASH is often accom- Inflamm-aging and liver function panied by a reduction in steatosis to the point of complete fat loss (van der Poorten et al.. 2009). 2003. 2013). example of antagonistic pleiotropy whereby cellular proliferation allows showed that NAFLD was found in 35. in old age. changes in mitochondrial metabolism (Caldwell & Crespo. BP-DGAT2 pathway is activated in human NAFLD. Fontana et al. caloric restriction (CR) has been demonstrated to (the master regulator of inflammatory responses) (Franceschi et al. overall liver function under normal synergistically exacerbate the clinical spectrum of NAFLD during aging physiological conditions is not dramatically impaired with aging.. (Koehler et al.. 1987. 2004).. in Czaja. 2013). 2013). 2000). A recent clinical study hormonal changes may drive the cell to enter a protective mode against by Noureddin et al. Also. average 68  3).. aging also causes an years. which have been positively associated with longevity. will respond differently as compared to younger high-fat regimen diet for 16 weeks. as well as decreased 1984). 2013). 2012). and collagen deposition in the liver theory. Ghosh et al. DNA damage (Aravinthan et al. caloric restriction. obtained with CR extends life span in a variety of in vivo models and has both groups displaying NAFLD.. telomere the incidence of some age-related diseases (Pekkanen et al. such as hepatectomy or acute liver Booth et al. Sheedfar et al. The natural decline of the PI3K/AKT and polarization and therefore increased inflammatory response and GSK3 axis during aging can be seen as a positive feature whereby these development of NASH (Fontana et al. 2010). 2010. and aged (18 months old) mice on a and. indicating that p300 Aging liver. F. By putting young (2 months old). Another increased NAFLD prevalence and severity and those showing an physiological change that negatively influences liver function is the attenuation is due to the fact that the former ones were conducted in redistribution of adipose tissue from subcutaneous to visceral sites middle-aged/old.. and rodents 2000). An increased protein level of HDAC1 is decline in the incidence of NAFLD in the very elderly as age advances also involved in tumor development (Halkidou et al. Fontana et al..952 Liver diseases and aging. 2013. respectively (Harrison & much larger population-based study to describe the prevalence of Day... In addition. 2013). In addition. reactive oxygen species (ROS). 2004) (Fig. The decrease of GH 47  11) and 61 elderly patients (>65 years old. One of the features decline in liver blood flow associated with aging is not affected by of the aging process. rather than in very old mice and humans (Vinciguerra. accumulation of reactive Physical activity and nutritional habits are variables in lifestyle that decrease oxygen species. 2007). led to the development of steatosis ipants aged older than 85 years (n = 265): overall. This paradoxical but well-replicated finding is As originally proposed by Franceschi (Franceschi et al.... the old liver is not able to regenerate properly middle-aged (8 months old). Though. which directly or indirectly affects liver function. 2013)... and in 21. Aravinthan et al. in 39. Gagliano et al. beneficial. control hepatocyte senescence by increasing the levels of cyclin D3 and by recently showed a different view of the impact of aging on NAFLD holding them in a G1 phase through a mechanism mediated by C/EBPa. development (Fontana et al. 2012). 1). catabolic state accompanying cirrhosis phase 1 detoxifying enzymes (inflamm-aging theory). 1995). although in part explain the reduction in NAFLD prevalence with advanced age. 2007) have also (Partridge. showed that elderly patients had a shown significant benefits in recovery from liver steatosis in humans higher prevalence of NASH and advanced fibrosis...1% of partic.. cytokines. aging per se does not affect the development of simple steatosis uncontrolled activation of this regenerative process has been demon- (Fontana et al. 1999)... 2012). 2011). chemokine. The upregulation of GH/IGF1 in hepatocytes is thus an NAFLD in the elderly (the Rotterdam study). However. when placed under stressful conditions..... the above-mentioned physiological injury. Blair shortening (Tomas-Loba et al.. Under normal conditions. 1992.. increase the maximum life span in yeast.. in 32. is the smoking habits (Vestal & Wood. in 36.1% increase in the protein levels of histone deacetylase 1 (HDAC1) which. worms...8% of participants aged for a better recovery from liver injury but may lead to HCC.. It is important to stress that the natural decrease in GH/ 2012.6% of participants aged 75–79 years (n = 787).. (Tchkonia et al. which undergo a 50% reduction between the ages of 20 and 75 NAFLD (Park et al. 1). disabilities (Fig. 1999). Noureddin et al. According to this (McCullough & Raguso. 2013). portosystemic shunting (Nosadini et al. levels of antioxidant enzymes such as superoxide dismutase (SOD) and 2004). 1).. 2013). 1980). 2007) (Fig. has to be coupled with practices aimed at reducing the We propose that the discrepancy between the studies showing increased levels of inflammation in order to lead to healthy aging. decrease in autophagy (Amir & et al. a consumption for periods of 2. when stressed. 2009. hypercholesterolemia (Bonomini et al.

biological age. background of ‘pure’ steatohepatitis (Rappa et al. Stienstra R. Bosch FX. The pathogenetic mechanisms and therapeutic insights. 2013). Penrhyn-Lowe S. all of which increase the chances of developing NAFLD (Tran et al. van de Sluis B. Kloosterhuis NJ. N. which is not Bucher NL. Gastroenterology 127. HCC arises in the setting of cirrhosis. Amir M. Muller H. Hofker MH. Rodella LF. In Amir M.. and up to Barzilai N. Cell Metab. 2006. is supported within the framework of intake may be key factors for healthy aging. 25. biochemical variables and plasma amino acids among centenarians. the very elderly protected against developing HCC? The mice studies Booth FW. surgical resection. J. 2011). Harvey R. Concomitantly with the rising rates of response? J. but hepatitis B Gastroenterol.. 95–96. most commonly References called radiofrequency ablation. Strong epidemiological data suggest that in humans the incidence of SE. when discussing age-related diseases such and new insights. 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JAMA 273. 18. This occurs (1995) Changes in physical fitness and all-cause mortality.. 1519–1523. 802–808. Liver Dis. Macera CA younger patients between ages 40 and 60 (El-Serag. 67. We propose that Fontana L. Med. but show that aging per se does not affect steatosis. 346. Ferrucci L (2012) Insulin resistance and aging: a cause or a protective 90+ (El-Serag. Czaja MJ (2011) Autophagy in nonalcoholic steatohepatitis. Clin. even in lean individuals (Slawik perspective. Rezzani R (2013) Apolipopro- expected to increase in developed countries because of the rising incidence tein E deficiency and a mouse model of accelerated liver aging. 2007). 2010). (mice or humans) become resistant to the development of injury. Liver diseases and aging. 2011. Hepatol. Horton JD. Acknowledgments acting inflamm-aging and adipose tissue redistribution in older people and F. which reflects health status De Minicis S. 2004). NASH. insulin resistance. 365. Koonen DP. 2010). 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