Journal of Gerontology: BIOLOGICAL SCIENCES
1998, Vol. 53A, No. 5. B315-B320
In the Public Domain
Aging and the Liver: An Update
Douglas L. Schmucker
Cell Biology and Aging Section, San Francisco Department of Veterans Affairs Medical Center;
Department of Anatomy and the Liver Center, University of California, San Francisco.
The issue of whether or not liver function is compromised in the elderly population remains unresolved. Numerous
age-related changes in hepatic structure and function have been described, but many of these observations are
qualitative, were made under suboptimal experimental conditions, or are simply contradictory. Changes in hepatocellular structural parameters, e.g., increased hepatocyte size, increase in the number of binucleated cells, altered
mitochondria, and endoplasmic reticulum, have been reported. However, quantitative morphological analyses have
refuted many of these observations. There are few functional data that correlate with structural changes. Serum
and biliary cholesterol appear to rise, predisposing elderly people to increased incidences of coronary disease and
gallstones, respectively. The rate of liver regeneration declines in old animals, but the regenerative capacity remains
unchanged, perhaps reflecting an age-associated reduction in the response to hepatotrophic factors. This senescent
change has important clinical implications with regard to surgical intervention for liver disease, e.g., resection or
transplantation. Nevertheless, most outcomes studies suggest that age alone should not be a determining factor in
such clinical decisions. Geriatric patients exhibit a decline in the hepatic clearance of certain drugs and a marked
increase in the frequency of adverse drug reactions, reflecting an increase in polypharmacy regimens and declines
in liver volume and blood flow rather than reduced Phase I metabolism. Although the livers of elderly subjects are
characterized by a decline in adaptive responsiveness and reduced reserve capacity, clinical tests suggest that liver
function is well-maintained in this age group.
A GING affects different organs, tissues, and cell types in
l \ the same organism in different ways; that is, the
extent of age-associated perturbations of structure and
function is site-specific. The effects of aging on the mammalian liver have not been clearly resolved. Despite the
plethora of age-associated changes in hepatic structure and
function that have been described, many of these observations are qualitative in nature, were made under less than
optimal experimental conditions, or are simply conflicting
[see (1,2) for reviews]. Therefore, the question of whether
or not the liver is compromised intrinsically in senescent
animals or elderly humans remains unclear. The late
pathologist and hepatologist Hans Popper stated some
years ago that "aging exerts a limited effect on the constitutive functions of the liver and more on its response to
extrahepatic factors..." (3). Inasmuch as it has been more
than eight years since we last visited this topic, this report
is a survey of the current understanding of the effects of
aging on liver structure and function.
Liver Morphology
There have been few comprehensive studies on liver morphology during aging, and most of these have been performed in rodents. The few studies that have described the
nature and extent of changes in human liver structure have
suffered from deficits in experimental design, e.g., a reliance
on post mortem samples or on tissues from subjects diagnosed with liver disease. Furthermore, there has been little
effort to distinguish changes associated with maturation
from those that are clearly a consequence of senescence.
The most frequently cited postmaturational change in
human liver is a decline in organ mass, although there has
been disagreement concerning even this basic parameter
(4-6). One study reported that liver mass declines >40% in
humans during the first two to three decades of life, but that
it remains virtually stable thereafter (7). Two more recent
studies, using more sophisticated and sensitive measurements, concluded that liver volume declines between maturity and senescence in humans (8,9). The implications of
reduced liver volume and hepatic blood flow in the elderly
are unclear, but may have a critical impact on such parameters as the pharmacokinetic profiles of drugs that undergo
mandatory hepatic oxidation.
The liver in elderly humans has been characterized as
having fewer, larger hepatocytes with increases in polyploidy and in the binuclear index (3,10-12). Unfortunately,
small sample sizes and the qualitative nature of many of
these studies preclude any meaningful correlations with
functional analyses (13). While nuclear ploidy increases in
rodent livers, the data from human tissue are conflicting
(14-17). A recent study in humans reported that the rate of
hepatocyte polyploidization is slow during the first five
decades of life, but that it increases substantially, with subjects between 86 and 92 years of age exhibiting 27% polyploid nuclei (18).
The frequency of hepatocytes with enlarged nuclei in
humans reportedly increases by 20% between thefirstand
eighth decades of life (10). Several studies reported no
change or an increase in the binuclear hepatocyte index
during aging in rodents and humans (19,20). However, our
own studies in inbred Fischer 344 rats did not demonstrate
a significant age-associated change in the number of binuclear hepatocytes (21). DePriester et al. (22) suggested
that an age-associated increase in the hepatocyte binuclear
B315
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SCHMUCKER
index, coupled with no change in hepatocyte volume, results in an increase in the nucleocytoplasmic ratio. In agreement with this and other studies, our own analyses demonstrated that age-associated changes in the hepatocyte
nucleocytoplasmic ratio reflected concomitant shifts in cell
and nuclear volumes (21,23,24; see Figure 1). Although
aging appears to be accompanied by an increase in hepatocyte nuclear ploidy, changes in cell and/or nuclear volumes
are less apparent owing, in part, to an age-associated increase in interindividual variability.
The results of most fine structural analyses have not
yielded evidence of marked or consistent age-associated
alterations in rodent hepatocytes (Figure 2). Although there
are conflicting data, several investigators have reported that
aging in rodents and humans is associated with (a) an
increase in individual mitochondrial volume and (b) a decline
in the number of mitochondria in the liver (19,25,26).
Recently, Sastre et al. (27) reported that hepatic mitochondria
isolated from old rats were larger than those obtained from
young adult animals. However, it should be noted that these
data were derived from mitochondrial suspensions using flow
cytometry, not from intact tissue using electron microscopy
and stereological analysis. The impact of such structural
changes on mitochondrial function has not been elucidated,
although two studies have demonstrated age-associated
deficits in liver mitochondrial respiratory rates (28,29).
Perhaps the only definitive evidence of an age-associated
structural change in the liver is an increase in the volume of
the dense body compartment, i.e., secondary lysosomes and
residual bodies, and the concomitant accumulation of lipofuscin (see ref. 1 for a review). Four separate stereological
analyses reported two- to eightfold increases in the relative
volume of the dense body subcellular compartment as a
function of increasing age (21-23,30). However, other studies have shown that constituent lysosomal acid hydrolases
exhibit variable activities and heterogenous distribution
patterns in rodent livers during aging, and that lysosomal
function does not necessarily correlate with an increase in
the volume of this organelle compartment (31-35).
Most hepatocyte subcellular compartments undergo few
or no changes in volume or distribution during aging. A few
organelles or cytoplasmic inclusions exhibit age-associated
alterations in appearance or density. For example, two stereological studies reported that the volume of rat hepatocyte
cytoplasmic lipid droplets undergoes a biphasic response
during aging, i.e., a gradual postmaturational increase followed by a decline during senescence (21,36; see ref. 1 for
a review). Quantitative structural and functional data from
several laboratories have suggested that the relative amount
of rough-surfaced endoplasmic reticulum reflects concomi-
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Figure I. The effect of aging on the hepatocyte nucleocytoplasmic ratio
in male Fischer 344 rats. The data were derived from nuclear and cytoplasmic volumes obtained by light and electron microscopic stereological
analyses of perfusion-fixed tissue (21). Each point represents the mean
value for six animals ± SD.
B
Figure 2. Electron micrographs of liver tissue from 1 month (A) and 30
months (B) male Fischer 344 rats depicting typical hepatocyte fine structure in these two age groups. There are no marked differences in hepatocyte architecture with the exception of an age-associated increase in the
number of lysosomal-derived dense bodies (arrowheads). Asterisks (*),
bile canaliculi; arrows, rough surfaced endoplasmic reticulum; S, sinusoidal surface or space of Disse. 7,000-9,500X
B317
AGING AND THE LIVER
tant shifts in the protein synthesizing capacity of the rat
liver during aging (21,37-41). Information concerning the
effects of aging on other hepatocellular membrane compartments, e.g., the smooth-surfaced endoplasmic reticulum
(SER), is conflicting. Our own stereological analyses
demonstrated a significant loss of SER from rat hepatocytes
in lobular zones 1 and 3 between maturity and senescence
(21,41). This observation correlates well with a concomitant decline in the yield of liver microsomal protein from
similarly aged rats of the same strain (42). The only other
study to measure SER surface area in rat hepatocytes during aging reported an initial loss of membrane followed by
an increase during maturation and senescence, such that the
oldest animals examined contained similar or greater
amounts of this organelle than young rats (24). The fact that
the liver contains a heterogenous population of hepatocytes
(a) whose individual ages do not correlate directly with
host age and (b) that exhibit structural differences according to their sublobular location may obscure age-associated
changes in cell structure.
Hepatic Function
Although there is evidence that aging affects certain hepatic functions, the field of geriatric hepatology remains conflicting and uncertain (see refs. 43-45 for reviews). This
uncertainty is attributable, in part, to the marked increase in
interindividual variability in many physiological parameters that characterizes elderly people.
Liver function tests.—The results of liver function tests
in elderly subjects are conflicting or inconclusive. Numerous tests have failed to identify significant age-associated
deficits in hepatic functions (46). In early studies, bromsulphthalein retention was the only index that changed as a
function of age in a comprehensive battery of liver function
tests (47). More recently, Tietz et al. (48) evaluated 15,000
laboratory values in more than 200 subjects across a substantial age spectrum and concluded that many liver functions were well maintained in the elderly subjects based on
parameters such as hepatic enzyme profiles, and serum
albumin and HDL cholesterol values (see Figure 3). Bilirubin values decline with increasing age, perhaps reflecting
reduced muscle mass and hemoglobin concentration. Fabbri et al. (49) reported a 30% decline in functional hepatic
nitrogen clearance (p < .01), i.e., the rate of conversion of
a-amino nitrogen into urea nitrogen, in subjects over 70
years in comparison to those under 55 years of age. Bohnen
et al. (50) measured a battery of liver functions in subjects
across an age span of 60 years and concluded that significant and clinically relevant changes in serum lipid and
enzyme levels occured in the elderly subjects.
Biliary function and cholesterol metabolism.—Studies in
several laboratories, including our own, demonstrated ageassociated deficits in a variety of biliary functions, including bile flow and bile acid secretion. For example, both
basal and taurocholate-stimulated bile flow and bile acid
secretion rates are diminished (p < .05) in old rats in comparison to young adult animals (51; see Figure 4). Bile acid
synthesis declines in geriatric subjects, although the hepatic
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HDL Cholesterol (mg/L)
Alk P'ase (U/L)
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50
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Young Adults
60-90
Age
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Figure 3. Clinical serum values in young adult and elderly subjects
derived from a comprehensive analysis of the effect of aging on liver
function tests in humans. The data are expressed as the percentage of the
young adult values, and the asterisks (*) denote statistically significant
differences (p < .05). Data from Tietz et al. (48).
12
24
Age (months)
Figure 4. The effect of aging on basal and taurocholate-induced bile
flow (A) and bile acid secretion (B) in male Fischer 344 rats. Bile flow
and total bile acid secretion rates were measured in untreated young,
mature, and old rats with bile duct fistulae (basal) or age cohorts infused
with physiological levels of taurocholate via the femoral vein (taurocholate). Each bar represents the mean value for five rats ± SD. Differences between young adult (3 months) and mature (12 months) or old (24
months) rats are statistically significant at the p < .05 level (51).
B318
SCHMUCKER
secretion of cholesterol increases with age (52). Reduced
bile acid synthesis in elders may reflect a significant diminution in the rate of cholesterol 7a-hydroxylation (53). An
age-associated decline in the hepatic metabolism of LDL
cholesterol further exacerbates elevated serum cholesterol
levels (54-56). Collectively, these events probably contribute to increases in the cholesterol saturation of bile, in
the frequency of gallstones, and in the incidence of coronary heart disease in elderly people.
Drug clearance.—Drug clearance in general, and the
clearance of drugs that undergo mandatory Phase I hepatic
metabolism in particular, appear to be compromised in
elders (see refs. 57,58 for reviews). Reduced drug clearance
predisposes elders to an increased incidence of adverse
drug reactions (ADRs), especially because many geriatric
patients are subject to polypharmacy regimens. The FDA
has reported that the percentage of polypharmacy, i.e., five
or more drugs taken simultaneously, in individuals over 60
years of age is equal to that measured in all younger age
groups combined. Prescribing potentially inappropriate drugs
may affect up to 25% of community-dwelling elders and
contribute to the well-documented increase in the incidence
of ADRs in this age group (59-61).
For many years, data derived from experiments using
inbred male rats, and from less than critical clinical pharmacokinetic studies, substantiated the belief that the ageassociated decline in hepatic drug clearance was due to
reduced Phase I metabolism. Declines in the amounts and
activities of specific liver microsomal monooxygenases, as
well as in the amount of the intracellular site of these
enzymes, the SER, contributed to this perception. Contrary
to the data in inbred male rats, there is little evidence that
reduced drug clearance in elderly humans reflects deficiencies in the cytochrome P-450-dependent metabolism of
these xenobiotics. Unlike the rat cytochromes P-450, the
human liver isoforms do not appear to exhibit many agedependent shifts in their relative concentrations or activities
(62-64). A recent correlated in vivo and in vitro study in
humans suggested that a 30% decline in hepatic drug
metabolism after 70 years of age reflected similar reductions in the liver cytochromes P-450 content and antipyrine
clearance rate (65). However, two 1988 studies have shown
that liver volume and hepatic blood flow in healthy, ambulatory elders declines appreciably in comparison to young
subjects (8,9). The losses of liver mass and hepatic blood
flow, rather than intrinsic alterations to constituents of the
microsomal monooxygenase system, contribute to reduced
drug clearance in the elderly subjects.
Liver regeneration.—Although the liver's regenerative
potential appears to remain intact in aging rats, the rate of
regeneration declines with increasing age (66). This conclusion is based on the observation that it takes considerably
longer for partially resected livers in old animals to regain
their original volume in comparison to young animals.
However, the regulation of hepatic regeneration is poorly
understood regardless of animal age. The effects of aging
on the circulating levels of hepatotrophic factors, e.g., epidermal growth factor (EGF), transforming growth factor-a
(TGF-a), and the hepatic responses to these factors are
important issues in any consideration of liver regeneration.
For example, circulating EGF levels decline markedly in
elderly humans, and the response of hepatocytes to this
trophic factor is diminished in old rats (67-69). The basis
for reduced hepatic responsiveness to EGF in senescent rats
has not been entirely resolved. Studies initiated in our laboratory demonstrated a significant age-associated loss of EGF
receptors (>50%) from rat hepatocytes, whereas Sawada
did not detect any differences in EGF binding kinetics between young and old rats (69-71). Sawada's data suggest
that deficits in events distal to receptor binding may contribute to the age-associated declines in hepatic responsiveness to EGF and, ultimately, in the rate of liver regeneration.
Despite the fact that diminished hepatic regeneration following surgery is a critical clinical issue in decisions of
whether or not to perform liver resections in elderly patients, there is a paucity of data concerning this function in
elders. Retrospective analyses have shown that mortality
rates associated with liver resection were somewhat higher
in subjects over 60 years of age (12-14). On the one hand,
Former and Lincer (72) demonstrated strong correlations
among patient age, increased operative mortality, extent of
resection, and hepatic insufficiency (Figure 5). On the other
hand, several studies have reported that major hepatic resection in elderly patients is not associated with increased
postoperative morbidity or mortality (75-79). Age is also a
major consideration in decisions concerning liver transplantation, for both the donor and the recipient. However, the
issue of age as a limiting factor in determining the suitability of a liver donor has been somewhat assuaged in recent
years with livers from donors up to 65 years of age being
considered viable for transplant. Nevertheless, the age of
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55-64
65-74
>75
Age (years)
Figure 5. Effect of aging on the postoperative mortality rates in patients
undergoing hepatic resection. Although the rate increases with patient
age, the number of patients undergoing this procedure diminishes
markedly with increasing age. The numbers above each respective bar
represent the number of deaths per number of procedures. Data from Fortner and Lincer (72).
AGING AND THE LIVER
potential recipients has both clinical and ethical implications, including whether or not elderly patients can tolerate
the physiological stress associated with liver transplant.
Another index of the age-associated decline in liver function is reduced hepatic responsiveness to a variety of extrinsic stimuli. The classic studies of Kato and Adelman
demonstrated significant lags in the induction of certain
liver enzymes, microsomal mixed function oxidases and
glucokinase to phenobarbital and glucose, respectively, in
old rats in comparison to young animals (80; see ref. 81 for
a review). A more recent example is the marked age-associated decline in the induction of heat-shock or stress proteins following injury (82,83). Increased expression of
these proteins is considered to be a protective response, and
there is evidence that they are important for liver repair.
Some researchers have postulated a correlation between
reduced expression of stress proteins and an increase in the
incidence and severity of liver diseases in elders.
Summary
There are few age-associated changes in liver structure
that correlate with perturbations in hepatic function. With
the exceptions of (a) a loss of organ volume and (b) an
increase in the relative volume of dense bodies, the evidence for other suspected age-associated changes in hepatic
structure is either conflicting or suspect. Aging is not a uniform process, as organ-specific aging and interindividual
variability in the elderly are well documented. Physiological and morphological studies suggest that, compared with
other organs, the liver seems to age fairly well. Perhaps the
most compelling evidence for the maintenance of hepatic
function into advanced age comes from clinical practice,
wherein livers from elderly subjects, including one donor
aged 86 years, have been transplanted successfully (84-86).
ACKNOWLEDGMENTS
Substantial portions of the author's research presented in this review
were supported by the Department of Veterans Affairs, the National Institutes of Health, the American Federation for Aging Research, Phillips
Petroleum Company, the University of California, and NATO.
Address correspondence to Dr. Douglas L. Schmucker, Cell Biology
and Aging Section (15IE), DVA Medical Center, 4150 Clement Street,
San Francisco, CA 94121. E-mail: SCHMUCKER.DOUGLAS_L@
SANFRANCISCO.VA.GOV
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Received February 23, 1998
Accepted May 19,1998
[oLE
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National Institutes of Health, Bethesda, Maryland
A Senior Executive Service Vacancy
ASSOCIATE DIRECTOR, BIOLOGY OF AGING RESEARCH PROGRAM
NATIONAL INSTITUTE ON AGING
THE POSITION:
Associate Director (AD) for the
Biology of Aging Research (BAP) Program, National Institute
on Aging (NIA), one of the world's largest and most comprehensive institutions in aging research. NIA conducts, fosters,
and supports biomedical, social, and behavioral research
and training pertaining to aging processes and common
problems and needs of the aged. The AD, BAP, serves as
the principal advisor to the Director, NIA, in the area of the
basic biological sciences, and oversees the BAP program as
well as collaborates with other NIA program activities. The
AD plans and directs extramural and collaborative research
and training at university medical centers and other basic
biological research institutions throughout the United States.
The AD administers the issuance of National Research
Service Awards to individuals and grants to institutions with
relation to training in aging; and collects and disseminates
information on research and findings in the area of aging.
T H E C H A L L E N G E : Leadership in the overall scientific administration of an innovative research program in the
field of basic biological research with a Fiscal Year 98 budget
of $80 million. Support a broad spectrum of research and
training aimed at a better understanding of the biological
aspects of aging. Evaluate the Program's needs in relation
to the mission of NIA as well as exploring new dimensions in
the field of research and training. Expand knowledge in the
areas of biology of aging research and guide the NIA's multidisciplinary approach to collaborating and disseminating
information to Federal agencies, the public, and at the international level.
T H E I D E A L C A N D I D A T E : Demonstrated scientific
leadership and management of a basic biological research
program of national and international standing. M.D. or
Ph.D. or comparable experience and training in one of the
biomedical sciences. Must have research experience in an
area of basic biological research which meets the following
requirements:
1. Knowledge and ability to lead a scientific program
of national and international scope in basic
biological research which includes managing a large,
multi-disciplinary research program. Experience
developing and implementing new or restructured
basic biological research programs to meet national
and international health and research needs.
Experience designing policies for the initiation and
execution of multi-disciplinary research and
determining the productivity and effectiveness of
current research.
2. Ability to provide leadership and broad vision to a
large research program with extensive managerial
and executive level responsibilities (i.e. training,
research resources, strategic planning, budgeting,
and human resource management) in a diverse
organization. Experience in managing and
directing a large scale, multi-disciplinary scientific
research program, with responsibility for recruiting,
retaining, and rewarding a highly capable,
culturally diverse work force; and for developing
and executing organizational, budgetary, and
human resource plans.
S A L A R Y R A N G E : This is a Civil Service position in the
Senior Executive Service (SES), with a salary ranging from
an ES-1 to ES-6 level per annum (currently $106,412 to
$125,900). Physicians may be eligible for an annual comparability allowance of up to $20,000. A recruitment bonus of
up to 25 percent of base pay may be available to a non-federal candidate, subject to individual approval; a relocation
bonus of up to 25 percent of base pay may be available to a
permanent Federal employee who must relocate, subject to
individual approval.
H O W T O A P P L Y : Applicants are required to submit a
bibliography and either a curriculum vitae, Application for
Federal Employment (SF-171), Optional Application for
Federal Employment (OF-612), resume, or any other written
format which addresses the requirements indicated in this
announcement. Application materials must be sent to the
address below.
Applications must be postmarked by November 6, 1998
and received by close of business November 13, 1998.
All application forms are subject to the provisions of the
Privacy Act and become the property of the DHHS.
For further information contact Ms. O'Connor in the NIA
Personnel Office at (301) 496-5460, or e-mail address:
[email protected]. To receive a faxed copy of the
vacancy announcement, call 1-800-728-5627, fax ID 1202.
Selection for this position will be based solely on merit, with
no discrimination for non-merit reasons such as race, color,
religion, sex, national origin, politics, marital status, physical
or mental disability, age, sexual orientation, or membership
or non-membership in an employee organization.
National Institute on Aging
Building 31, Room 2C02, 31 Center Drive MSC 2292
Bethesda, Maryland 20892-2292
Attn: Ms. O'Connor, OR E-mail: [email protected]
NIH is an Equal Opportunity Employer
TEJ