Physicians need to take the lead in deprescribing.

Inappropriate polypharmacy and its associated harm pose a significant threat to older patients. The prescribing decisions of physicians greatly influence what other practitioners prescribe. Minimising medication-related harm requires physicians to adopt a systematic approach to the deliberate and judicious deprescribing of potentially inappropriate medicines in at-risk individuals.

Predictors of the rate of BMD loss in older men: findings from the CHAMP study.

UNLABELLED: Though bone loss tends to accelerate with age there are modifiable factors that may influence the rate of bone loss even in very old men. INTRODUCTION: The aim of this 2-year longitudinal study was to examine potential predictors of change in total hip bone mineral density (BMD) in older men. METHODS: The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia. For this study, 1,122 men aged 70-97 years had baseline and follow-up measures of total hip BMD measured with dual X-ray absorptiometry. Data about mobility, muscle strength, balance, medication use, cognition, medical history and lifestyle factors were collected using questionnaires and clinical assessments. Serum 25-hydroxyvitamin D [25(OH)D] was also measured. Multivariate linear regression models were used to assess relationships between baseline predictors and change in BMD. RESULTS: Over a mean of 2.2 years, there was a mean annualised loss of total hip BMD of 0.006 g/cm(2)/year (0.6 %) and hip BMC of 0.14 g/year (0.3 %). Annual BMD loss accelerated with increasing age, from 0.4 % in men aged between 70 and 75 years, to 1.2 % in men aged 85+ years. In multivariate regression models, predictors of faster BMD loss were anti-androgen, thiazolidinedione and loop-diuretic medications, kidney disease, poor dynamic balance, larger hip bone area, older age and lower serum 25(OH)D. Factors associated with attenuated bone loss were walking for exercise and use of beta-blocker medications. Change in BMD was not associated with baseline BMD, smoking, alcohol consumption, BMI, frailty, or osteoarthritis. CONCLUSION: There was considerable variation in the rate of hip bone loss in older men. Walking, better balance and beta blockers may attenuate the acceleration of BMD loss that occurs with age.

Haem Iron Intake Is Associated with Increased Major Adverse Cardiovascular Events, All-Cause Mortality, Congestive Cardiac Failure, and Coronary Revascularisation in Older Men: The Concord Health and Ageing in Men Project.

BACKGROUND: Nutritional intake can influence major adverse cardiovascular events (MACE). Dietary iron is found in two forms: haem-iron (HI) only found in animal sources and non-haem iron (NHI) present mostly in plant sources. OBJECTIVE: We evaluated the associations between dietary iron intakes with MACE and iron status biomarkers. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 539 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent nutritional assessment using a validated diet history questionnaire. Entries were converted to food groups and nutrients. The dietary calculation was used to derive HI and NHI intakes from total iron intakes. Analyses of iron intakes with iron status biomarkers were conducted using linear regression, and with MACE and individual endpoints were conducted using Cox regression. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality. RESULTS: At a median of 5.3 (4.6 - 6.3) years follow-up, the incidences were: 31.2% (n = 168) five-point MACE, 17.8% (n = 96) four-point MACE excluding all-cause mortality, 20.1% (n = 111) all-cause mortality, 11.3% (n = 61) CCF, and 3.1% (n = 15) coronary revascularisation. In adjusted analyses, higher HI intake (per 1mg increment) was associated with increased five-point MACE (HR: 1.45 [95% CI: 1.16, 1.80, P = .001]), four-point MACE excluding all-cause mortality (HR: 1.64 [95% CI: 1.26, 2.15, P <.001]), all-cause mortality (HR: 1.51 [95% CI: 1.15, 1.99, P = .003]), CCF (HR: 2.08 [95% CI: 1.45, 2.98, P <.001]), and coronary revascularisation (HR: 1.89 [95% CI: 1.15, 3.10, P = .012]). Compared with the bottom tertile of NHI intake, the middle tertile of NHI intake was associated with reduced risk of all-cause mortality (HR: 0.56 [95% CI: 0.33, 0.96, P = .035]). Total iron intake was not associated with MACE and individual endpoints. Dietary iron intakes were not associated with serum iron and haemoglobin. CONCLUSION: Higher haem iron intake was independently associated with increased risks of five-point MACE, four-point MACE excluding all-cause mortality, all-cause mortality, CCF, and coronary revascularisation in older men over 5 years.

Does social support predict increased use of dental services in older men?

BACKGROUND: Past research on social support and dental visits in older people has been limited by cross-sectional design, limited social support dimensions and non-representative samples. METHODS: Data came from men with natural teeth completing Waves 3 and 4 of the Concord Health and Ageing in Men Project in Sydney, Australia. The relationship between social support at Wave 3 (2011-2012) and at least one dental visit per year at Wave 4 (2014-2016) was examined by Poisson regression. Social support was measured by structural (marital status, living arrangements, family support and social interaction) and functional (social support satisfaction) domains. RESULTS: About 673 men were analysed. Structural and functional social support were not associated with the pattern of usual dental visits 5 years later in univariable or multivariable analyses. The only consistent significant factor was income source, with older men who had other sources of income more likely to regularly visit the dentist than older men solely reliant on the pension for income (prevalence ratio: 1.31, 95% CI: 1.13-1.52). CONCLUSIONS: We found no differences in the pattern of usual dental visits between older men with different levels and types of social support. For older Australian men, income source seems to be the most important determinant of regular dental visits. © 2022 Australian Dental Association.

Lifestyle factors, medications, and disease influence bone mineral density in older men: findings from the CHAMP study.

UNLABELLED: Aging alone is not the only factor accounting for poor bone health in older men. There are modifiable factors and lifestyle choices that may influence bone health and result in higher bone density and lower fracture risk even in very old men. INTRODUCTION: The aim of this cross-sectional analysis was to identify the factors associated with areal bone mineral density (BMD) and their relative contribution in older men. METHODS: The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia, involving 1,705 men aged 70-97. Data were collected using questionnaires and clinical assessments. BMD of the hip and spine was measured by dual X-ray absorptiometry. RESULTS: In multivariate regression models, BMD of the hip was associated with body weight and bone loading physical activities, but not independently with age. The positive relationship between higher BMD and recreational activities is attenuated with age. Factors independently associated with lower BMD at the hip were inability to stand from sitting, a history of kidney stones, thyroxine use, and Asian birth and at the spine, chronic obstructive pulmonary disease, paternal fracture history, and thyroxine use. Higher body weight, participation in dancing, tennis or jogging, quadriceps strength, alcohol consumption, and statin use were associated with higher hip BMD, while older age, osteoarthritis, higher body weight, and aspirin use were associated with higher spinal BMD. CONCLUSION: Maintaining body weight, physical activity, and strength were positively associated with BMD even in very elderly men. Other parameters were also found to influence BMD, and once these were included in multivariate analysis, age was no longer associated with BMD. This suggests that age-related diseases, lifestyle choices, and medications influence BMD rather than age per se.

Iterative Development of Clinician Guides to Support Deprescribing Decisions and Communication for Older Patients in Hospital: A Novel Methodology.

BACKGROUND/OBJECTIVES: Medication review is an important component of the management of older hospital patients. Deprescribing (supervised withdrawal of inappropriate medicines) is one outcome of review. This study aimed to iteratively develop and test the usability of deprescribing guides, which support multidisciplinary clinicians to reduce inappropriate polypharmacy in older inpatients. METHODS: Deprescribing guides for hospital clinicians were developed using a novel mixed-methods, ten-step process. Iterative development and usability testing were applied. This included content development through review of the literature; expert consensus through five rounds of feedback using a modified Delphi approach; and usability testing by 16 multidisciplinary hospital clinicians on hypothetical clinical scenarios involving observations, semi-structured interviews, and administration of the System Usability Scale. RESULTS: This novel process was used to develop deprescribing guides that facilitate implementation of evidence on deprescribing in routine hospital care. The guides present evidence-based information in a format that aligns with workflows of multidisciplinary hospital clinicians. The guides were adapted for various clinical roles to navigate efficiently to suit differing workflow needs. Guides include unique communication support in the form of "preferred language". Clinicians can use the "preferred language" to apply the evidence to the individual patient and relay decisions between health providers and with patients/carers. The total System Usability Scale score was 80.6 ± 2.0 (mean ± standard error of the mean), indicating excellent usability. Guides have been developed using consistent format for nine medication classes that are common targets for deprescribing and are publicly available. CONCLUSION: This study demonstrates a novel approach to the development and implementation of evidence-based recommendations that support deprescribing in routine hospital care.

Circulating Sex Steroid Measurements of Men by Mass Spectrometry Are Highly Reproducible after Prolonged Frozen Storage.

Long-term studies investigating hormone-dependent cancers and reproductive health often require prolonged frozen storage of serum which assumes that the steroid molecules and measurements are stable over that time. Previous studies of reproducibility of circulating steroids have relied upon flawed historical rather than contemporaneous controls. We measured serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) in 150 randomly selected serum samples by liquid chromatography-mass spectrometry (LC-MS) from men 70 years or older (mean age 77 years) in the CHAMP study. The original measurements in 2009 were repeated 10 years later using the identical serum aliquot (having undergone 2-4 freeze-thaw cycles in the interim) in 2019 together with another never-thawed aliquot of the same serum sample. The results of all three sets of measurements were evaluated by Passing-Bablok regression and Bland-Altman difference analysis. Serum androgens (T, DHT) and estrogens (E2, E1) measured by LC-MS display excellent reproducibility when stored for 10 years at -80 C without thawing. Serum T and DHT displayed high level of reproducibility across all three sets of measurements. Multiple freeze-thaw cycles over those storage conditions do not significantly affect serum T, DHT and E1 concentrations but produce a modest increase (21%) in serum E2 measurements.

Frailty and Cause-Specific Hospitalizations in Community-Dwelling Older Men.

OBJECTIVES: The types of medical conditions leading to hospitalization in frail older people have not been investigated. The objectives were to evaluate associations between frailty and (a) risk of all-cause and cause-specific hospitalization, and (b) rate of all-cause and cause-specific hospitalizations. DESIGN, SETTING AND PARTICIPANTS: Community-dwelling men aged 70+ years in the Concord Health and Ageing in Men Project (CHAMP) were assessed for frailty at baseline (2005-2007, n=1705). MEASUREMENTS: Frailty was determined by both the Fried frailty phenotype (FP) and the Rockwood frailty index (FI). Non-elective and elective hospitalization data were accessed from the New South Wales (NSW) Admitted Patient Data Collection and mortality from the NSW Deaths Registry for the period 2005-2017. Causes of hospitalization were categorized using ICD-10 classification of principal diagnoses based on organ system involved into 14 major categories. RESULTS: Nearly 80% of CHAMP men had at least one non-elective hospitalization and 63% had an elective hospitalization over a 9-year follow-up. Men with FP frailty were twice as likely to have a non-elective hospitalization (HR: 1.98, 95%CI: 1.61-2.44) and a greater number of non-elective hospitalizations (IRR: 1.44, 95%CI: 1.22-1.70). Similar relationships were found between FI frailty and non-elective hospitalizations. Men with frailty (either FP or FI) were more likely to have at least one non-elective hospitalization for 13 of the 14 cause-related admissions. In contrast, frailty was only associated with 3 cause-related elective hospitalizations. Men with frailty were also more likely to have an increased number of non-elective hospitalizations for all 14 causes, but only for 6 causes of elective hospitalizations. CONCLUSIONS: Our findings suggest frailty increases the risk and number of non-elective hospitalizations in older men for a wide range of cause. Strategies on early identification of frailty, followed by appropriate preventative strategies to lower the risk of non-elective hospital admissions are warranted.

Do medical courses adequately prepare interns for safe and effective prescribing in New South Wales public hospitals?

AIMS: To assess ability of interns immediately before starting clinical practice in New South Wales (NSW) teaching hospitals to prescribe medications safely and appropriately and to describe their impressions of the adequacy of their clinical pharmacology training in medical school. METHODS: A cross-sectional study was performed on all interns (n= 191) who attended intern orientation programmes at four NSW hospitals in January 2008. A clinical case scenario that tested prescribing ability and a survey investigating impressions of clinical pharmacology training in medical school were administered to the interns in exam format. Outcome measures were: (i) ability to prescribe medications safely and appropriately for the clinical case scenario and (ii) interns' impressions of their training in clinical pharmacology at medical school. RESULTS: No intern completed all prescribing tasks correctly. No intern charted the patient's usual medications on admission completely correctly, only six wrote an accurate discharge medication list, and none wrote both an accurate discharge medication list and a legal Schedule 8 discharge script. None of the respondents strongly agreed that they felt adequately trained to prescribe medications in their intern year and 84% would have liked to have more training in pharmacology as medical students. CONCLUSIONS: Interns about to commence clinical practice in NSW teaching hospitals demonstrated significant deficits in prescribing of regular medications, initiation of new therapies, prescribing of discharge medications, and particularly prescribing of Schedule 8 medications. Most interns recognized these deficits and would have liked more clinical pharmacology training at medical school.

Oral health behaviours of older Australian men: the Concord Health and Ageing in Men Project.

BACKGROUND: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of older Australian men. The aim of this paper is to describe the oral health behaviours and dental service use of CHAMP participants and explore associations between oral health behaviours with and general health status. METHOD: Information collected related to socio-demographics, general health, oral health service-use and oral health behaviours. Key general health conditions were ascertained from the health questionnaire and included physical capacity and cognitive status. RESULTS: Fifty-seven percent of the men reported visiting a dental provider at least once or more a year and 56.7% did so for a "dental check-up". Of those with some natural teeth, 59.3% claimed to brush their teeth at least twice or more a day. Most men (96%) used a standard fluoride toothpaste. Few participants used dental floss, tooth picks or mouth-rinses to supplement oral hygiene. Cognitive status and self-rated general health were associated with dental visiting patterns and toothbrushing behaviour. CONCLUSIONS: Most older men in CHAMP perform favourable oral health behaviours. Smoking behaviour is associated with less favourable dental visiting patterns, and cognitive status with toothbrushing behaviour.

Oral health of community-dwelling older Australian men: the Concord Health and Ageing in Men Project (CHAMP).

BACKGROUND: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of Australian men aged 70 years and older. The aim of this report is to describe the oral health of these men. METHODS: Oral health was assessed when the men were all aged 78 years or older. Two calibrated examiners conducted a standardized intraoral assessment. Descriptive data were analysed by statistical association tests. Participants were excluded from the collection of some periodontal assessments if they had a medical contraindication. RESULTS: Dental assessments of 614 participants revealed 90 (14.6%) were edentate. Men had a mean of 13.8 missing teeth and 10.3 filled teeth. Dentate participants had a mean of 1.1 teeth with active coronal decay. Those in the low-income group had a higher rate of decayed teeth and lower rate of filled teeth. Thirty-four participants (5.5%) had one or more dental implants, and 66.3% relied on substitute natural teeth for functional occlusion. Of those with full periodontal assessments; 90.9% had sites with pocket depths of 3 mm or more, 96.6% had sites with CAL of 5 mm or more, and 79.7% had three or more sites with GI scores of 2 or more. CONCLUSIONS: There was a high prevalence of periodontal diseases and restorative burden of dentitions, which suggests that greater attention needs to be given to prevention and health maintenance in older Australian men.

The C-caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy.

BACKGROUND: The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. AIM: To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. METHODS: Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. RESULTS: Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P < 0.001). The 13C-caffeine breath test independently predicted significant (F > or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. CONCLUSION: The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.

A randomized clinical trial of activated charcoal for the routine management of oral drug overdose.

BACKGROUND: Activated charcoal (AC) is commonly used for the routine management of oral drug overdose. AIM: To determine whether the routine use of activated charcoal has an effect on patient outcomes. DESIGN: Randomized controlled unblinded trial. METHODS: We recruited all adult patients presenting with an oral overdose at The Canberra Hospital, excluding only transfers, late presenters, those who had ingested drugs not adsorbed by activated charcoal or where administration was contraindicated, and very serious ingestions (at the discretion of the admitting physician). Patients were randomized to either activated charcoal or no decontamination. RESULTS: The trial recruited 327 patients over 16 months. Of 411 presentations, four refused consent, 27 were protocol violations and 53 were excluded from the trial. Only seven were excluded due to the severity of their ingestion. The most common substances ingested were benzodiazepines, paracetamol and selective serotonin reuptake inhibitor antidepressants. More than 80% of patients presented within 4 h following ingestion. There were no differences between AC and no decontamination in terms of length of stay (AC 6.75 h, IQR 4-14 vs. controls 5.5 h, IQR 3-12; p=0.11) or secondary outcomes including vomiting, mortality and intensive care admission. DISCUSSION: Routine administration of charcoal following oral overdose did not significantly influence length of stay or other patient outcomes following oral drug overdose. There were few adverse events. This does not exclude a role in patients who present shortly after ingestion of highly lethal drugs.

Suicidal emperipolesis: a process leading to cell-in-cell structures, T cell clearance and immune homeostasis.

"Suicidal emperipolesis" is one of the most recently reported processes leading to cell-in-cell structures that promote cell death. This process was discovered in studies investigating the fate of autoreactive CD8 T cells activated within the liver. Recently, we reported that activated T cells invaded hepatocytes, formed transient cell-in-cell structures, and were rapidly degraded within endosomal/lysosomal compartments by a non-apoptotic pathway. Importantly, pharmacological inhibition of this process caused intrahepatic accumulation of tissue-reactive T cells and breach of immune tolerance. The characterization of the molecular mechanisms of suicidal emperipolesis is still in its infancy, but initial studies suggest this phenomenon is distinct from other reported cell-in-cell structures. As opposed to the formation of other cell-in-cell structures, suicidal emperipolesis takes place in a non-malignant environment, and without obvious pathology. It is therefore the first cell-in-cell structure described to have a role in maintaining homeostasis in normal physiology in higher organisms. T cell emperipolesis within hepatocytes has also been observed by pathologists in a range of chronic human liver pathologies. As T cell-in-hepatocyte structures resulting from suicidal emperipolesis are very transiently observed in normal physiology, their accumulation during liver disease would suggest that severe tissue injury is promoted by, or associated with, defective T cell clearance. In this review, we compare "suicidal emperipolesis" to other processes leading to cell-in-cell structures, and consider its potential biological roles in maintaining immune homeostasis and tolerance in the context of the hepatic environment.

The dopamine transporter gene and Parkinson's disease in a Chinese population.

We studied a variable number tandem repeat polymorphism within the dopamine transporter gene (DAT) for an association with Parkinson's disease in a Chinese population. Five alleles were detected, consisting of 6, 8, 9, 10, and 11 copies of the 40 base pair repeat sequence. The 10-copy allele was most common, accounting for 90% of alleles. There were no significant differences between the patients and the control subjects in the distribution frequencies of the alleles or genotypes. Therefore, this polymorphism is not associated with Parkinson's disease in Chinese populations.

The effects of aging and nutritional state on hypoxia-reoxygenation injury in the perfused rat liver.

During liver transplantation, donor livers are subject to hypoxia and reoxygenation. Recently, because of a shortage of suitable donors, the livers of older donors have been used for transplantation. In this study, we examined the influence of aging and nutritional state on hepatic intracellualr pH (pHi) and the susceptibility of the rat liver to hypoxia-reoxygenation injury. Perfused livers from fasted and fed, young (2-3 months) and aged (24-28 months) male Wistar rats were compared during 30 min of nitrogen hypoxia followed by 20 min of reoxygenation. Under control conditions, pHi was significantly lower and glucose release higher in livers from fed young rats (7.24 +/- 0.04, 3.4 +/- 1.8 mumol/min/g) than in those from fasted young (7.33 +/- 0.04, 0.0 +/- 1.3), fasted aged (7.32 +/- 0.03, -0.1 +/- 0.5), and fed aged rats (7.29 +/- 0.06, 0.9 +/- 1.0). In all groups, pHi fell by approximately 0.15 U during hypoxia. Lactate dehydrogenase (LDH) release from the livers of fed young livers was unaffected by hypoxia-reoxygenation as was that from the livers of fed aged rats, despite features that would be expected to predispose to injury (reduced glucose output and more alkaline pHi). In contrast, livers from fasted young and aged rats had substantially increased LDH release and reduced bile flow during hypoxia. There were no age-related differences in these parameters, but, during reoxygenation, LDH release was significantly less in the aged livers. These results indicate that the livers of fed rats are resistant to hypoxia-reoxygenation injury and that aging does not increase the susceptibility of the liver to injury in the fasted state.

Immunohistochemistry of omega class glutathione S-transferase in human tissues.

Omega class glutathione transferase (GSTO) has been recently described in a number of mammalian species. We used immunohistochemistry to determine the cellular and tissue distribution of GSTO1-1 in humans. Expression of GSTO1-1 was abundant in a wide range of normal tissues, particularly liver, macrophages, glial cells, and endocrine cells. We also found nuclear staining in several types of cells, including glial cells, myoepithelial cells of the breast, neuroendocrine cells of colon, fetal myocytes, hepatocytes, biliary epithelium, ductal epithelium of the pancreas, Hoffbauer cells of the placenta, and follicular and C-cells of the thyroid. These observations and the known activity of GSTO1-1 suggest biological functions that are not shared with other GSTs.

The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis.

A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations. Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the 'oxygen diffusion barrier' hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion. Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.