Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

Objective

Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.

Methods

We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.

Results

Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R ² = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.

Conclusion

Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.     

Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation

Although chronological donor age is the most potent predictor of long-term outcome after renal transplantation, it does not incorporate individual differences of the aging-process itself. We therefore hypothesized that an estimate of biological organ age as derived from markers of cellular senescence in zero hour biopsies would be of higher predictive value. Telomere length and mRNA expression levels of the cell cycle inhibitors CDKN2A (p16INK4a) and CDKN1A (p21WAF1) were assessed in pre-implantation biopsies of 54 patients and the association of these and various other clinical parameters with serum creatinine after 1 year was determined. In a linear regression analysis, CDKN2A turned out to be the best single predictor followed by donor age and telomere length. A multiple linear regression analysis revealed that the combination of CDKN2A values and donor age yielded even higher predictive values for serum creatinine 1 year after transplantation. We conclude that the molecular aging marker CDKN2A in combination with chronological donor age predict renal allograft function after 1 year significantly better than chronological donor age alone.     

Associations between rotating night shifts, sleep duration, and telomere length in women

Background

Telomere length has been proposed as a marker of aging. However, our knowledge of lifestyle risk factors determining telomere length is limited.

Methods

We evaluated the associations between years of rotating night shifts, self-reported sleep duration, and telomere length in 4,117 female participants from the Nurses'' Health Study. Telomere length in peripheral blood leukocytes was determined by Real-Time PCR assay. Information on rotating night shifts and sleep duration was collected via questionnaires prior to blood collection. We used multivariable linear regression to investigate the associations between rotating night shifts, sleep duration, and telomere length.

Results

Compared with women in the category (9 hours), those in the lowest category of sleep duration (≤6 hours) had a 0.12 unit decrease in z score after adjustment for age, BMI and cigarette smoking (equivalent to 9-year telomere attrition, P for trend  = 0.05). Significant positive association between sleep duration and telomere length was seen among women under age of 50 (P for trend  = 0.004), but not among those over 50 (P for trend  = 0.33) (P for interaction  = 0.005). In addition, we observed that women with a longer history of rotating night shifts tended to have shorter telomere length, but this relation was not statistically significant (P for trend  = 0.36).

Conclusion

We found that sleep duration was positively associated with telomere length among women under 50 years old. Further research is needed to confirm the observed associations.     

Abdominal Adipose Tissue was Associated with Glomerular Hyperfiltration among Non- Diabetic and Normotensive Adults with a Normal Body Mass Index

Glomerular hyperfiltration is recognized as an early marker of progressive kidney dysfunction in the obese population. This study aimed to identify the relationship between glomerular hyperfiltration and body fat distribution measured by computed tomography (CT) in healthy Korean adults. The study population included individuals aged 20–64 years who went a routine health check-up including an abdominal CT scan. We selected 4,378 individuals without diabetes and hypertension. Glomerular filtration rate was estimated using the CKD-EPI equation, and glomerular hyperfiltration was defined as the highest quintile of glomerular filtration rate. Abdominal adipose tissue areas were measured at the level of the umbilicus using a 16-detector CT scanner, and the cross-sectional area was calculated using Rapidia 2.8 CT software. The prevalence of glomerular hyperfiltration increased significantly according to the subcutaneous adipose tissue area in men (OR = 1.74 (1.16–2.61), P for trend 0.016, for the comparisons of lowest vs. highest quartile) and visceral adipose tissue area in women (OR = 2.34 (1.46–3.75), P for trend < 0.001) in multivariate analysis. After stratification by body mass index (normal < 23 kg/m², overweight ≥ 23 kg/m²), male subjects with greater subcutaneous adipose tissue, even those in the normal BMI group, had a higher prevalence of glomerular hyperfiltration (OR = 2.11 (1.17–3.80), P for trend = 0.009). Among women, the significance of visceral adipose tissue area on glomerular hyperfiltration resulted from the normal BMI group (OR = 2.14 (1.31–3.49), P for trend = 0.002). After menopause, the odds ratio of the association of glomerular hyperfiltration with subcutaneous abdominal adipose tissue increased (OR = 2.96 (1.21–7.25), P for trend = 0.013). Subcutaneous adipose tissue areas and visceral adipose tissue areas are positively associated with glomerular hyperfiltration in healthy Korean adult men and women, respectively. In post-menopausal women, visceral adipose tissue area shows significant positive association with glomerular hyperfiltration as in men.     

Longer telomeres associated with higher survival in birds

Differences in individual quality and survival within species are a major focus in evolutionary ecology, but we know very little about the underlying physiological mechanisms that determine these differences. Telomere shortening associated with cellular senescence and ageing may be one such mechanism. To date, however, there is little evidence linking telomere length and survival. Here, we show that tree swallows (Tachycineta bicolor) with relatively short telomeres at the age of 1 year have lower survival than tree swallows of the same age with relatively long telomeres. The survival advantage in the long telomere group continues for at least three breeding seasons. It will be important to identify mechanisms that link telomere length with survival early in life.     

Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes

Although shortened telomeres were shown associated with several risk factors of diabetes, there is lack of data on their relationship with mitochondrial dysfunction. Therefore, we compared the relationship between telomere length and mitochondrial DNA (mtDNA) content in patients with type 2 diabetes mellitus (T2DM; n = 145) and in subjects with normal glucose tolerance (NGT; n = 145). Subjects were randomly recruited from the Chennai Urban Rural Epidemiology Study. mtDNA content and telomere length were assessed by Real-Time PCR. Malonodialdehyde, a marker of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS) using fluorescence methodology. Adiponectin levels were measured by radioimmunoassay. Oxidative stress as determined by lipid peroxidation (TBARS) was significantly (p < 0.001) higher in patients with T2DM compared to NGT subjects. In contrast, the mean telomere length, adiponectin and mtDNA content were significantly (p < 0.001) lower in patients with T2DM compared to NGT subjects. Telomere length was positively correlated with adiponectin, HDL, mtDNA content and good glycemic/lipid control and negatively correlated with adiposity and insulin resistance. On regression analysis, shortened telomeres showed significant association with T2DM even after adjusting for waist circumference, insulin resistance, triglyceride, HDL, adiponectin, mtDNA & TBARS. mtDNA depletion showed significant association with T2DM after adjusting for waist circumference and adiponectin but lost its significance when further adjusted for telomere length, TBARS and insulin resistance. Our study emphasizes the clustering of accelerated aging features viz., shortened telomeres, decreased mtDNA content, hypoadiponectinemia, low HDL, and increased oxidative stress in Asian Indian type 2 diabetes patients.     

Elevated serum 25(OH)D concentrations, vitamin D, and calcium intakes are associated with reduced adipocyte size in women

Recent studies have suggested a beneficial effect of vitamin D and calcium on adipocyte metabolism and the metabolic profile. Our objective was to examine associations of vitamin D intake, calcium and dairy products as well as serum 25(OH)D concentration with adiposity measures and adipocyte size in women. Omental and subcutaneous adipose tissue samples were obtained from 43 women undergoing gynecological surgeries. Adipocyte size was measured using adipocyte suspensions from collagenase-digested fat tissues. Total and visceral adiposity were assessed by dual-energy X-ray absorptiometry and computed tomography, respectively. Serum 25(OH)D was measured by radioimmmunoassay. Dietary intakes were assessed using a food frequency questionnaire. Women consuming two or more dairy product portions daily had smaller adipocytes in the omental depot compared to women consuming less than two portions daily (79 ± 12 vs. 94 ± 16 μm, P ≤ 0.01). Dietary intakes of calcium (r = -0.55) and vitamin D (r = -0.43) as well as serum 25(OH)D (r = -0.35) were also inversely and significantly associated with omental adipocyte size (P ≤ 0.05 for all). Dietary vitamin D intake was inversely associated with visceral adipose tissue area (r = -0.34, P ≤ 0.05). Serum 25(OH)D was also inversely associated with visceral adipose tissue area (r = -0.32) as well as with total adipose tissue area (r = -0.44), subcutaneous adipose tissue area (r = -0.36), BMI (r =-0.43) and total body fat mass (r = -0.41, P ≤ 0.05 for all). In conclusion, elevated dietary vitamin D intake and serum 25(OH)D values are related to lower visceral adiposity and omental adipocyte size in women.     

The distribution pattern of critically short telomeres in human osteoarthritic knees

Introduction  

Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence.     

The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo

Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2delta B delta M). We show that the level of telomere dysfunction correlates with the level of TRF2delta B delta M protein expression resulting in chromosomal fusions, aberrant mitotic figures and aneuploidy of liver cells. These alterations provoked p53-independent apoptosis, but a strictly p53-dependent senescence response in distinct populations of mouse liver cells depending on the cellular level of TRF2delta B delta M expression. Apoptosis was associated with higher expression of TRF2delta B delta M, whereas cellular senescence was associated with low levels of TRF2delta B delta M) expression. Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function.     

The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer

Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age-matched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors ( i.e. , lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.     

Stabilization of telomere length and karyotypic stability are directly correlated with the level of hTERT gene expression in primary fibroblasts

Telomere shortening and lack of telomerase activity have been implicated in cellular senescence in human fibroblasts. Expression of the human telomerase (hTERT) gene in sheep fibroblasts reconstitutes telomerase activity and extends their lifespan. However, telomere length is not maintained in all cell lines, even though in vitro telomerase activity is restored in all of them. Cell lines expressing higher levels of hTERT mRNA do not exhibit telomere erosion or genomic instability. By contrast, fibroblasts expressing lower levels of hTERT do exhibit telomere shortening, although the telomeres eventually stabilize at a shorter length. The shorter telomere lengths and the extent of karyotypic abnormalities are both functions of hTERT expression level. We conclude that telomerase activity is required to bypass senescence but is not sufficient to prevent telomere erosion and genomic instability at lower levels of expression.     

Paternal age is positively linked to telomere length of children

Telomere length is linked to age-associated diseases, with shorter telomeres in blood associated with an increased probability of mortality from infection or heart disease. Little is known about how human telomere length is regulated despite convincing data from twins that telomere length is largely heritable, uniform in various tissues during development until birth and variable between individuals. As sperm cells show increasing telomere length with age, we investigated whether age of fathers at conception correlated with telomere length of their offspring. Telomere length in blood from 125 random subjects was shown to be positively associated with paternal age (+22 bp yr -1, 95% confidence interval 5.2-38.3, P = 0.010), and paternal age was calculated to affect telomere length by up to 20% of average telomere length per generation. Males lose telomeric sequence faster than females (31 bp yr -1, 17.6-43.8, P < 0.0001 vs. 14 bp yr -1, 3.5-24.8, P < 0.01) and the rate of telomere loss slows throughout the human lifespan. These data indicate that paternal age plays a role in the vertical transmission of telomere length and may contribute significantly to the variability of telomere length seen in the human population, particularly if effects are cumulative through generations.     

Longevity, stress response, and cancer in aging telomerase-deficient mice

Telomere maintenance is thought to play a role in signaling cellular senescence; however, a link with organismal aging processes has not been established. The telomerase null mouse provides an opportunity to understand the effects associated with critical telomere shortening at the organismal level. We studied a variety of physiological processes in an aging cohort of mTR-/- mice. Loss of telomere function did not elicit a full spectrum of classical pathophysiological symptoms of aging. However, age-dependent telomere shortening and accompanying genetic instability were associated with shortened life span as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, we found an increased incidence of spontaneous malignancies. These findings demonstrate a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism.     

MicroRNA-340-5p increases telomere length by targeting telomere protein POT1 to improve Alzheimer's disease in mice

Alzheimer′s disease (AD) is a chronic neurodegenerative disorder which is the primary cause of dementia in the elderly. Telomere attrition has been proposed as a hallmark of aging. Our study aimed to explore the mechanism of the protection of telomere 1 (POT1) in regulating telomere length and affecting cellular senescence in AD. The AD mouse model was established by d -galactose and aluminum chloride, and the water maze test and dark avoidance test were used to detect the behaviors of mice and confirm the success of AD mouse model. AD cell model was established with HT22 cells induced by Aβ₄₂ oligomers. POT1 expression in the AD model was detected by quantitative real-time polymerase chain reaction. Cellular telomere length in hippocampal tissue was analyzed by telomere restriction fragment. Localization of intracellular POT1, telomerase, and telomeres was analyzed by immunofluorescence and fluorescence in situ hybridization. Dual-luciferase assay was used to validate the targeted binding relationship between microRNA-340-5p (miR-340-5p) and POT1. After inhibiting POT1 expression, the symptoms of AD in mice were improved. Aβ_1–42 deposition was reduced, whereas telomere length and telomerase activity was increased. Dual-luciferase assay verified the binding relationship between miR-340-5p and POT1. An increase in miR-340-5p expression could alleviate cellular senescence and AD symptoms. miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms. This study made a conclusion that miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms in mice.     

Significant role for p16INK4a in p53-independent telomere-directed senescence

Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16(INK4a)/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16(INK4a) is controversial. Attempts to dissect the significance of p16(INK4a) in response to telomere shortening have been hampered by the concomitant induction of p16(INK4a) by cell culture conditions. To circumvent this problem, we studied the role of p16(INK4a) in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2(Delta B Delta M). This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2(Delta B Delta M) resulted in induction of p16(INK4a) in the majority of cells as detected by immunohistochemistry. Inhibition of p16(INK4a) with shRNA or overexpression of BMI1 had a significant effect on the telomere damage response in p53-deficient cells. While p53 deficiency alone only partially abrogated the telomere damage-induced cell cycle arrest, combined inhibition of p16(INK4a) and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16(INK4a) contributes to the p53-independent response to telomere damage.     

Significant Role for p16 in p53-Independent Telomere-Directed Senescence

Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16(INK4a)/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16(INK4a) is controversial. Attempts to dissect the significance of p16(INK4a) in response to telomere shortening have been hampered by the concomitant induction of p16(INK4a) by cell culture conditions. To circumvent this problem, we studied the role of p16(INK4a) in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2(Delta B Delta M). This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2(Delta B Delta M) resulted in induction of p16(INK4a) in the majority of cells as detected by immunohistochemistry. Inhibition of p16(INK4a) with shRNA or overexpression of BMI1 had a significant effect on the telomere damage response in p53-deficient cells. While p53 deficiency alone only partially abrogated the telomere damage-induced cell cycle arrest, combined inhibition of p16(INK4a) and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16(INK4a) contributes to the p53-independent response to telomere damage.     

Association of telomere instability with senescence of porcine cells

Telomeres are essential for the maintenance of genomic stability, and telomere dysfunction leads to cellular senescence, carcinogenesis, aging, and age-related diseases in humans. Pigs have become increasingly important large animal models for preclinical tests and study of human diseases, and also may provide xeno-transplantation sources. Thus far, Southern blot analysis has been used to estimate average telomere lengths in pigs. Telomere quantitative fluorescence in situ hybridization (Q-FISH), however, can reveal status of individual telomeres in fewer cells, in addition to quantifying relative telomere lengths, and has been commonly used for study of telomere function of mouse and human cells. We attempted to investigate telomere characteristics of porcine cells using telomere Q-FISH method. The average telomere lengths in porcine cells measured by Q-FISH correlated with those of quantitative real-time PCR method (qPCR) or telomere restriction fragments (TRFs) by Southern blot analysis. Unexpectedly, we found that porcine cells exhibited high incidence of telomere doublets revealed by Q-FISH method, coincided with increased frequency of cellular senescence. Also, telomeres shortened during subculture of various porcine primary cell types. Interestingly, the high frequency of porcine telomere doublets and telomere loss was associated with telomere dysfunction-induced foci (TIFs). The incidence of TIFs, telomere doublets and telomere loss increased with telomere shortening and cellular senescence during subculture. Q-FISH method using telomere PNA probe is particularly useful for characterization of porcine telomeres. Porcine cells exhibit high frequency of telomere instability and are susceptible to telomere damage and replicative senescence.     

Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression,Telomere Length,Senescence, Inflammation and Fibrosis

BackgroundChronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase.MethodsLiver samples from patients with chronic HBV (n = 91), normal liver (n = 55) and regenerating liver (n = 15) were studied. Immunohistochemistry for cell cycle phase markers and HBV antigens was used to determine host cell cycle phase. Hepatocyte-specific telomere length was evaluated by quantitative fluorescent in-situ hybridization (Q-FISH) in conjunction with hepatocyte nuclear area and HBV antigen expression. The effects of induced cell cycle arrest and induced cellular senescence on HBV production were assessed in vitro.Results13.7% hepatocytes in chronic HBV had entered cell cycle, but expression of markers for S, G2 and M phase was low compared with regenerating liver. Hepatocyte p21 expression was increased (10.9%) in chronic HBV and correlated with liver fibrosis. Mean telomere length was reduced in chronic HBV compared to normal. However, within HBV-affected livers, hepatocytes expressing HBV antigens had longer telomeres. Telomere length declined and hepatocyte nuclear size increased as HBV core antigen (HBcAg) expression shifted from the nucleus to cytoplasm. Nuclear co-expression of HBcAg and p21 was not observed. Cell cycle arrest induced in vitro was associated with increased HBV production, in contrast to
in vitro induction of cellular senescence, which had no effect.ConclusionChronic HBV infection was associated with hepatocyte G1 cell cycle arrest and accelerated hepatocyte ageing, implying that HBV induced cellular senescence. However, HBV replication was confined to biologically younger hepatocytes. Changes in the cellular location of HBcAg may be related to the onset of cellular senescence.     

Intra-abdominal adipose tissue is independently associated with sex-hormone binding globulin in premenopausal women

Lower serum concentrations of sex-hormone binding globulin (SHBG) are associated with increased risk for several obesity-related diseases in women including hormone-sensitive cancers, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Previous investigations have reported that body composition, specifically central obesity, and/or higher insulin concentrations are key factors associated with lower SHBG in overweight and obese women; however, these studies were limited by their cross-sectional design. We hypothesized that intra-abdominal adipose tissue (IAAT), a fat depot linked with an abnormal metabolic profile, is inversely and independently associated with SHBG. Therefore, we determined the longitudinal associations among SHBG, insulin, and IAAT in 107 premenopausal women enrolled in a weight loss study. Overweight (BMI 27-30 kg/m(2)) women were weight reduced until BMI of ≤ 24 was achieved. Body composition and IAAT were measured at baseline and after weight loss with dual-energy X-ray absorptiometry and computed tomography, respectively. Serum concentrations of insulin and SHBG were determined. Paired t-test showed that insulin and IAAT decreased significantly and SHBG increased significantly following weight loss (P < 0.0001 for all). Simple correlations from baseline showed no association with insulin and SHBG (r = -0.142, P = 0.143) and a significant inverse association between IAAT and SHBG (r = -0.43, P < 0.0001). Repeated measures mixed-model showed that after adjusting for age and time (weight loss), IAAT was significantly inversely associated with SHBG (P = 0.0002) and there was no association with insulin and SHBG (P = 0.180). We conclude that SHBG concentrations are influenced by IAAT and not insulin in premenopausal women.     

Serum alanine aminotransferase is associated with serum adiponectin, C-reactive protein and apolipoprotein B in young healthy men.

Several studies have reported an association between markers of liver injury, including elevated concentrations of alanine aminotransferase (ALT) aspartate aminotransferase (AST), and prospective risk of type 2 diabetes. We therefore examined the relationship between ALT and AST on the one hand, and serum adiponectin and highly sensitive CRP on the other, both of which have been reported to be associated with prospective risk of type 2 diabetes; we also tested for variable components of metabolic syndrome in 198 male college students aged 18-20 years. ALT showed a positive relationship with percentage body fat (r = 0.19, p = 0.02), serum leptin (r = 0.21, p = 0.01), LDL cholesterol (r = 0.29, p = 0.0003), triglyceride (r = 0.28, p = 0.0004) and apolipoprotein B (r = 0.35, p < 0.0001) even after adjustment for body mass index (BMI). Although there was a significant relationship with serum insulin, adiponectin (inversely), homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure, HDL cholesterol (inversely) and LDL particle diameter in simple regression analysis, significance disappeared after adjustment for BMI. In contrast, CRP (r = 0.16, p = 0.04) was associated with ALT after adjustment for BMI, although simple regression analysis revealed no association between the two. Relationships were smaller for AST, and significance disappeared after adjustment for BMI. Multiple regression analysis excluding lipid variables revealed significant and independent associations of ALT with adiponectin and percentage body fat. In a model including lipid variables, apolipoprotein B emerged as an independent predictor of ALT in addition to adiponectin and percentage body fat. These variables explained 29 % of ALT variability. In conclusion, serum ALT levels were associated with leptin and CRP as well as many components of the insulin resistance syndrome in young healthy men. Adiponectin, apolipoprotein B and percentage body fat emerged as significant and independent predictors of ALT. Since adiponectin and chronic subclinical inflammation have been reported to predict the development of type 2 diabetes and since abnormalities in apolipoprotein B metabolism occur in the early course of insulin resistance, these findings may be compatible with the association between liver markers and risk of diabetes.