Ulf Smith’s research while affiliated with University of Gothenburg and other places

Background Cell senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood. Objectives This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention. Methods Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, in vitro experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling. Results Individuals with obesity showed significantly elevated CS markers, along with reduced expression of GLUT4 and PAX7, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit. Conclusions These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.

Background: Breast hypertrophy seems to be a risk factor for breast cancer and the amount and characteristics of breast adipose tissue may play important roles. The main aim of this study was to investigate associations between breast volume in normal weight women and hypertrophic adipose tissue and inflammation. Methods: Fifteen non-obese women undergoing breast reduction surgery were examined. Breast volume was measured with plastic cups and surgery was indicated if the breast was 800 ml or larger according to Swedish guidelines. We isolated adipose cells from the breasts and ambient subcutaneous tissue to measure cell size, cell inflammation and other known markers of risk of developing breast cancer including COX2 gene activation and MAPK, a cell proliferation regulator. Results: Breast adipose cell size was characterized by cell hypertrophy and closely related to breast volume. The breast adipose cells were also characterized by being pro-inflammatory with increased IL-6, IL-8, IL-1β, CCL-2, TNF-a and an increased marker of cell senescence GLB1/β-galactosidase, commonly increased in hypertrophic adipose tissue. The prostaglandin synthetic marker COX2 was also increased in the hypertrophic cells and COX2 has previously been shown to be an important marker of risk of developing breast cancer. Interestingly, the phosphorylation of the proliferation marker MAPK was also increased in the hypertrophic adipose cells. Conclusion: Taken together, these findings show that increased breast volume in non-obese women is associated with adipose cell hypertrophy and dysfunction and characterized by increased inflammation and other markers of increased risk for developing breast cancer. Trial registration: Projektdatabasen FoU i VGR, project number: 249191 (https://www.researchweb.org/is/vgr/project/249191).

Background First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR. Results Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM -siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM -siRNA significantly expanded hydrogen peroxide (H 2 O 2 )-induced senescence, while H 2 O 2 did not affect TFAM expression. Conclusions Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk. Graphical abstract

Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.

In the last decades the prevalence of obesity has increased dramatically, and the worldwide epidemic of obesity and related metabolic diseases has contributed to an increased interest for the adipose tissue (AT), the primary site for storage of lipids, as a metabolically dynamic and endocrine organ. Subcutaneous AT is the depot with the largest capacity to store excess energy and when its limit for storage is reached hypertrophic obesity, local inflammation, insulin resistance and ultimately type 2 diabetes (T2D) will develop. Hypertrophic AT is also associated with a dysfunctional adipogenesis, depending on the inability to recruit and differentiate new mature adipose cells. Lately, cellular senescence (CS), an aging mechanism defined as an irreversible growth arrest that occurs in response to various cellular stressors, such as telomere shortening, DNA damage and oxidative stress, has gained a lot of attention as a regulator of metabolic tissues and aging-associated conditions. The abundance of senescent cells increases not only with aging but also in hypertrophic obesity independent of age. Senescent AT is characterized by dysfunctional cells, increased inflammation, decreased insulin sensitivity and lipid storage. AT resident cells, such as progenitor cells (APC), non-proliferating mature cells and microvascular endothelial cells are affected with an increased senescence burden. Dysfunctional APC have both an impaired adipogenic and proliferative capacity. Interestingly, human mature adipose cells from obese hyperinsulinemic individuals have been shown to re-enter the cell cycle and senesce, which indicates an increased endoreplication. CS was also found to be more pronounced in mature cells from T2D individuals, compared to matched non-diabetic individuals, with decreased insulin sensitivity and adipogenic capacity. Graphical abstract Factors associated with cellular senescence in human adipose tissue

The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16–1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37–1.43), IVCB (HR 1.23, 95% CI 1.18–1.28) and VT/VF (HR 1.08, 95% CI 1.04–1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05–1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94–1.18), IVCB (HR 0.80, 95% CI 0.60–0.98), and for VT/VF (HR 0.97, 95% CI 0.80–1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D.

Obesity with dysfunctional adipose cells is the major cause of the current epidemic of T2D. We examined senescence in human adipose tissue cells from age- and BMI-matched lean, obese and obese T2D individuals and found mature and fully differentiated adipose cells from obese and, more pronounced, from T2D individuals to exhibit increased senescence similar to what we previously have shown in the progenitor cells. Degree of adipose cell senescence was positively correlated with whole-body insulin resistance and adipose cell size. Adipose cell protein analysis revealed dysfunctional cells in T2D with increased senescence markers, reduced PPARγ, GLUT4 and pS473AKT. Consistent with a recent study, we found the cell cycle regulator cyclin D1 to be increased in obese cells but also further elevated in T2D cells, closely correlating with senescence markers, ambient donor glucose and, more inconsistently, with plasma insulin levels. Furthermore, fully differentiated adipose cells were susceptible to experimentally induced senescence, to conditioned medium increasing cyclin D1 and also responsive to senolytic agents. Thus, fully mature human adipose cells from obese and, more pronounced, T2D subjects become senescent and SASP secretion by senescent progenitor cells can play an important role in addition to donor hyperinsulinemia.

Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines HepG2 and IHH with the senescence-inducing drugs nutlin-3a, doxorubicin and etoposide. The senescence-associated markers p16, p21, p53 and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis. Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of IR, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.

Aims/hypothesis The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Methods Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. Results The analyses included data from 617,00 patients with T2D and 2,303,391 matched controls. During the study period, 219,444 developed AF/AFI, 33,511 cases of SND, AV-block or pacemaker implantation, 11,029 cases of IVCB and 10,110 cases of VT/VF. Patients with diabetes and the general population demonstrated a gradual increase in rates for AF/AFl and conduction abnormalities. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI, 1.16 to 1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI, 1.37 to 1.43), IVCB (HR 1.23, 95% CI, 1.18 to 1.28) and VT/VF (HR 1.08, 95% CI, 1.04 to 1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI, 1.05 to 1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI, 0.94 to 1.18), IVCB (HR 0.80, 95% CI, 0.60 to 0.98), and for VT/VF (HR 0.97, 95% CI, 0.80 to 1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Conclusion/interpretation Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D. Research in context To investigate long-term trends in incidence rates for cardiac arrhythmias and conduction abnormalities among patients with T2D and the general population, and to investigate if cardiometabolic risk factor levels lower than recommended therapeutic target values was associated with lower risk for outcomes and risk associated with multifactorial risk factor control. Our results show that incidence of arrhythmias and conduction abnormalities is gradually increasing among both patients with T2D and matched controls. BMI, SBP and eGFR shows a clear risk association for cardiac outcomes in patients with diabetes. Finally, according to observational analyses, excess risk for arrhythmias among individuals with T2D and several risk factors within target range is associated with just slightly higher risk among patients with T2D, compared with matched controls.