Background: Ageing is the inevitable time-dependent decline in physiological organ function that eventually leads to death. Age is a major risk factor for many of the most common medical conditions, such as cardiovascular disease, cancer, diabetes and Alzheimer's disease. This study reviews currently known hallmarks of ageing and their clinical implications.Methods: A literature search of PubMed/MEDLINE was conducted covering the last decade. Results: Average life expectancy has increased dramatically over the past century and is estimated to increase even further. Maximum longevity, however, appears unchanged, suggesting a universal limitation to the human organism. Understanding the underlying molecular processes of ageing and health decline may suggest interventions that, if used at an early age, can prevent, delay, alleviate or even reverse age-related diseases. Hallmarks of ageing can be grouped into three main categories. The primary hallmarks cause damage to cellular functions: genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis. These are followed by antagonistic responses to such damage: deregulated nutrient sensing, altered mitochondrial function and cellular senescence. Finally, integrative hallmarks are possible culprits of the clinical phenotype (stem cell exhaustion and altered intercellular communication), which ultimately contribute to the clinical effects of ageing as seen in physiological loss of reserve, organ decline and reduced function. Conclusion:The sum of these molecular hallmarks produces the clinical picture of the elderly surgical patient: frailty, sarcopenia, anaemia, poor nutrition and a blunted immune response system. Improved understanding of the ageing processes may give rise to new biomarkers of risk or prognosis, novel treatment targets and translational approaches across disciplines that may improve outcomes.

Cyclic AMP (cAMP)-dependent processes are pivotal during the early stages of adipocyte differentiation. We show that exchange protein directly activated by cAMP (Epac), which functions as a guanine nucleotide exchange factor for the Ras-like GTPases Rap1 and Rap2, was required for cAMP-dependent stimulation of adipocyte differentiation. Epac, working via Rap, acted synergistically with cAMP-dependent protein kinase (protein kinase A [PKA]) to promote adipogenesis. The major role of PKA was to down-regulate Rho and Rho-kinase activity, rather than to enhance CREB phosphorylation. Suppression of Rho-kinase impaired proadipogenic insulin/insulin-like growth factor 1 signaling, which was restored by activation of Epac. This interplay between PKA and Epac-mediated processes not only provides novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of cAMP signaling whereby cAMP uses both PKA and Epac to achieve an appropriate cellular response.Adipocytes are derived from multipotent mesenchymal stem cells in a process involving commitment to the adipocyte lineage followed by terminal differentiation of the committed preadipocytes. The process is regulated via complex interaction of external and internal clues, where cell shape and cytoskeletal tension converging on regulation of Rho and Rhokinase activity have been demonstrated to play pivotal roles (48,63). Whereas our understanding of the early steps of lineage determination still is limited, regulatory cascades controlling terminal adipocyte differentiation have been elucidated in great detail, particularly the sequential action of different transcription factors culminating in the expression of adipocyte-specific genes (25,30,58). Much information on terminal adipocyte differentiation has been obtained using model cell lines such as 3T3-L1 and 3T3-F442A or mouse embryo fibroblasts (MEFs). In both MEFs and 3T3-L1 preadipocytes, terminal differentiation is initiated upon treatment with fetal calf serum, glucocorticoids, and high levels of insulin or physiological concentrations of insulin-like growth factor 1 (IGF-1). Factors that increase cellular cyclic AMP (cAMP), such as isobutylmethylxanthine (IBMX) or forskolin, strongly accelerate the initiation of the differentiation program (for review, see references 25 and 45).Elevation of cellular cAMP concentration has been associated with crucial events in the early program of differentiation, such as suppression of Wnt10b (5) and Sp1 (64) and induction of CCAAT/enhancer-binding protein ␤ (C/EBP␤) (10,29,70). Moreover, the transcriptional activity of peroxisome proliferator-activated receptor ␦ (PPAR␦) is regulated synergistically by ligands and cAMP (32). In addition, cAMP has been implicated in the production of endogenous PPAR␥ ligand(s) occurring during the initial stages of differentiation (46, 67). The cAMP-responsive element-binding protein (CREB) is a central transcriptional activator of the adipocyte differentiation program. Activated CREB induces expres...

BackgroundAn organic extract of the recreational herb khat (Catha edulis Forsk.) triggers cell death in various leukemia cell lines in vitro. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity.ResultsKhat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation.ConclusionKhat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.

Colorectal cancer (CRC) is the third most common cancer worldwide. Survival is largely stage-dependant, guided by the tumor-node-metastases (TNM) system for TNM assessment. Histopathological evaluation, including assessment of lymph node status, is important for correct TNM staging. However, recent updates in the TNM system have resulted in controversy. A continued debate on definitions resulting in potential up- and downstaging of patients, which may obscure survival data, has led the investigators to investigate other or alternative staging tools. Consequently, additional prognostic factors have been searched for using the regular light microscopy. Among the factors evaluated by histopathology include the evaluation of tumor budding and stromal environment, angiogenesis, as well as involvement of the immune system (including the 'Immunoscore'). We review the current role of histopathology, controversies in TNM-staging and suggested alternatives to better predict outcome for CRC patients in the era of genomic medicine.