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Growth differentiation factor-15 (GDF15) might be involved in the development of cognitive frailty and depression. Therefore, we evaluated cross-sectional associations of plasma GDF15 with combined cognitive-frailty-and-depression in older (i.e. ≥ 55 years) and younger adults of the MARK-AGE study. In the present work, samples and data of MARK-AGE (“European study to establish bioMARKers of human AGEing“) participants (N= 2736) were analyzed. Cognitive frailty was determined by the global cognitive functioning score (GCF) and depression by the Self-Rating Depression Scale (SDS score). Adults were classified into three groups: (I) neither-cognitive-frailty-nor-depression, (II) either-cognitive-frailty-or-depression or (III) both-cognitive-frailty-and-depression. Cross-sectional associations were determined by unadjusted and by age, BMI, sex, comorbidities and hsCRP-adjusted linear and logistic regression analyses. Cognitive frailty, depression, age and GDF15 were significantly related within the whole study sample. High GDF15 levels were significantly associated with both-cognitive-frailty-and-depression (adjusted β = 0.177 [0.044 – 0.310], p= 0.009), and with low GCF scores and high SDS scores. High GDF15 concentrations and quartiles were significantly associated with higher odds to have both-cognitive-frailty-and-depression (adjusted odds ratio = 2.353 [1.267 – 4.372], p= 0.007; and adjusted odds ratio = 1.414 [1.025 – 1.951], p= 0.035, respectively) independent of age, BMI, sex, comorbidities and hsCRP. These associations remained significant when evaluating older adults. We conclude that plasma GDF15 concentrations are significantly associated with combined cognitive-frailty-and-depression status and, with cognitive frailty and depressive symptoms separately in old as well as young community-dwelling adults.

In this work, we explore the evolution of the physicochemical properties of silicon carbide and titanium carbide nanoparticles in human reconstituted gastric fluid in the conditions of a normal digestion. The nanoparticles were pre-dispersed in water or in a pluronic F108 solution. Key parameters as the particle size distribution and the surface composition of the nanoparticles were monitored. The results show that the modifications produced during the simulated digestion are dispersion medium dependent. Carbon and nitrogen were found to be adsorbed on the surface of both nanoparticles in a dispersion medium dependent way. The reported results contribute to understand the biological impact of these nanoparticles in biofluids and biocompatible media.

Background and aims:Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community-dwelling seniors, these markers have not been studied from this perspective in acutely ill older patients. This prospective study was designed to determine whether biological markers can improve the predictive value of a clinical screening tool to assess the risk of functional decline in hospitalized older patients. Methods:Patients aged 75 years and over admitted for hip fracture, acute heart failure or infection (n=118) were recruited. The clinical screening tool SHERPA was filled in on admission, with concomitant measurement of interleukin-6 (IL-6), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP), white blood cells, urea, albumin, pre-albumin and total cholesterol. Functional decline was defined as a decrease of one point in the activities of daily living scale between pre-admission and 3-month post-discharge status. We compared the discrimination calibration of SHERPA vs SHERPA+, a logistic regression model including SHERPA and selected biomarkers. Results:Three months after discharge, functional decline had occurred in 46 patients. Interleukin-6 (IL-6) and insulinlike growth factor 1 (IGF-1) were selected, since their levels were significantly different between decliners and non-decliners, and were included in the new logistic regression model SHERPA+. Areas under the ROC curve [95% CI] for functional decline prediction were 0.73 [0.63–0.81] for SHERPA vs 0.79 [0.69–0.86] for SHERPA+ (p=0.14). However, SHERPA+ was better calibrated, as the average predicted risk of functional decline within subgroups matched the proportion which actually underwent functional decline (Brier score=0.185). Since functional decline was higher in patients with hip fracture, the SHERPA+ model was challenged by including the diagnosis. Only SHERPA, IGF-1 and diagnosis were significantly associated with functional decline. Conclusions:Selected biological markers may marginally improve the clinical prediction of post-discharge functional decline in hospitalized patients, and to stratify them appropriately. The predictive value of these biomarkers is not fully independent of disease status. Further studies are needed to confirm these results in a cohort representative of older patients admitted through the emergency department.

Background and aims:Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community-dwelling seniors, these markers have not been studied from this perspective in acutely ill older patients. This prospective study was designed to determine whether biological markers can improve the predictive value of a clinical screening tool to assess the risk of functional decline in hospitalized older patients. Methods:Patients aged 75 years and over admitted for hip fracture, acute heart failure or infection (n=118) were recruited. The clinical screening tool SHERPA was filled in on admission, with concomitant measurement of interleukin-6 (IL-6), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP), white blood cells, urea, albumin, pre-albumin and total cholesterol. Functional decline was defined as a decrease of one point in the activities of daily living scale between pre-admission and 3-month post-discharge status. We compared the discrimination calibration of SHERPA vs SHERPA+, a logistic regression model including SHERPA and selected biomarkers. Results:Three months after discharge, functional decline had occurred in 46 patients. Interleukin-6 (IL-6) and insulinlike growth factor 1 (IGF-1) were selected, since their levels were significantly different between decliners and non-decliners, and were included in the new logistic regression model SHERPA+. Areas under the ROC curve [95% CI] for functional decline prediction were 0.73 [0.63–0.81] for SHERPA vs 0.79 [0.69–0.86] for SHERPA+ (p=0.14). However, SHERPA+ was better calibrated, as the average predicted risk of functional decline within subgroups matched the proportion which actually underwent functional decline (Brier score=0.185). Since functional decline was higher in patients with hip fracture, the SHERPA+ model was challenged by including the diagnosis. Only SHERPA, IGF-1 and diagnosis were significantly associated with functional decline. Conclusions:Selected biological markers may marginally improve the clinical prediction of post-discharge functional decline in hospitalized patients, and to stratify them appropriately. The predictive value of these biomarkers is not fully independent of disease status. Further studies are needed to confirm these results in a cohort representative of older patients admitted through the emergency department.

Since ageing is a universal human feature, it is not surprising that, from the Babylonian epic of Gilgamesh to Ponce de Leon seeking the "Fountain of Youth," countless people have dreamed of finding a way to avoid ageing, to no avail. Yet the search continues. In this review, we present one of the latest candidates: the enzyme telomerase, capable of elongating the tips of chromosomes, the telomeres. Research into the causes of cellular ageing established the telomeres as the molecular clock that counts the number of times cells divide and triggers cellular senescence. Herein, we review arguments both in favor and against the use of telomerase as an anti-ageing therapy. The importance of the telomeres in cellular ageing, the low or non-existent levels of telomerase activity in human tissues, and the ability of telomerase to immortalize human cells suggest that telomerase can be used as an anti-ageing therapy. On the other hand, recent experiments in mice have raised doubts whether telomerase affects organismal ageing. Results from human cells expressing telomerase have also suggested telomerase may promote tumorigenesis. We conclude that, though telomerase may be used in regenerative medicine and to treat specific diseases, it is unlikely to become a source of anti-ageing therapies.

In this work we show that the steady state mRNA level of TGF-?1 is significantly increased in UVB-induced premature senescence.

WI‐38 human diploid fibroblasts underwent accelerated telomere shortening (490 bp/stress) and growth arrest after exposure to four subcytotoxic 100 μM tert‐butylhydroperoxide (t‐BHP) stresses, with a stress at every two population doublings (PD). After subcytotoxic 160 μM H2O2stress or five repeated 30 μM t‐BHP stresses along the same PD, respectively a 322±55 and 380±129 bp telomere shortening was observed only during the first PD after stress. The percentage of cells resuming proliferation after stress suggests this telomere shortening is due to the number of cell divisions accomplished to reach confluence during the first PD after stress.

Stress-induced premature senescence (SIPS) is induced 3 days after exposure of human diploid fibroblasts to subcytotoxic oxidative stress with H2O2, with appearance of several biomarkers of replicative senescence. In this work, we show that transforming growth factor-β1 (TGF-β1) regulates the induction of several of these biomarkers in SIPS: cellular morphology, senescence-associated β-galactosidase activity, increase in the steady-state level of fibronectin, apolipoprotein J, osteonectin, and SM22 mRNA. Indeed, the neutralization of TGF-β1 or its receptor (TGF-β RII) using specific antibodies decreases sharply the percentage of cells positive for the senescent-associated β-galactosidase activity and displaying a senescent morphology. In the presence of each of these antibodies, the steady-state level of fibronectin, osteonectin, apolipoprotein J, and SM22 mRNA is no more increased at 72 h after stress. Results obtained on fibroblasts retrovirally transfected with the human papillomavirus E7 cDNA suggest that retinoblastoma protein (Rb) regulates the expression of TGF-β1 in stressful conditions, leading to SIPS and overexpression of these four genes.

WI-38 human diploid fibroblasts underwent accelerated telomere shortening (490 bp/stress) and growth arrest after exposure to four subcytotoxic 100 μM tert-butylhydroperoxide (t-BHP) stresses, with a stress at every two population doublings (PD). After subcytotoxic 160 μM H 2O 2stress or five repeated 30 μM t-BHP stresses along the same PD, respectively a 322±55 and 380±129 bp telomere shortening was observed only during the first PD after stress. The percentage of cells resuming proliferation after stress suggests this telomere shortening is due to the number of cell divisions accomplished to reach confluence during the first PD after stress.

Early passage human diploid fibroblasts develop senescent morphology prematurely within a week after a 2-hour pulse treatment with low or mild dose H2O2. We test here the role of cell cycle checkpoints, cytoskeletal proteins and de novo protein synthesis in senescent morphogenesis following H2O2 treatment. H2O2 treatment causes transient elevation of p53 protein and prolonged inhibition of Rb hyperphosphorylation. Expression of human papillomaviral E6 gene prevented elevation of p53 but did not affect senescent morphogenesis. Expression of human papillomaviral E7 gene reduced the level of Rb protein and prevented induction of senescent morphology by H2O2. The mutants of the E7 gene, in which the Rb family protein binding site was destroyed, could not reduce Rb protein or prevent H2O2 from inducing senescent morphology. Senescent-like cells showed enhanced actin stress fibers. In untreated cells, vinculin and paxillin preferentially distributed along the edge of the cells. In contrast, vinculin and paxillin distributed randomly and sporadically throughout senescent-like cells. E7 expression prevented enhancement of actin filament formation and redistribution of vinculin or paxillin. Neither wild-type nor E7 cells showed changes in the protein level of actin, vinculin or paxillin measured by western blot after H2O2 treatment. Finally, depletion of methionine in the culture medium after H2O2 treatment prevented senescent morphogenesis without affecting dephosphorylation of Rb protein. Our results suggest that senescent morphology likely develops by a program involving activated Rb family proteins, enhancement of actin stress fibers, redistribution of focal adhesion proteins and de novo protein synthesis.

Sublethal oxidative stresses increase the proportions of human fibroblasts positive for senescence associated β‐galactosidase activity and accelerate the transition in the fibroblast morphotypes characterising fibroblast ageing. Stimulation of fibroblasts with TNF‐α or IL‐1α transiently increases the production of reactive oxygen species (ROS) in human fibroblasts. Here we propose that repeated stimulation of WI‐38 fibroblasts with TNF‐α or IL‐1α can generate enough ROS to accelerate the transition in the fibroblast morphotypes and increase the proportion of cells positive for senescence associated β‐galactosidase activity. The involvement of ROS is suggested by experiments where the stimulation of fibroblasts with TNF‐α or IL‐1α are performed in the presence of N‐acetylcysteine which increases the intracellular antioxidant potential. It is proposed that the decrease in the proportions of morphotypes I and II, and the increase in the proportions of morphotypes III to VI observed after successive stimulation with TNF‐α or IL1‐α is attributed to an increased ROS production occurring during the stimulation.