Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia. METHODS: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. RESULTS: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).

WNT/beta-catenin signalling interrupts a senescence-induction cascade in human mesenchymal stem cells that restricts their expansion.

Senescence, the irreversible cell cycle arrest of damaged cells, is accompanied by a deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Senescence and the SASP are major factors in aging, cancer, and degenerative diseases, and interfere with the expansion of adult cells in vitro, yet little is known about how to counteract their induction and deleterious effects. Paracrine signals are increasingly recognized as important senescence triggers and understanding their regulation and mode of action may provide novel opportunities to reduce senescence-induced inflammation and improve cell-based therapies. Here, we show that the signalling protein WNT3A counteracts the induction of paracrine senescence in cultured human adult mesenchymal stem cells (MSCs). We find that entry into senescence in a small subpopulation of MSCs triggers a secretome that causes a feed-forward signalling cascade that with increasing speed induces healthy cells into senescence. WNT signals interrupt this cascade by repressing cytokines that mediate this induction of senescence. Inhibition of those mediators by interference with NF-κB or interleukin 6 signalling reduced paracrine senescence in absence of WNT3A and promoted the expansion of MSCs. Our work reveals how WNT signals can antagonize senescence and has relevance not only for expansion of adult cells but can also provide new insights into senescence-associated inflammatory and degenerative diseases.

Continuum beliefs of mental illness: a systematic review of measures.

PURPOSE: The continuum of mental health/illness has been subject to scientific debate for decades. While current research indicates that continuum belief interventions can reduce mental health stigma and improve treatment seeking in affected populations, no study has yet systematically examined measures of continuum beliefs. METHODS: This preregistered systematic review summarizes measures of continuum beliefs. Following the PRISMA statement, three scientific databases (PubMed, PsycInfo and PsycArticles via EBSCOhost, Web of Science) are searched, instruments are described and discussed regarding their scope, and methodological quality. RESULTS: Overall, 7351 records were identified, with 35 studies reporting relevant findings on 11 measures. Most studies examined general population samples and used vignette-based measures. Schizophrenia and depression were most commonly examined, few studies focused on dementia, ADHD, OCD, eating disorders, and problematic alcohol use, or compared continuum beliefs across disorders. Validity was very good for most measures, but reliability was rarely tested. Measures mostly assessed beliefs in the normality of mental health symptoms or the normality of persons with such symptoms but rarely nosological aspects (i.e., categorical v continuous conceptualization of mental disorders). CONCLUSIONS: Current research provides psychometrically sound instruments to examine continuum beliefs for a variety of mental disorders. While studies suggest utility for general population samples and mental health professionals, more research is necessary to corroborate findings, for instance, regarding age (e.g., in adolescents), gender, or type of mental disorder. Future research should also compare self-report ratings, and vignette-based measures, include measures of nosological concepts to fully grasp the continuum concept of mental illness. PREREGISTRATION: PROSPERO: CRD42019123606.

Evaluation of the distribution and excretion of [14C]-inclisiran following single subcutaneous administration in cynomolgus monkeys.

Inclisiran is a small interfering RNA molecule that was designed to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels by inhibiting proprotein convertase subtilisin/kexin type 9 synthesis in the liver. This study aimed to characterize the tissue distribution and excretion of inclisiran after dosing in monkeys. A single 20 mg/kg subcutaneous injection of [14C]-inclisiran was administered to 12 male cynomolgus monkeys. Plasma concentrations and tissue binding parameters for inclisiran were assessed up to 42 days after injection using liquid scintillation of blood samples and tissue homogenates, as well as quantitative whole-body autoradiography. Radioactivity was highest in the liver at all time points from 24 h onward and remained elevated throughout the entire study period. Radioactivity was also detected in the kidneys and bladder wall, returning to low levels by 24 h. The concentration of radioactivity in the liver (402.97 µg equivalent/g) was 15.7-fold higher than in the kidneys (25.70 µg equivalent/g). Very low amounts of radioactivity were detected in all other tissues examined. The highest radioactivity in tissue homogenates was in the liver and kidney pyramid (327 and 351 µg equivalent/g, respectively). This study confirmed the selective uptake of inclisiran by the liver, indicating that the N-acetylgalactosamine linker allows for selective uptake via the asialoglycoprotein receptors expressed on hepatocytes compared with other tissues that lack asialoglycoprotein receptors. The long tissue retention in the liver supports the infrequent, biannual dosing schedule for inclisiran in the clinic and the temporal disconnect between short-term systemic exposure and sustained lowering of LDL-C.

Do High-Volume Injections Affect the Ultrasonographic Neovascularization in Chronic Achilles Tendinopathy? A Randomized Placebo-Controlled Clinical Trial.

OBJECTIVE: High-volume injections (HVIs) are thought to target neovascularization in chronic midportion Achilles tendinopathy (AT), yet the mechanism has not been clarified. Therefore, we aim to evaluate whether a HVI decreases ultrasonographic Doppler flow in patients with chronic midportion AT. DESIGN: A double-blind, randomized, placebo-controlled clinical trial. SETTING: Sports medicine department at a district general hospital. PATIENTS: Sixty-two patients with clinically diagnosed chronic midportion AT were included and randomized into the intervention group (HVI-group, n = 30) and placebo group (n = 32). INTERVENTION: A daily calf-muscle exercise program combined with either (1) a HVI (HVI-group: 50 mL) or (2) a placebo-injection (placebo-group: 2 mL) with a mixture of saline and lidocaine. MAIN OUTCOME MEASURES: Primary outcome was the surface area quantification (SAQ) score (%) of the Doppler flow during a 24-week follow-up period. Secondary outcome was the association between SAQ scores and symptoms [Victorian Institute of Sports Assessment-Achilles (VISA-A)]. Outcomes were measured before, directly after, and 1 hour after the injection and at 2, 6, 12, and 24 weeks of follow-up. RESULTS: There was no significant between-group difference at 24 weeks [-0.1%; 95% confidence interval (CI), -4.9 to 4.7] or at any of the other time points. Change in SAQ score did not correlate with the change in VISA-A score (P = 0.93). CONCLUSION: A HVI does not affect Doppler flow in patients with chronic midportion AT. Also, changes in Doppler flow were not associated with the clinical outcome. These findings challenge the theoretical basis of a HVI. TRIAL REGISTRATION: NCT02996409.

One fifth of patients with Achilles tendinopathy have symptoms after 10 years: A prospective cohort study.

Patients with midportion Achilles tendinopathy (AT) are thought to experience a gradual symptomatic improvement over time. The aim of this study was to prospectively investigate if patients with midportion AT have symptoms at 10-year follow-up. Patients withmidportion AT were invited to complete an online questionnaire 10 years after inclusion in an intervention trial. The primary outcomewas the presence of AT symptoms. Secondary outcomes were: the Victorian Institute of Sports Assessment-Achilles tendinopathy (VISA-A, 0-100) score and sports activity level. Of the 54 patientsincluded, 43 (80%) completed the questionnaire at an average follow-up of 10.4 years. Persisting symptoms were reported by 19%. The mean (standard deviation-SD) VISA-A score improved from 52 (17) at baseline to 79 (21) at 10-years follow-up with a mean change of 27 points (95% confidence interval: 21; 35, p < 0.001). Of the 38 active patients, 16 (42%) returned to their pre-injury level sports,of whom 14 (37%) performed them pain free. One-fifth of patients with conservatively treated midportion AT still have symptoms after 10years. One-third of patients were able to perform sports pain-free atpre-injury level. Patients should be adequately counselled to giverealistic expectations. Trial registration number: clinicaltrials.gov (identifier: NCT00761423).

Isometric exercises do not provide immediate pain relief in Achilles tendinopathy: A quasi-randomized clinical trial.

BACKGROUND: Isometric exercises may provide an immediate analgesic effect in patients with lower-limb tendinopathy and have been proposed as initial treatment and for immediate pain relief. Current evidence is conflicting, and previous studies were small. OBJECTIVE: To study whether isometric exercises result in an immediate analgesic effect in patients with chronic midportion Achilles tendinopathy. METHODS: Patients with clinically diagnosed chronic midportion Achilles tendinopathy were quasi-randomized to one of four arms: isometric calf-muscle exercises (tiptoes), isometric calf-muscle exercises (dorsiflexed ankle position), isotonic calf-muscle exercises, or rest. The primary outcome was pain measured on a visual analogue scale (VAS) score (0-100) during a functional task (10 unilateral hops) both before and after the intervention. Between-group differences were analyzed using a generalized estimation equations model. RESULTS: We included 91 patients. There was no significant reduction in pain on the 10 hop test after performing any of the four interventions: isometric (tiptoes) group 0.2, 95%CI -11.2 to 11.5; isometric (dorsiflexed) group -1.9, 95%CI -13.6 to 9.7; isotonic group 1.4, 95%CI -8.3 to 11.1; and rest group 7.2, 95%CI -2.4 to 16.7. There were also no between-group differences after the interventions. CONCLUSION: The isometric exercises investigated in this study did not result in immediate analgesic benefit in patients with chronic midportion Achilles tendinopathy. We do not recommend isometric exercises if the aim is providing immediate pain relief. Future research should focus on the use of isometric or isotonic exercise therapy as initial treatment as all exercise protocols used in this study were well-tolerated.

Ultrasound Doppler Flow in Patients With Chronic Midportion Achilles Tendinopathy: Is Surface Area Quantification a Reliable Method?

OBJECTIVES: Ultrasound assessments of patients with chronic midportion Achilles tendinopathy include determining the degree of neovascularization using Doppler flow. A frequently used measure to quantify neovascularization is the modified Öhberg score. It is unknown whether the semiquantitative modified Öhberg score (0-4+) has higher reliability than a quantified measure of Doppler flow (0-100%). The purpose of this cross-sectional study was to evaluate the interobserver reliability of the modified Öhberg score and a surface area quantification (SAQ) method for Doppler flow in patients with chronic midportion Achilles tendinopathy. METHODS: Two observers examined the degree of Doppler flow independently using SAQ and the modified Öhberg score during a single consultation. The intraclass correlation coefficient, standard error of measurement, and minimal detectable difference were determined to evaluate the reliability and measurement properties of the SAQ method and the modified Öhberg score. RESULTS: In total, 28 consecutive patients with chronic midportion Achilles tendinopathy participated. The intraclass correlation coefficient for interobserver reliability of the SAQ method was 0.81 (95% confidence interval, 0.58-0.91), compared to 0.64 (95% confidence interval, 0.45-0.81) for the modified Öhberg score. The standard error of measurement and minimal detectable difference values for the SAQ method were 2.9% and 8.0%, respectively, and for the modified Öhberg score, they were 0.55 and 1.53 points. CONCLUSIONS: The SAQ method shows good reliability to evaluate the degree of Doppler flow in patients with chronic midportion Achilles tendinopathy, and it overcomes the ceiling effect of the modified Öhberg score. Future research should focus on the relationship between the SAQ method and clinical outcomes and use this method to monitor treatment responses.

Age-related differences in task-induced brain activation is not task specific: Multivariate pattern generalization between metacognition, cognition and perception.

Adolescence is associated with widespread maturation of brain structures and functional connectivity profiles that shift from local to more distributed and better integrated networks, which are active during a variety of cognitive tasks. Nevertheless, the approach to examine task-induced developmental brain changes is function-specific, leaving the question open whether functional maturation is specific to the particular cognitive demands of the task used, or generalizes across different tasks. In the present study we examine the hypothesis that functional brain maturation is driven by global changes in how the brain handles cognitive demands. Multivariate pattern classification analysis (MVPA) was used to examine whether age discriminative task-induced activation patterns generalize across a wide range of information processing levels. 25 young (13-years old) and 22 old (17-years old) adolescents performed three conceptually different tasks of metacognition, cognition and visual processing. MVPA applied within each task indicated that task-induced brain activation is consistent and reliably different between ages 13 and 17. These age-discriminative activation patterns proved to be common across the different tasks used, despite the differences in cognitive demands and brain structures engaged by each of the three tasks. MVP classifiers trained to detect age-discriminative patterns in brain activation during one task were significantly able to decode age from brain activation maps during execution of other tasks with accuracies between 63 and 75%. The results emphasize that age-specific characteristics of task-induced brain activation have to be understood at the level of brain-wide networks that show maturational changes in their organization and processing efficacy during adolescence.

Blood perfusion of patellar bone measured by dynamic contrast-enhanced MRI in patients with patellofemoral pain: A case-control study.

BACKGROUND: Altered perfusion might play an important role in the pathophysiology of patellofemoral pain (PFP), a common knee complaint with unclear pathophysiology. PURPOSE: To investigate differences in dynamic contrast-enhanced (DCE)-MRI perfusion parameters between patients with PFP and healthy control subjects. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Thirty-five adult patients with PFP and 44 healthy adult control subjects. FIELD STRENGTH/SEQUENCE: 3T DCE-MRI consisting of a sagittal, anterior-posterior, frequency-encoded, fat-suppressed 3D spoiled gradient-echo sequence with intravenous contrast administration. ASSESSMENT: Patellar bone volumes of interest (VOIs) were delineated by a blinded observer. Quantitative perfusion parameters (kep and ktrans ) were calculated from motion-compensated DCE-MRI data by fitting Tofts' model. Weighted mean and unweighted median values of kep and ktrans were computed within the patellar bone VOIs. STATISTICAL TESTS: Differences in patellar bone perfusion parameters were compared between groups by linear regression analyses, adjusted for confounders. RESULTS: Mean differences of weighted mean and unweighted median were 0.0039 (95% confidence interval [CI] -0.0013; 0.0091) and 0.0052 (95% CI -0.0078; 0.018) for ktrans , and 0.046 (95% CI -0.021; 0.11) and 0.069 (95% CI -0.017; 0.15) for kep , respectively. All perfusion parameters were not significantly different between groups (P-values: 0.32; 0.47 for ktrans , and 0.24; 0.15) for kep . However, a significant difference in variance between populations was observed for ktrans (P-value 0.007). DATA CONCLUSION: Higher patellar bone perfusion parameters were found in patients with PFP when compared to healthy control subjects, but these differences were not statistically significant. This result, and the observed significant difference in ktrans variance, warrant further research. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1344-1350.

History and highlights of the teratological collection in the Museum Anatomicum of Leiden University, The Netherlands.

The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742-1814) and his son Gerard Sandifort (1779-1848). Efforts were made to re-describe, re-diagnose and re-categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730-1783) and Andreas Bonn (1738-1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands.

Cellular senescence as a therapeutic target to improve renal transplantation outcome.

Kidney transplants from aged donors are more vulnerable to ischemic injury, suffer more from delayed graft function and have a lower graft survival compared to kidneys from younger donors. On a cellular level, aging results in an increase in cells that are in a permanent cell cycle arrest, termed senescence, which secrete a range of pro-inflammatory cytokines and growth factors. Consequently, these senescent cells negatively influence the local milieu by causing inflammaging, and by reducing the regenerative capacity of the kidney. Moreover, the oxidative damage that is inflicted by ischemia-reperfusion injury during transplantation can induce senescence and accelerate aging. In this review, we describe recent developments in the understanding of the biology of aging that have led to the development of a new class of therapeutic agents aimed at eliminating senescent cells. These compounds have already shown to be able to restore tissue homeostasis in old mice, improve kidney function and general health- and lifespan. Use of these anti-senescence compounds holds great promise to improve the quality of marginal donor kidneys as well as to remove senescent cells induced by ischemia-reperfusion injury. Altogether, senescent cell removal may increase the donor pool, relieving the growing organ shortage and improve long-term transplantation outcome.

High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients.

OBJECTIVE: To determine effects of single ascending doses of MDCO-216 on high-density lipoprotein (HDL) subfractions in relation to changes in cholesterol efflux capacity in healthy volunteers and in patients with stable angina pectoris. APPROACH AND RESULTS: Doses of 5- (in volunteers only), 10-, 20-, 30-, and 40-mg/kg MDCO-216 were infused during 2 hours, and plasma and serum were collected during 30 days. Plasma levels of HDL subfractions were assessed by 2-dimensional gel electrophoresis, immunoblotting, and image analysis. Lipoprotein particle concentrations and sizes were also assessed by proton nuclear magnetic resonance ((1)H-NMR). There was a rapid dose-dependent increase of total apolipoprotein A-I (apoA-I) in pre-ß1, α-1, and α-2 HDL levels and decrease in α-3 and α-4 HDL. Using a selective antibody apoA-IMilano was detected in the large α-1 and α-2 HDL on all doses and at each time point. ApoA-IMilano was also detected at the α-4 position but only at high doses. (1)H-NMR analysis similarly showed a rapid and dose-dependent shift from small- to large-sized HDL particles. The increase of basal and ATP-binding cassette transporter A1-mediated efflux capacities reported previously correlated strongly and independently with the increase in pre-ß1-HDL and α-1 HDL, but not with that in α-2 HDL. CONCLUSIONS: On infusion, MDCO-216 rapidly eliminates small HDL and leads to formation of α-1 and α-2 HDL containing both wild-type apoA-I and apoA-IMilano. In this process, endogenous apoA-I is liberated appearing as pre-ß1-HDL. In addition to pre-ß1-HDL, the newly formed α-1 HDL particle containing apoA-I Milano may have a direct effect on cholesterol efflux capacity.

Are immunosenescent T cells really senescent?

Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases.

Difficulty sensitivity replaces reward sensitivity during adolescence: Task-related fMRI and functional connectivity during self-regulative learning choices.

AIM: We examined age-related differences in valuation and cognitive control circuits during value-based decision-making. METHODS: 13-year-olds (N = 25) and 17-year-olds (N = 22) made a metacognitive choice to be tested or not on an upcoming learning task, based on reward and difficulty associated with word-pairs. To investigate whether these determinants of subjective value are differently processed at different ages, we performed region-of-interest(ROI)-based analyses of task-related and functional connectivity data. RESULTS: We observed age-related differences in responsiveness of valuation structures (amygdala, ventral striatum, ventromedial prefrontal cortex) and caudate nucleus, with activity modulated by reward in 13-year-olds, while in 17-year-olds activity being responsive to difficulty. These accompanied age-related differences in functional connectivity between medial prefrontal and striatal/amygdala seeds. DISCUSSION: These results are in line with current views that sensitivity changes for reward and difficulty during adolescence are the result of a maturational switch in effort-related signalling in the cognitive control circuit, which increasingly regulates value-signalling structures.