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A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment.
Orr, ME, Kotkowski, E, Ramirez, P, Bair-Kelps, D, Liu, Q, Brenner, C, Schmidt, MS, Fox, PT, Larbi, A, Tan, C, et al
GeroScience. 2024;(1):665-682
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Abstract
Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, μ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, μ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888.
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Effects of multi-domain lifestyle interventions on sarcopenia measures and blood biomarkers: secondary analysis of a randomized controlled trial of community-dwelling pre-frail and frail older adults.
Lu, Y, Niti, M, Yap, KB, Tan, CTY, Nyunt, MSZ, Feng, L, Tan, BY, Chan, G, Khoo, SA, Chan, SM, et al
Aging. 2021;(7):9330-9347
Abstract
Few studies have comprehensively described changes in blood biomarkers of the physiological responses underlying sarcopenia reduction associated with lifestyle interventions. In this study, we performed secondary analyses of data in a randomized controlled trial of multi-domain lifestyle interventions (6-month duration physical exercise, nutritional enrichment, cognitive training, combination and standard care control) among 246 community-dwelling pre-frail and frail elderly, aged ≥65 years, with and without sarcopenia. Appendicular lean mass (ALM), lower limb strength, gait speed, and blood levels of markers of muscle metabolism, inflammation, anti-oxidation, anabolic hormone regulation, insulin signaling, tissue oxygenation were measured at baseline, 3-month and 6-month post-intervention. Multi-domain interventions were associated with significant (p < 0.001) reduction of sarcopenia at 3-month and 6-month post-intervention, improved gait speed, enhanced lower limb strength, and were equally evident among sarcopenic participants who were slower at baseline than non-sarcopenic participants. Active intervention was associated with significantly reduced inflammation levels. Sarcopenia status and reduction were associated with blood biomarkers related to muscle metabolism, steroid hormone regulation, insulin-leptin signaling, and tissue oxygenation. Physical, nutritional and cognitive intervention was associated with measures of sarcopenia reduction, together with changes in circulating biomarkers of anabolic and catabolic metabolism underlying sarcopenia.
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Systemic and Metabolic Signature of Sarcopenia in Community-Dwelling Older Adults.
Lu, Y, Karagounis, LG, Ng, TP, Carre, C, Narang, V, Wong, G, Tan, CTY, Zin Nyunt, MS, Gao, Q, Abel, B, et al
The journals of gerontology. Series A, Biological sciences and medical sciences. 2020;(2):309-317
Abstract
BACKGROUND Evidence suggests the pivotal contribution of nutrition as a modifiable risk factor for sarcopenia. The present cross-sectional study characterized the nutritional and metabolic profile of sarcopenia through an extensive exploration of a wide array of blood biomarkers related to muscle protein metabolism and transcriptomic signatures in community-dwelling elderly adults. METHODS Among 189 older individuals with a mean age of 73.2 years, sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria based on appendicular lean mass measured by dual-energy X-ray absorptiometry scan, muscle strength, and gait speed. Nutritional status was evaluated using the mini-nutritional assessment (MNA). In addition, we assessed specific blood biomarkers of nutritional status (plasma essential amino acids [EAAs], vitamins), nicotine-derived metabolites, and an extensive microarray analysis from peripheral blood mononuclear cells. RESULTS Malnutrition defined by low MNA score was independently associated with sarcopenia (p < .001). Sarcopenic elderly showed lower body mass index and leptin and higher adiponectin and high-density lipoproteins. Levels of EAAs including lysine, methionine, phenylalanine, threonine, as well as branched-chain AAs and choline, were inversely associated with sarcopenia. Furthermore, nicotine metabolites (cotinine and trans-3'-hydroxycotine) and vitamin B6 status were linked to one or more clinical and functional measures of sarcopenia. Differentially expressed genes and ingenuity pathway analysis supported the association of nutrition with sarcopenia. CONCLUSIONS Herein, the characterization of a nutritional and metabolic signature of sarcopenia provides a firm basis and potential identification of specific targets and directions for the nutritional approach to the prevention and treatment of sarcopenia in aging populations.
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The conundrum of human immune system "senescence".
Pawelec, G, Bronikowski, A, Cunnane, SC, Ferrucci, L, Franceschi, C, Fülöp, T, Gaudreau, P, Gladyshev, VN, Gonos, ES, Gorbunova, V, et al
Mechanisms of ageing and development. 2020;:111357
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Abstract
There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as "immunosenescence". But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.
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Assessment of Sarcopenia Among Community-Dwelling At-Risk Frail Adults Aged 65 Years and Older Who Received Multidomain Lifestyle Interventions: A Secondary Analysis of a Randomized Clinical Trial.
Lu, Y, Niti, M, Yap, KB, Tan, CTY, Zin Nyunt, MS, Feng, L, Tan, BY, Chan, G, Khoo, SA, Chan, SM, et al
JAMA network open. 2019;(10):e1913346
Abstract
IMPORTANCE There is little understanding of the outcomes associated with active lifestyle interventions for sarcopenia among older persons. OBJECTIVE To determine the association of 6-month multidomain lifestyle interventions (physical exercise, nutritional enhancement, cognitive training, combined treatment, and standard care) with change in sarcopenia status and physical function among adults 65 years and older. DESIGN, SETTING, AND PARTICIPANTS Post hoc secondary analysis of a parallel-group randomized clinical trial conducted from September 1, 2012, to September 1, 2014, at community centers providing services to elderly individuals in Singapore. Participants included a subsample of 92 community-dwelling prefrail or frail older persons with sarcopenia aged 65 years and older. Data were analyzed from June 1, 2017, to January 1, 2018. INTERVENTIONS The 5 intervention groups were a 6-month duration of physical exercise that included resistance and balance training, nutritional enhancement with a commercial oral nutrition supplement formula, cognitive training, a combination of the preceding 3 interventions, and standard care (control). MAIN OUTCOMES AND MEASURES Primary outcomes were changes in sarcopenia status and its components, appendicular skeletal muscle index (ASMI), knee extension strength (KES), and gait speed (GS) at 3 months and 6 months following the intervention. Sarcopenia was defined as the presence of both low ASMI and low KES and/or GS. RESULTS In 92 participants with sarcopenia, the mean (SD) age was 70.0 (4.7) years and 59 (64.1%) were female. Seventy-eight participants received active interventions and 14 received standard care. Of 92 total participants, the number who remained sarcopenic was reduced to 48 (of 73) after 3 months and 51 (of 75) after 6 months of intervention, indicating that 25 of 92 participants (27.2%) experienced sarcopenia reduction at 3 months and 24 of 92 (26.1%) had sarcopenia reduction at 6 months. Low KES was present in 88 of 92 patients (95.6%), and low GS in 30 of 92 patients (32.6%) at baseline. Among the components of sarcopenia, GS had the greatest change associated with active interventions, with 22 of 30 participants (73.3%) free of low GS at 6 months; in comparison, 17 of 88 participants (19.3%) were free of low KES at 6 months and 7 of 92 participants (7.6%) were free of low ASMI at 6 months. Men experienced greater reduction in sarcopenia than women (χ2 = 5.925; P = .02), as did those with younger age (t = -2.078; P = .04) or higher ASMI (mean [SD] ASMI, 5.74 [0.77] vs 5.14 [0.77] kg/m2; P = .002). Participants in the active intervention group experienced statistically significant decreases in sarcopenia score and its components at 3 months and 6 months from baseline (F = 14.138; P < .001), but the intervention was not associated with significant differences in ASMI, KES, and GS vs standard care. CONCLUSIONS AND RELEVANCE This study suggests that older persons with sarcopenia are responsive to the effects of multidomain lifestyle interventions. Sarcopenia reduction was most pronounced through improved gait speed, and occurred more among those who were male, were younger, or had greater muscle mass.
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Adaptive NKG2C+CD57+ Natural Killer Cell and Tim-3 Expression During Viral Infections.
Kared, H, Martelli, S, Tan, SW, Simoni, Y, Chong, ML, Yap, SH, Newell, EW, Pender, SLF, Kamarulzaman, A, Rajasuriar, R, et al
Frontiers in immunology. 2018;:686
Abstract
Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.
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Prevalence and characteristics of intravertebral enhancement on contrast-enhanced CT scans in cancer patients.
Rasselet, B, Larbi, A, Viala, P, Molinari, N, Tetreau, R, Faruch-Bilfeld, M, Taourel, P, Cyteval, C
European journal of radiology. 2017;:1-5
Abstract
STUDY DESIGN This was a single center, retrospective observational study. OBJECTIVE to investigate-in a cancer population-the prevalence and hallmarks of intravertebral enhancement (IVE) detected on contrast-enhanced CT. SUMMARY OF BACKGROUND DATA Intravertebral enhancements secondary to iodinated contrast stagnation have been described. Cancer patients have an increased risk of perivertebral venous thrombosis or stenosis secondary to several risk factors (cancer or drug induced hypercoagulability, deterioration of venous flow linked to catheter insertion, prolonged immobilization). In case of a high density lesion identified on CT, the diagnostic choice between metastasis and contrast media within bone marrow vessels may be an issue, especially as oncologic follow-up CT scans are usually performed with contrast medium injection. METHODS 2572 contrast-enhanced body CT scans performed in cancer patients over 3 months in the medical imaging department of a university hospital were retrospectively reviewed. IVE was sought when paravertebral venous collateral circulation was detected and bone metastasis ruled out and classified as linear or nodular. Their locations within vertebra, their relation to the injection side and the predominant collateral venous network side were evaluated. RESULTS Sixty-seven (2.8%) patients had a collateral paravertebral venous system and among them 21 had IVE (37%). There were 208 IVE locations involving 75 vertebrae. 199 IVE were linear-shaped (95.7%) and 9 nodular-shaped (4.3%). 80.8% were located between C6 and T4. 88.9% were localized in the vertebral body. 73.1% were located medially or ipsilateral to the injection side. CONCLUSION Intravertebral enhancement is found in 37% of the patients with paraspinal collateral venous circulation when a CT scan is performed for cancer. The ipsilateral or medial position of the IVE relative to the injection side and the side of the dominant perivertebral venous system, and the possibility of connecting the IVE to a paravertebral vein may be in favor of vascular opacification.
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Novel imaging techniques reshape the landscape in high-risk prostate cancers.
Lecouvet, FE, Lhommel, R, Pasoglou, V, Larbi, A, Jamar, F, Tombal, B
Current opinion in urology. 2013;(4):323-30
Abstract
PURPOSE OF REVIEW High-risk prostate cancers (PCa), that is, those with prostate-specific antigen greater than 20 ng/dl, Gleason Score of at least 8, or extraprostatic spread, are nowadays commonly treated by surgery and radiotherapy combined with a fixed period of systemic treatment. Implementing these strategies requires an exhaustive assessment of metastatic spread. This review addresses the latest development in integrated imaging techniques. RECENT FINDINGS In contrast to the progress that has been made in PCa treatment, diagnostic strategies have not much evolved. Most guidelines still recognize (99m)Tc bone scintigraphy and computed tomography (CT) as cornerstone modalities to assess metastatic spread in bones and lymph nodes. Therefore, modern imaging techniques should primarily focus on these two targets. PET with various tracers, including (11)C or (18)F-choline and (18)F-sodium fluoride, and MRI with or without diffusion-weighted imaging are competing to supplant bone scan and CT scan as reference imaging techniques. This review focuses on the latest development of these techniques and analyses their potential impact in everyday urology practice. SUMMARY Although certain hurdles remain, PET and whole-body MRI have the ability to supplant (99m)Tc bone scan and CT as upfront test to assess metastatic spread in high-risk PCa.
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Effects of cadmium on cork oak (Quercus suber L.) plants grown in hydroponics.
Gogorcena, Y, Larbi, A, Andaluz, S, Carpena, RO, Abadía, A, Abadía, J
Tree physiology. 2011;(12):1401-12
Abstract
Cork oak (Quercus suber L.) is an autochthonous tree species that is being used for reforestation in heavy-metal-contaminated areas in Spain. A hydroponics experiment was carried out to characterize the effects of Cd on several morphological and physiological parameters in this species, including shoot length, nutrient concentrations and allocation in different organs, leaf pigment concentrations, photosynthetic efficiency, root ferric chelate reductase (FCR) activity and organic acid concentrations in xylem sap. Four different Cd treatments were applied, adding Cd chelated with EDTA or as chloride salt at two different concentrations (10 and 50 µM Cd). After 1 month of Cd treatment, plant growth was significantly inhibited in all treatments. Results indicate that Cd accumulates in all organs 7- to 500-fold when compared with control plants. The highest Cd concentration was found in the 50 µM CdCl(2) treatment, which led to concentrations of ~30, 123 and 1153 µg Cd g(-1) dry weight in leaves, stems and roots, respectively. In the strongest Cd treatments the concentrations of P and Ca decreased in some plant parts, whereas the Mn leaf concentrations decreased with three of the four Cd treatments applied. The concentrations of chlorophyll and carotenoids on an area basis decreased, whereas the (zeaxanthin plus antheraxanthin)/(total violaxanthin cycle carotenoids) ratio and the non-photochemical quenching increased significantly in all Cd treatments. Cadmium treatments caused significant increases in the activity of the enzyme FCR in roots and in the concentrations of organic acids in xylem sap. Some of the physiological changes found support the fact that Cd induces a deficiency of Fe in cork oak, although the plant Fe concentrations were not reduced significantly. At higher concentrations the effects of Cd were more pronounced, and were more marked when Cd was in the free ion form than when present in the form of Cd-EDTA.
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Changes in iron and organic acid concentrations in xylem sap and apoplastic fluid of iron-deficient Beta vulgaris plants in response to iron resupply.
Larbi, A, Morales, F, Abadía, A, Abadía, J
Journal of plant physiology. 2010;(4):255-60
Abstract
In this study, the effects of Fe resupply on the composition of the xylem sap and apoplastic fluid of Fe-deficient sugar beet plants were investigated. Experiments were carried out in growth chambers with plants grown in hydroponics, and Fe resupply to Fe-deficient plants was carried out by adding 45muM Fe(III)-EDTA to the nutrient solution. In the short term (within 24h), Fe resupply caused marked changes in the xylem sap and apoplastic fluid composition and in leaf physiological parameters when de novo chlorophyll (Chl) synthesis was still beginning. Major changes included: (i) 10- and 5-fold increases in Fe concentrations in apoplastic fluid and xylem sap, respectively; (ii) marked decreases in the concentrations of organic acids in apoplastic fluid, but not in xylem sap and (iii) large decreases in the citrate/Fe ratios, both in apoplastic fluid and in xylem sap. Two to four days after Fe resupply, xylem sap and apoplastic fluid Fe and organic acid concentrations and pH reached values similar to those obtained in Fe-sufficient leaves. Leaf mesophyll ferric chelate-reductase (FC-R) activities and photosynthetic rates increased gradually during recovery from Fe deficiency.