Metabolic syndrome and Growth Differentiation Factor 15 in older adults - Adrián Carballo-Casla; Esther García-Esquinas; Antonio Buño-Soto; Ellen A. Struijk; Esther López-García; Fernando Rodríguez-Artalejo; Rosario Ortolá (GeroScience, 2022)

Growth hormone increases DNA damage in ovarian follicles and macrophage infiltration in the ovaries - Tatiana D. Saccon; Monique T. Rovani; Driele N. Garcia; Jorgea Pradiee; Rafael G. Mondadori; Luis Augusto X. Cruz; Carlos C. Barros; Yimin Fang; Samuel McFadden; Jeffrey B. Mason; Andrzej Bartke; Michal M. Masternak; et al. (GeroScience, 2022)

Pharmacologic treatment with OKN-007 reduces alpha-motor neuron loss in spinal cord of aging mice - Katarzyna M. Piekarz; Constantin Georgescu; Jonathan D. Wren; Rheal A. Towner; Holly Van Remmen (GeroScience, 2022)

Neuronavigated Magnetic Stimulation combined with cognitive training for Alzheimer’s patients: an EEG graph study - Fabrizio Vecchio; Davide Quaranta; Francesca Miraglia; Chiara Pappalettera; Riccardo Di Iorio; Federica L’Abbate; Maria Cotelli; Camillo Marra; Paolo Maria Rossini (GeroScience, 2022)

Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians - Ines Sanchez-Roman; Beatriz Ferrando; Camilla Myrup Holst; Jonas Mengel-From; Signe Høi Rasmussen; Mikael Thinggaard; Vilhelm A. Bohr; Kaare Christensen; Tinna Stevnsner (GeroScience, 2022)

Early manifestation of aging-related vascular dysfunction in human penile vasculature—A potential explanation for the role of erectile dysfunction as a harbinger of systemic vascular disease - Mariam El Assar; Javier Angulo; Esther García-Rojo; Alejandro Sevilleja-Ortiz; Borja García-Gómez; Argentina Fernández; Alberto Sánchez-Ferrer; José M. La Fuente; Javier Romero-Otero; Leocadio Rodríguez-Mañas (GeroScience, 2022)

Editorial: Comparison of antibody and T cell responses elicited by BBIBP-CorV (Sinopharm) and BNT162b2 (Pfizer-BioNTech) vaccines against SARS-CoV-2 in healthy adult humans - Veronica Galvan; Jorge Quarleri (GeroScience, 2022)

Omicron variant of the SARS-CoV-2: a quest to define the consequences of its high mutational load - Jorge Quarleri; Veronica Galvan; M. Victoria Delpino (GeroScience, 2022)

The effect of systemic factors on retinal blood flow in patients with carotid stenosis: an optical coherence tomography angiography study - Lilla István; Cecilia Czakó; Fruzsina Benyó; Ágnes Élő; Zsuzsa Mihály; Péter Sótonyi; Andrea Varga; Zoltán Zsolt Nagy; Illés Kovács (GeroScience, 2022)
Carotid artery stenosis (CAS) is among the leading causes of mortality and permanent disabilities in the Western world. CAS is a consequence of systemic atherosclerotic disease affecting the majority of the aging population. Optical coherence tomography angiography (OCTA) is a novel imaging technique for visualizing retinal blood flow. It is a noninvasive, fast method for qualitative and quantitative assessment of the microcirculation. Cerebral and retinal circulation share similar anatomy, physiology, and embryology; thus, retinal microvasculature provides a unique opportunity to study the pathogenesis of cerebral small vessel disease in vivo. In this study, we aimed to analyze the effect of systemic risk factors on retinal blood flow in the eyes of patients with significant carotid artery stenosis using OCT angiography. A total of 112 eyes of 56 patients with significant carotid stenosis were included in the study. We found that several systemic factors, such as decreased estimated glomerular filtration rate (eGFR), hypertension, and carotid occlusion have a significant negative effect on retinal blood flow, while statin use and carotid surgery substantially improve ocular microcirculation. Neither diabetes, clopidogrel or acetylsalicylic acid use, BMI, serum lipid level, nor thrombocyte count showed a significant effect on ocular blood flow. Our results demonstrate that a systematic connection does exist between certain systemic risk factors and retinal blood flow in this patient population. OCTA could help in the assessment of cerebral circulation of patients with CAS due to its ability to detect subtle changes in retinal microcirculation that is considered to represent changes in intracranial blood flow.

miR-146a-5p modulates cellular senescence and apoptosis in visceral adipose tissue of long-lived Ames dwarf mice and in cultured pre-adipocytes - Allancer D. C. Nunes; Moritz Weigl; Augusto Schneider; Sarah Noureddine; Lin Yu; Collin Lahde; Tatiana Dandolini Saccon; Kunal Mitra; Esther Beltran; Johannes Grillari; James L. Kirkland; Tamara Tchkonia; et al. (GeroScience, 2022)

Physical activity reduces the risk of pneumonia: systematic review and meta-analysis of 10 prospective studies involving 1,044,492 participants - Setor K. Kunutsor; Samuel Seidu; Jari A. Laukkanen (GeroScience, 2022)
The beneficial effects of regular physical activity in promoting health and preventing chronic diseases are well documented. The relationship between regular physical activity and the risk of pneumonia is uncertain. We aimed to evaluate the magnitude and specificity of the prospective association between regular physical activity and the risk of pneumonia using a systematic review and meta-analysis of published observational cohort studies in general populations. Relevant studies with at least 1 year of follow-up were sought from inception until 15 September 2021 in MEDLINE, Embase, Web of Science, and manual search of relevant articles. Relative risks (RRs) with 95% confidence intervals (CIs) for the maximum versus the minimal amount of physical activity groups were pooled using fixed effects meta-analysis. The quality of the evidence was evaluated using the GRADE tool. A total of 10 prospective cohort studies comprising 1,044,492 participants and 7681 events were eligible. The pooled multivariable-adjusted RR (95% CI) of pneumonia comparing the most versus the least physically active groups was 0.69 (0.64–0.74). This association was significantly modified by type of outcome ( p- value for meta-regression = .002): 0.82 (0.72–0.93) for incident pneumonia and 0.64 (0.59–0.70) for pneumonia-related mortality. There was no evidence of heterogeneity and publication bias. The GRADE quality of the evidence ranged from moderate to low. Aggregate analysis of 10 cohort studies shows that regular physical activity is associated with lowered risk of incident pneumonia and pneumonia-related mortality in the general population. Physical activity types that are attractive to and feasible for high-risk populations need to be identified and encouraged. Systematic review registration: PROSPERO 2021: CRD42021277514.

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects - Marco Raffaele; Kristina Kovacovicova; Tommaso Biagini; Oriana Lo Re; Jan Frohlich; Sebastiano Giallongo; James D. Nhan; Antonino Giulio Giannone; Daniela Cabibi; Martin Ivanov; Anton B. Tonchev; Martin Mistrik; et al. (GeroScience, 2022)

Extracerebral microvascular dysfunction is related to brain MRI markers of cerebral small vessel disease: The Maastricht Study - Maud van Dinther; Miranda T. Schram; Jacobus F. A. Jansen; Walter H. Backes; Alfons J. H. M. Houben; Tos T. J. M. Berendschot; Casper G. Schalkwijk; Coen D. A. Stehouwer; Robert J. van Oostenbrugge; Julie Staals (GeroScience, 2022)
Background Cerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers. Methods Cross-sectional data of the population-based Maastricht Study was used ( n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI. Results The eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010–0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803–1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896–1.242], p value 0.52). Conclusion A compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.

Diabetes mellitus correlates with increased biological age as indicated by clinical biomarkers - Nadine Bahour; Briana Cortez; Hui Pan; Hetal Shah; Alessandro Doria; Cristina Aguayo-Mazzucato (GeroScience, 2022)
Chronological age (CA) is determined by time of birth, whereas biological age (BA) is based on changes on a cellular level and strongly correlates with morbidity, mortality, and longevity. Type 2 diabetes (T2D) associates with increased morbidity and mortality; thus, we hypothesized that BA would be increased and calculated it from biomarkers collected at routine clinical visits. Deidentified data was obtained from three cohorts of patients (20–80 years old)—T2D, type 1 diabetes (T1D), and prediabetes—and compared to gender- and age-matched non-diabetics. Eight clinical biomarkers that correlated with CA in people without diabetes were used to calculate BA using the Klemera and Doubal method 1 (KDM1) and multiple linear regression (MLR). The phenotypic age (PhAge) formula was used with its predetermined biomarkers. BA of people with T2D was, on average, 12.02 years higher than people without diabetes ( p < 0.0001), while BA in T1D was 16.32 years higher ( p < 0.0001). Results were corroborated using MLR and PhAge. The biomarkers with the strongest correlation to increased BA in T2D using KDM were A1c ( R 2 = 0.23, p < 0.0001) and systolic blood pressure ( R 2 = 0.21, p < 0.0001). BMI had a positive correlation to BA in non-diabetes subjects but disappeared in those with diabetes. Mortality data using the ACCORD trial was used to validate our results and showed a significant correlation between higher BA and decreased survival. In conclusion, BA is increased in people with diabetes, irrespective of pathophysiology, and to a lesser extent in prediabetes.

Cardiovascular risk prediction in healthy older people - Johannes T. Neumann; Le T. P. Thao; Emily Callander; Enayet Chowdhury; Jeff D. Williamson; Mark R. Nelson; Geoffrey Donnan; Robyn L. Woods; Christopher M. Reid; Katrina K. Poppe; Rod Jackson; Andrew M. Tonkin; et al. (GeroScience, 2022)
Identification of individuals with increased risk of major adverse cardiovascular events (MACE) is important. However, algorithms specific to the elderly are lacking. Data were analysed from a randomised trial involving 18,548 participants ≥ 70 years old (mean age 75.4 years), without prior cardiovascular disease events, dementia or physical disability. MACE included coronary heart disease death, fatal or nonfatal ischaemic stroke or myocardial infarction. Potential predictors tested were based on prior evidence and using a machine-learning approach. Cox regression analyses were used to calculate 5-year predicted risk, and discrimination evaluated from receiver operating characteristic curves. Calibration was also assessed, and the findings internally validated using bootstrapping. External validation was performed in 25,138 healthy, elderly individuals in the primary care environment. During median follow-up of 4.7 years, 594 MACE occurred. Predictors in the final model included age, sex, smoking, systolic blood pressure, high-density lipoprotein cholesterol (HDL-c), non-HDL-c, serum creatinine, diabetes and intake of antihypertensive agents. With variable selection based on machine-learning, age, sex and creatinine were the most important predictors. The final model resulted in an area under the curve (AUC) of 68.1 (95% confidence intervals 65.9; 70.4). The model had an AUC of 67.5 in internal and 64.2 in external validation. The model rank-ordered risk well but underestimated absolute risk in the external validation cohort. A model predicting incident MACE in healthy, elderly individuals includes well-recognised, potentially reversible risk factors and notably, renal function. Calibration would be necessary when used in other populations.

Mesenchymal stromal cell-derived small extracellular vesicles promote neurological recovery and brain remodeling after distal middle cerebral artery occlusion in aged rats - Danut-Adrian Dumbrava; Roxana Surugiu; Verena Börger; Mihai Ruscu; Tobias Tertel; Bernd Giebel; Dirk M. Hermann; Aurel Popa-Wagner (GeroScience, 2022)
Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) promote neurological recovery after middle cerebral artery occlusion (MCAO) in young rodents. Ischemic stroke mainly affects aged humans. MSC-sEV effects on stroke recovery in aged rodents had not been assessed. In a head-to-head comparison, we exposed young (4–5 months) and aged (19–20 months) male Sprague–Dawley rats to permanent distal MCAO. At 24 h, 3 and 7 days post-stroke, vehicle or MSC-sEVs (2 × 10 6 or 2 × 10 7 MSC equivalents/kg) were intravenously administered. Neurological deficits, ischemic injury, brain inflammatory responses, post-ischemic angiogenesis, and endogenous neurogenesis were evaluated over 28 days. Post-MCAO, aged vehicle-treated rats exhibited more severe motor-coordination deficits evaluated by rotating pole and cylinder tests and larger brain infarcts than young vehicle-treated rats. Although infarct volume was not influenced by MSC-sEVs, sEVs at both doses effectively reduced motor-coordination deficits in young and aged rats. Brain macrophage infiltrates in periinfarct tissue, which were evaluated as marker of a recovery-aversive inflammatory environment, were significantly stronger in aged than young vehicle-treated rats. sEVs reduced brain macrophage infiltrates in aged, but not young rats. The tolerogenic shift in immune balance paved the way for structural brain tissue remodeling. Hence, sEVs at both doses increased periinfarct angiogenesis evaluated by CD31/BrdU immunohistochemistry in young and aged rats, and low-dose sEVs increased neurogenesis in the subventricular zone examined by DCX/BrdU immunohistochemistry. Our study provides robust evidence that MSC-sEVs promote functional neurological recovery and brain tissue remodeling in aged rats post-stroke. This study encourages further proof-of-concept studies in clinic-relevant stroke settings.

Seasonality of cognitive function in the general population: the Rotterdam Study - Sanne S. Mooldijk; Silvan Licher; Meike W. Vernooij; M. Kamran Ikram; M. Arfan Ikram (GeroScience, 2022)
Seasonal variation in cognitive function and underlying cerebral hemodynamics in humans has been suggested, but not consistently shown in previous studies. We assessed cognitive function in 10,276 participants from the population-based Rotterdam Study, aged 45 years and older without dementia, at baseline and at subsequent visits between 1999 and 2016. Seasonality of five cognitive test scores and of a summary measure of global cognition were determined, as well as of brain perfusion. Using linkage with medical records, we also examined whether a seasonal variation was present in clinical diagnoses of dementia. We found a seasonal variation of global cognition (0.05 standard deviations [95% confidence interval: 0.02–0.08]), the Stroop reading task, the Purdue Pegboard test, and of the delayed world learning test, with the best performance in summer months. In line with these findings, there were fewer dementia diagnoses of dementia in spring and summer than in winter and fall. We found no seasonal variation in brain perfusion. These findings support seasonality of cognition, albeit not explained by brain perfusion.

Pleiotropic predisposition to Alzheimer’s disease and educational attainment: insights from the summary statistics analysis - Alexander M. Kulminski; Elena Loiko; Yury Loika; Irina Culminskaya (GeroScience, 2022)

Aging-induced impaired endothelial wall shear stress mechanosensing causes arterial remodeling via JAM-A/F11R shedding by ADAM17 - Yanna Tian; Katie Anne Fopiano; Vadym Buncha; Liwei Lang; R. Daniel Rudic; Jessica A. Filosa; Huijuan Dou; Zsolt Bagi (GeroScience, 2022)

Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49th Annual Meeting of the American Aging Association - Michaela E. Murphy; Akilavalli Narasimhan; Alexis Adrian; Ankur Kumar; Cara L. Green; Carolina Soto-Palma; Chathurika Henpita; Christina Camell; Christopher S. Morrow; Chung-Yang Yeh; Claire E. Richardson; Cristal M. Hill; et al. (GeroScience, 2022)

Effects of aging on protein expression in mice brain microvessels: ROS scavengers, mRNA/protein stability, glycolytic enzymes, mitochondrial complexes, and basement membrane components - Partha K. Chandra; Sinisa Cikic; Ibolya Rutkai; Jessie J. Guidry; Prasad V. G. Katakam; Ricardo Mostany; David W. Busija (GeroScience, 2022)
Differentially expressed (DE) proteins in the cortical microvessels (MVs) of young, middle-aged, and old male and female mice were evaluated using discovery-based proteomics analysis (> 4,200 quantified proteins/group). Most DE proteins (> 90%) showed no significant differences between the sexes; however, some significant DE proteins showing sexual differences in MVs decreased from young (8.3%), to middle-aged (3.7%), to old (0.5%) mice. Therefore, we combined male and female data for age-dependent comparisons but noted sex differences for examination. Key proteins involved in the oxidative stress response, mRNA or protein stability, basement membrane (BM) composition, aerobic glycolysis, and mitochondrial function were significantly altered with aging. Relative abundance of superoxide dismutase-1/-2, catalase and thioredoxin were reduced with aging. Proteins participating in either mRNA degradation or pre-mRNA splicing were significantly increased in old mice MVs, whereas protein stabilizing proteins decreased. Glycolytic proteins were not affected in middle age, but the relative abundance of these proteins decreased in MVs of old mice. Although most of the 41 examined proteins composing mitochondrial complexes I–V were reduced in old mice, six of these proteins showed a significant reduction in middle-aged mice, but the relative abundance increased in fourteen proteins. Nidogen, collagen, and laminin family members as well as perlecan showed differing patterns during aging, indicating BM reorganization starting in middle age. We suggest that increased oxidative stress during aging leads to adverse protein profile changes of brain cortical MVs that affect mRNA/protein stability, BM integrity, and ATP synthesis capacity.

Older age, male sex, and cerebral microbleeds predict white matter loss after traumatic brain injury - David J. Robles; Ammar Dharani; Kenneth A. Rostowsky; Nikhil N. Chaudhari; Van Ngo; Fan Zhang; Lauren J. O’Donnell; Lauren Green; Nasim Sheikh-Bahaei; Helena C. Chui; Andrei Irimia (GeroScience, 2022)

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy - Steve Horvath; Amin Haghani; Joseph A. Zoller; Asieh Naderi; Elham Soltanmohammadi; Elena Farmaki; Vimala Kaza; Ioulia Chatzistamou; Hippokratis Kiaris (GeroScience, 2022)
DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice ( Peromyscus ) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus , spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human- Peromyscus clocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude in Peromyscus . The human- Peromyscus epigenetic clocks are expected to provide a significant boost to the attractiveness of Peromyscus as a biological model.

Divergent regulation of lncRNA expression by ischemia in adult and aging mice - Tamás Kaucsár; Beáta Róka; Pál Tod; Phuong Thanh Do; Zoltán Hegedűs; Gábor Szénási; Péter Hamar (GeroScience, 2022)
Elderly patients have increased susceptibility to acute kidney injury (AKI). Long noncoding RNAs (lncRNA) are key regulators of cellular processes, and have been implicated in both aging and AKI. Our aim was to study the effects of aging and ischemia–reperfusion injury (IRI) on the renal expression of lncRNAs. Adult and old (10- and 26–30-month-old) C57BL/6 N mice were subjected to unilateral IRI followed by 7 days of reperfusion. Renal expression of 90 lncRNAs and mRNA expression of injury, regeneration, and fibrosis markers was measured by qPCR in the injured and contralateral control kidneys. Tubular injury, regeneration, and fibrosis were assessed by histology. Urinary lipocalin-2 excretion was increased in old mice prior to IRI, but plasma urea was similar. In the control kidneys of old mice tubular cell necrosis and apoptosis, mRNA expression of kidney injury molecule-1, fibronectin-1, p16, and p21 was elevated. IRI increased plasma urea concentration only in old mice, but injury, regeneration, and fibrosis scores and their mRNA markers were similar in both age groups. AK082072 and Y lncRNAs were upregulated, while H19 and RepA transcript were downregulated in the control kidneys of old mice. IRI upregulated Miat, Igf2as, SNHG5, SNHG6, RNCR3, Malat1, Air, Linc1633, and Neat1 v1, while downregulated Linc1242. LncRNAs H19, AK082072, RepA transcript, and Six3os were influenced by both aging and IRI. Our results indicate that both aging and IRI alter renal lncRNA expression suggesting that lncRNAs have a versatile and complex role in aging and kidney injury. An Ingenuity Pathway Analysis highlighted that the most downregulated H19 may be linked to aging/senescence through p53.

Early onset of aging phenotype in vascular repair by Mas receptor deficiency - Goutham Vasam; Shrinidh Joshi S; Su Yamin Miyat; Hashim Adam; Yagna P. Jarajapu (GeroScience, 2022)

Cholinesterase inhibitors for the treatment of dementia: real-life data in Hungary - Nóra Balázs; Dániel Bereczki; András Ajtay; Ferenc Oberfrank; Tibor Kovács (GeroScience, 2022)
Dementia is one of the leading causes of death and disability in older population. Previous reports have shown that antidementia medications are associated with longer survival; nonetheless, the prevalence of their use and the compliance with them are quite different worldwide. There is hardly any available information about the pharmacoepidemiology of these drugs in the Eastern-European region; we aimed to analyze the use of cholinesterase inhibitors (ChEis) for the treatment of dementia to provide real-life information from the Eastern European region. All medical and medication prescription reports of the in- and outpatient specialist services collected in the NEUROHUN database in Hungary were analyzed between 2013 and 2016. Survival, adherence, and persistence values were calculated. 8803 patients were treated with ChEis during the study period, which was only 14.5% of the diagnosed demented patients. The survival of treated patients (more than 4 years) was significantly longer than patients without ChEi treatment (2.50 years). The best compliance was observed with rivastigmine patch. Choosing the appropriate medication as soon as possible after the dementia diagnosis may lead to increased life expectancy.

Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet - Rita Cervera-Juanes; Priscila Darakjian; Megan Ball; Steven G. Kohama; Henryk F. Urbanski (GeroScience, 2022)

Oolonghomobisflavans from Camellia sinensis increase Caenorhabditis elegans lifespan and healthspan - Chatrawee Duangjan; Sean P. Curran (GeroScience, 2022)
Tea polyphenols are widely considered as excellent antioxidant agents which can contribute to human health and longevity. However, the identification of the active biomolecules in complex tea extracts that promote health and longevity are not fully known. Here we used the nematode Caenorhabditis elegans to analyze the health benefits and longevity effects of Camellia sinensis oolong tea extracts (QFT, NFT, and CFT) and oolonghomobisflavan A and oolonghomobisflavan B, which are present in oolong tea extracts. Our results showed that oolong tea extracts and oolonghomobisflavans prolong lifespan and improved healthspan by curtailing the age-related decline in muscle activity and the accumulation of age pigment (lipofuscin). We found that the lifespan and healthspan promoting effects of oolong tea extracts and oolonghomobisflavans were positively correlated with the stress resistance via DAF-16/FOXO transcription factor. Furthermore, oolong tea extracts and oolonghomobisflavans displayed protective effects against Aβ- and polyQ-induced neuro/proteotoxicity. Overall, our study provides new evidence to support the health benefits of oolong tea and importantly identify oolonghomobisflavans as potent bioactive molecules that promote health when supplemented with a normal diet. As such, oolonghomobisflavans represent a valuable new class of compounds that promote healthy aging.

Cell therapy rescues aging-induced beta-1 adrenergic receptor and GRK2 dysfunction in the coronary microcirculation - Gabrielle Rowe; Evan Tracy; Jason E. Beare; Amanda J. LeBlanc (GeroScience, 2022)

Expanding the horizon of research into the pathogenesis of the white matter diseases: Proceedings of the 2021 Annual Workshop of the Albert Research Institute for White Matter and Cognition - Shawn N. Whitehead; Askiel Bruno; Jeffrey M. Burns; S. Thomas Carmichael; Anna Csiszar; Jodi D. Edwards; Fanny M. Elahi; Giuseppe Faraco; Douglas B. Gould; Deborah R. Gustafson; Vladimir Hachinski; Gary Rosenberg; et al. (GeroScience, 2022)

Apolipoprotein E ɛ4–related effects on cognition are limited to the Alzheimer’s disease spectrum - Alberto Fernández; Lucía Vaquero; Ricardo Bajo; Pilar Zuluaga; Michael W. Weiner; Andrew J. Saykin; John Q. Trojanowski; Leslie Shaw; Arthur W. Toga; Laurel Beckett; Clifford R. Jack; Paul Aisen; et al. (GeroScience, 2022)
Whether the deleterious effects of APOE4 are restricted to the Alzheimer’s disease (AD) spectrum or cause cognitive impairment irrespectively of the development of AD is still a matter of debate, and the focus of this study. Our analyses included APOE4 genotype, neuropsychological variables, amyloid-βeta (Aβ) and Tau markers, FDG-PET values, and hippocampal volumetry data derived from the healthy controls sample of the ADNI database. We formed 4 groups of equal size ( n = 30) based on APOE4 carriage and amyloid-PET status. Baseline and follow-up (i.e., 48 months post-baseline) results indicated that Aβ-positivity was the most important factor to explain poorer cognitive performance, while APOE4 only exerted a significant effect in Aβ-positive subjects. Additionally, multiple regression analyses evidenced that, within the Aβ-positive sample, hippocampal volumetry explained most of the variability in cognitive performance for APOE4 carriers. These findings represent a strong support for the so-called preclinical/prodromal hypothesis , which states that the reported differences in cognitive performance between healthy carriers and non-carriers are mainly due to the APOE4’s capability to increase the risk of AD. Moreover, our results reinforce the notion that a synergistic interaction of Aβ and APOE4 elicits a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance.

Hippocampus is more susceptible to hypoxic injury: has the Rosetta Stone of regional variation in neurovascular coupling been deciphered? - Huawei Zhang; Richard J. Roman; Fan Fan (GeroScience, 2022)

Higher-order resting state network association with the useful field of view task in older adults - Cheshire Hardcastle; Hanna K. Hausman; Jessica N. Kraft; Alejandro Albizu; Nicole D. Evangelista; Emanuel M. Boutzoukas; Andrew O’Shea; Kailey Langer; Emily Van Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; et al. (GeroScience, 2022)

Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice - Anjanet Loon; Frank Zamudio; Awa Sanneh; Breanna Brown; Shayna Smeltzer; Milene L. Brownlow; Zainuddin Quadri; Melinda Peters; Edwin Weeber; Kevin Nash; Daniel C. Lee; Marcia N. Gordon; et al. (GeroScience, 2022)

Editorial Focus: White matter-associated microglia (WAMs) represent an important link between aging, white matter disease and microglial activity - A. D. Roseborough; V. M. Jaremek; S. N. Whitehead (GeroScience, 2022)

Effect of environmental enrichment and isolation on behavioral and histological indices following focal ischemia in old rats - Andrei Gresita; Ruscu Mihai; Dirk M. Hermann; Flavia Semida Amandei; Bogdan Capitanescu; Aurel Popa-Wagner (GeroScience, 2022)
Stroke is a disease of aging. In stroke patients, the enriched group that received stimulating physical, eating, socializing, and group activities resulted in higher activity levels including spending more time on upper limb, communal socializing, listening and iPad activities. While environmental enrichment has been shown to improve the behavioral outcome of stroke in young animals, the effect of an enriched environment on behavioral recuperation and histological markers of cellular proliferation, neuroinflammation, and neurogenesis in old subjects is not known. We used behavioral testing and immunohistochemistry to assess the effect of environment on post-stroke recovery of young and aged rats kept either in isolation or stimulating social, motor, and sensory environment (( +)Env). We provide evidence that post-stroke animals environmental enrichment ( +)Env had a significant positive effect on recovery on the rotating pole, the inclined plane, and the labyrinth test. Old age exerted a small but significant effect on lesion size, which was independent of the environment. Further, a smaller infarct volume positively correlated with better recovery of spatial learning based on positive reinforcement, working and reference memory of young, and to a lesser extent, old animals kept in ( +)Env. Histologically, isolation/impoverishment was associated with an increased number of proliferating inflammatory cells expressing ED1 cells in the peri-infarcted area of old but not young rats. Further, ( +)Env and young age were associated with an increased number of neuroepithelial cells expressing nestin/BrdU as well as beta III tubulin cells in the damaged brain area which correlated with an increased performance on the inclined plane and rotating pole. Finally, ( +)Env and an increased number of neurons expressing doublecortin/BrdU cells exerted a significant effect on performance for working memory and performance on the rotating pole in both age groups. A stimulating social, motor and sensory environment had a limited beneficial effect on behavioral recovery (working memory and rotating pole) after stroke in old rats by reducing neuroinflammation and increasing the number of neuronal precursors expressing doublecortin. Old age however, exerted a small but significant effect on lesion size, which was independent of the environment.

The understudied links of the retromer complex to age-related pathways - Kenneth A. Wilson (GeroScience, 2022)
Neuronal aging is associated with numerous diseases resulting in memory impairment and functional decline. A common hallmark of these disorders is the accumulation of intracellular and extracellular protein aggregates. The retromer complex plays a central role in sorting proteins by marking them for reuse rather than degradation. Retromer dysfunction has been shown to induce protein aggregates and neurodegeneration, suggesting that it may be important for age-related neuronal decline and disease progression. Despite this, little is known about how aging influences retromer stability and the proteins with which it interacts. Detailed insights into age-dependent changes in retromer structure and function could provide valuable information towards treating and preventing many age-related neurodegenerative disorders. Here, we visit age-related pathways which interact with retromer function that ought to be further explored to determine its role in age-related neurodegeneration.

Slowing down as we age: aging of the cardiac pacemaker’s neural control - Sabrina Choi; Matthias Baudot; Oscar Vivas; Claudia M. Moreno (GeroScience, 2022)
The cardiac pacemaker ignites and coordinates the contraction of the whole heart, uninterruptedly, throughout our entire life. Pacemaker rate is constantly tuned by the autonomous nervous system to maintain body homeostasis. Sympathetic and parasympathetic terminals act over the pacemaker cells as the accelerator and the brake pedals, increasing or reducing the firing rate of pacemaker cells to match physiological demands. Despite the remarkable reliability of this tissue, the pacemaker is not exempt from the detrimental effects of aging. Mammals experience a natural and continuous decrease in the pacemaker rate throughout the entire lifespan. Why the pacemaker rhythm slows with age is poorly understood. Neural control of the pacemaker is remodeled from birth to adulthood, with strong evidence of age-related dysfunction that leads to a downshift of the pacemaker. Such evidence includes remodeling of pacemaker tissue architecture, alterations in the innervation, changes in the sympathetic acceleration and the parasympathetic deceleration, and alterations in the responsiveness of pacemaker cells to adrenergic and cholinergic modulation. In this review, we revisit the main evidence on the neural control of the pacemaker at the tissue and cellular level and the effects of aging on shaping this neural control.

The aging venous system: from varicosities to vascular cognitive impairment - Andrea Ágnes Molnár; György László Nádasy; Gabriella Dörnyei; Bernadett Bettina Patai; Jordan Delfavero; Gábor Áron Fülöp; Angelia C. Kirkpatrick; Zoltán Ungvári; Béla Merkely (GeroScience, 2021)
Aging-induced pathological alterations of the circulatory system play a critical role in morbidity and mortality of older adults. While the importance of cellular and molecular mechanisms of arterial aging for increased cardiovascular risk in older adults is increasingly appreciated, aging processes of veins are much less studied and understood than those of arteries. In this review, age-related cellular and morphological alterations in the venous system are presented. Similarities and dissimilarities between arterial and venous aging are highlighted, and shared molecular mechanisms of arterial and venous aging are considered. The pathogenesis of venous diseases affecting older adults, including varicose veins, chronic venous insufficiency, and deep vein thrombosis, is discussed, and the potential contribution of venous pathologies to the onset of vascular cognitive impairment and neurodegenerative diseases is emphasized. It is our hope that a greater appreciation of the cellular and molecular processes of vascular aging will stimulate further investigation into strategies aimed at preventing or retarding age-related venous pathologies.

A toolkit for quantification of biological age from blood chemistry and organ function test data: BioAge - Dayoon Kwon; Daniel W. Belsky (GeroScience, 2021)

Intrinsic motoneuron excitability is reduced in soleus and tibialis anterior of older adults - Lucas B. R. Orssatto; David N. Borg; Anthony J. Blazevich; Raphael L. Sakugawa; Anthony J. Shield; Gabriel S. Trajano (GeroScience, 2021)

Leukocyte-derived ratios are associated with late-life any type dementia: a cross-sectional analysis of the Mugello study - Gemma Lombardi; Roberto Paganelli; Michele Abate; Alex Ireland; Raffaele Molino-Lova; Sandro Sorbi; Claudio Macchi; Raffaello Pellegrino; Angelo Di Iorio; Francesca Cecchi (GeroScience, 2021)
Immunosenescence, vascular aging, and brain aging, all characterized by elevated levels of inflammatory markers, are thought to share a common pathogenetic pathway: inflamm-aging. Retrospective cross-sectional analysis was conducted using data from the Mugello study (Tuscany, Italy), a representative Italian cohort of free-living nonagenarians. to assess the association between specific peripheral inflammation markers derived from white blood cell counts, and the diagnosis of dementia. All the variables of interest were reported for 411 subjects (110 males and 301 females) out of 475 enrolled in the study. Anamnestic dementia diagnosis was obtained from clinical certificate and confirmed by a General Practitioner, whereas leukocyte ratios were directly calculated from white blood cell counts. Body mass index and comorbidities were considered potential confounders. Diagnosis of any type dementia was certified in 73 cases (17.8%). Subjects affected by dementia were older, more frequently reported a previous stroke, had lower body mass index, and lower Mini-Mental-State-Examination score. Moreover, they had a higher lymphocyte count and lymphocyte-to-monocyte ratio compared to the non-demented nonagenarians. We found that higher levels of lymphocyte counts are cross-sectionally associated with a clinical diagnosis of dementia. Furthermore, lymphocyte-to-monocyte ratio is directly associated with any type of dementia, independently of age, sex, lymphocyte count, and comorbidities. Lymphocyte-to-monocyte ratio may be considered a marker of immunological changes in the brain of dementia patients; moreover, it is low-cost, and easily available, thus enabling comparisons among different studies and populations, although the timeline and the extent of lymphocyte-to-monocyte ratio role in dementia development must be further investigated.

Correction to: Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline - Carlos J. Padilla; Markus E. Harrigan; Hallie Harris; Jan M. Schwab; Seward B. Rutkove; Mark M. Rich; Brian C. Clark; W. David Arnold (GeroScience, 2021)

Targeting senescent retinal pigment epithelial cells facilitates retinal regeneration in mouse models of age-related macular degeneration - Jae-Byoung Chae; Hyoik Jang; Chanok Son; Chul-Woo Park; Huyeon Choi; Seongeon Jin; Ho-Yeon Lee; Hyungwoo Lee; Ja-Hyoung Ryu; Namshin Kim; Chaekyu Kim; Hyewon Chung (GeroScience, 2021)

Six weeks of high-intensity interval training enhances contractile activity induced vascular reactivity and skeletal muscle perfusion in older adults - Philip J. J. Herrod; Philip J. Atherton; Kenneth Smith; John P. Williams; Jonathan N. Lund; Bethan E. Phillips (GeroScience, 2021)
Impairments in muscle microvascular function are associated with the pathogenesis of sarcopenia and cardiovascular disease. High-intensity interval training (HIIT) is an intervention by which a myriad of beneficial skeletal muscle/cardiovascular adaptations have been reported across age, including capillarisation and improved endothelial function. Herein, we hypothesised that HIIT would enhance muscle microvascular blood flow and vascular reactivity to acute contractile activity in older adults, reflecting HIIT-induced vascular remodelling. In a randomised controlled-trial, twenty-five healthy older adults aged 65–85 years (mean BMI 27.0) were randomised to 6-week HIIT or a no-intervention control period of an equal duration. Measures of microvascular responses to a single bout of muscle contractions (i.e. knee extensions) were made in the m. vastus lateralis using contrast-enhanced ultrasound during a continuous intravenous infusion of Sonovue™ contrast agent, before and after the intervention period, with concomitant assessments of cardiorespiratory fitness and resting blood pressure. HIIT led to improvements in anaerobic threshold (13.2 ± 3.4 vs. 15.3 ± 3.8 ml/kg/min, P < 0.001), dynamic exercise capacity (145 ± 60 vs. 159 ± 59 W, P < 0.001) and resting (systolic) blood pressure (142 ± 15 vs. 133 ± 11 mmHg, P < 0.01). Notably, HIIT elicited significant increases in microvascular blood flow responses to acute contractile activity (1.8 ± 0.63 vs. 2.3 ± 0.8 (arbitrary contrast units (AU), P < 0.01)), with no change in any of these parameters observed in the control group. Six weeks HIIT improves skeletal muscle microvascular responsiveness to acute contractile activity in the form of active hyperaemia-induced by a single bout of resistance exercise. These findings likely reflect reports of enhanced large vessel distensibility, improved endothelial function, and muscle capillarisation following HIIT. Moreover, our findings illustrate that HIIT may be effective in mitigating deleterious alterations in muscle microvascular mediated aspects of sarcopenia.

Resistance exercise intervention on muscular strength and power, and functional capacity in acute hospitalized older adults: a systematic review and meta-analysis of 2498 patients in 7 randomized clinical trials - Marcelo A. S. Carneiro; Cristiane M. C. Franco; Alan L. Silva; Pâmela Castro-e-Souza; Gabriel Kunevaliki; Mikel Izquierdo; Edilson S. Cyrino; Camila S. Padilha (GeroScience, 2021)

Reversal of deficits in aged skeletal muscle during disuse and recovery in response to treatment with a secrotome product derived from partially differentiated human pluripotent stem cells - Dennis K. Fix; Ziad S. Mahmassani; Jonathan J. Petrocelli; Naomi M.M.P. de Hart; Patrick J. Ferrara; Jessie S. Painter; Gabriel Nistor; Thomas E. Lane; Hans S. Keirstead; Micah J. Drummond (GeroScience, 2021)
Aged individuals are at risk to experience slow and incomplete muscle recovery following periods of disuse atrophy. While several therapies have been employed to mitigate muscle mass loss during disuse and improve recovery, few have proven effective at both. Therefore, the purpose of this study was to examine the effectiveness of a uniquely developed secretome product (STEM) on aged skeletal muscle mass and function during disuse and recovery. Aged (22 months) male C57BL/6 were divided into PBS or STEM treatment ( n = 30). Mice within each treatment were assigned to either ambulatory control (CON; 14 days of normal cage ambulation), 14 days of hindlimb unloading (HU), or 14 days of hindlimb unloading followed by 7 days of recovery (recovery). Mice were given an intramuscular delivery into the hindlimb muscle of either PBS or STEM every other day for the duration of their respective treatment group. We found that STEM-treated mice compared to PBS had greater soleus muscle mass, fiber cross-sectional area (CSA), and grip strength during CON and recovery experimental conditions and less muscle atrophy and weakness during HU. Muscle CD68 +, CD11b + and CD163 + macrophages were more abundant in STEM-treated CON mice compared to PBS, while only CD68 + and CD11b + macrophages were more abundant during HU and recovery conditions with STEM treatment. Moreover, STEM-treated mice had lower collagen IV and higher Pax7 + cell content compared to PBS across all experimental conditions. As a follow-up to examine the cell autonomous role of STEM on muscle, C2C12 myotubes were given STEM or horse serum media to examine myotube fusion/size and effects on muscle transcriptional networks. STEM-treated C2C12 myotubes were larger and had a higher fusion index and were related to elevated expression of transcripts associated with extracellular matrix remodeling. Our results demonstrate that STEM is a unique cocktail that possesses potent immunomodulatory and cytoskeletal remodeling properties that may have translational potential to improve skeletal muscle across a variety of conditions that adversely effect aging muscle.

Association between psychological resilience and cognitive function in older adults: effect modification by inflammatory status - Sun Jae Jung; Ga Bin Lee; Kristen Nishimi; Lori Chibnik; Karestan C. Koenen; Hyeon Chang Kim (GeroScience, 2021)
To examine the association between psychological resilience and cognitive function and investigate the role of acute inflammation as an effect modifier. Total 7535 people from the Cardiovascular and Metabolic Disease Etiology Research Center (CMERC), aged ≥ 50 years and residing in areas near Seoul, South Korea, were included in this cross-sectional analysis. Stressful life events in the past 6 months were gauged by the Life Experience Survey, and current depression symptoms were analyzed with the Beck Depression Inventory-II. Participants were categorized into the following four groups according to their past experience and depression status: reference, resilient, reactive depression, and vulnerable depression. Cognitive function was evaluated using the mini-mental state examination (MMSE). The level of high-sensitivity C-reactive protein (hsCRP) was measured from blood samples. A generalized linear model was used. Upon adjusting for socio-demographic factors, comorbidity, and lifestyle factors, the final model was stratified with the highest quartile of the hsCRP level by sex. Compared to the reference group, the resilient group showed higher MMSE, which was also significant in women (adj- β = 0.280, p -value < 0.001). Vulnerable depression group showed a significantly lower MMSE (adj- β = − -0.997, p -value 0.002), especially in men. This pattern seemed to be limited to the low hsCRP subgroup. We provided evidence from the largest Korean population used to evaluate the association between psychological resilience and cognition, which was more prominent in low inflammatory status. Psychological resilience was associated with a lower likelihood of cognitive deficit in women. This pattern was modulated by inflammatory status.

Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue - Haihui Zhuang; Sira Karvinen; Timo Törmäkangas; Xiaobo Zhang; Xiaowei Ojanen; Vidya Velagapudi; Markku Alen; Steven L. Britton; Lauren G. Koch; Heikki Kainulainen; Sulin Cheng; Petri Wiklund (GeroScience, 2021)
Aerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

Greater habitual moderate-to-vigorous physical activity is associated with better executive function and higher prefrontal oxygenation in older adults - Myles W. O’Brien; Derek S. Kimmerly; Said Mekari (GeroScience, 2021)

Aerobic fitness is inversely associated with neurohemodynamic transduction and blood pressure variability in older adults - Myles W. O’Brien; Diane J. Ramsay; Carley D. O’Neill; Jennifer L. Petterson; Shilpa Dogra; Said Mekary; Derek S. Kimmerly (GeroScience, 2021)

Combined in vivo muscle mass, muscle protein synthesis and muscle protein breakdown measurement: a ‘Combined Oral Stable Isotope Assessment of Muscle (COSIAM)’ approach - Jessica Cegielski; Daniel J. Wilkinson; Matthew S. Brook; Catherine Boereboom; Bethan E. Phillips; John F. R. Gladman; Kenneth Smith; Philip J. Atherton (GeroScience, 2021)
Optimising approaches for measuring skeletal muscle mass and turnover that are widely applicable, minimally invasive and cost effective is crucial in furthering research into sarcopenia and cachexia. Traditional approaches for measurement of muscle protein turnover require infusion of expensive, sterile, isotopically labelled tracers which limits the applicability of these approaches in certain populations (e.g. clinical, frail elderly). To concurrently quantify skeletal muscle mass and muscle protein turnover i.e. muscle protein synthesis (MPS) and muscle protein breakdown (MPB), in elderly human volunteers using stable-isotope labelled tracers i.e. Methyl-[D 3 ]-creatine (D 3 -Cr), deuterium oxide (D 2 O), and Methyl-[D 3 ]-3-methylhistidine (D 3 -3MH), to measure muscle mass, MPS and MPB, respectively. We recruited 10 older males (71 ± 4 y, BMI: 25 ± 4 kg . m 2 , mean ± SD) into a 4-day study, with DXA and consumption of D 2 O and D 3 -Cr tracers on day 1. D 3 -3MH was consumed on day 3, 24 h prior to returning to the lab. From urine, saliva and blood samples, and a single muscle biopsy (vastus lateralis), we determined muscle mass, MPS and MPB. D 3 -Cr derived muscle mass was positively correlated to appendicular fat-free mass (AFFM) estimated by DXA (r = 0.69, P = 0.027). Rates of cumulative myofibrillar MPS over 3 days were 0.072%/h (95% CI, 0.064 to 0.081%/h). Whole-body MPB over 6 h was 0.052 (95% CI, 0.038 to 0.067). These rates were similar to previous literature. We demonstrate the potential for D 3 -Cr to be used alongside D 2 O and D 3 -3MH for concurrent measurement of muscle mass, MPS, and MPB using a minimally invasive design, applicable for clinical and frail populations.

Changes in the SARS-CoV-2 cellular receptor ACE2 levels in cardiovascular patients: a potential biomarker for the stratification of COVID-19 patients - Miklós Fagyas; Viktor Bánhegyi; Katalin Úri; Attila Enyedi; Erzsébet Lizanecz; Ivetta Siket Mányiné; Lilla Mártha; Gábor Áron Fülöp; Tamás Radovits; Miklós Pólos; Béla Merkely; Árpád Kovács; et al. (GeroScience, 2021)
Angiotensin-converting enzyme 2 (ACE2) is essential for SARS-CoV-2 cellular entry. Here we studied the effects of common comorbidities in severe COVID-19 on ACE2 expression. ACE2 levels (by enzyme activity and ELISA measurements) were determined in human serum, heart and lung samples from patients with hypertension ( n = 540), heart transplantation (289) and thoracic surgery ( n = 49). Healthy individuals ( n = 46) represented the controls. Serum ACE2 activity was increased in hypertensive subjects (132%) and substantially elevated in end-stage heart failure patients (689%) and showed a strong negative correlation with the left ventricular ejection fraction. Serum ACE2 activity was higher in male (147%), overweight (122%), obese (126%) and elderly (115%) hypertensive patients. Primary lung cancer resulted in higher circulating ACE2 activity, without affecting ACE2 levels in the surrounding lung tissue. Male sex resulted in elevated serum ACE2 activities in patients with heart transplantation or thoracic surgery (146% and 150%, respectively). Left ventricular (tissular) ACE2 activity was unaffected by sex and was lower in overweight (67%), obese (62%) and older (73%) patients with end-stage heart failure. There was no correlation between serum and tissular (left ventricular or lung) ACE2 activities. Neither serum nor tissue (left ventricle or lung) ACE2 levels were affected by RAS inhibitory medications. Abandoning of ACEi treatment (non-compliance) resulted in elevated blood pressure without effects on circulating ACE2 activities. ACE2 levels associate with the severity of cardiovascular diseases, suggestive for a role of ACE2 in the pathomechanisms of cardiovascular diseases and providing a potential explanation for the higher mortality of COVID-19 among cardiovascular patients. Abandoning RAS inhibitory medication worsens the cardiovascular status without affecting circulating or tissue ACE2 levels.

Comparison of antibody and T cell responses elicited by BBIBP-CorV (Sinopharm) and BNT162b2 (Pfizer-BioNTech) vaccines against SARS-CoV-2 in healthy adult humans - István Vályi-Nagy; Zsolt Matula; Márton Gönczi; Szabolcs Tasnády; Gabriella Bekő; Marienn Réti; Éva Ajzner; Ferenc Uher (GeroScience, 2021)
In the present study, humoral and T cell-mediated immune responses elicited by BBIBP-CorV (inactivated virus) and BNT162b2 (mRNA-based) vaccines against SARS-CoV-2 virus were compared. Convalescent volunteers were also investigated to evaluate adaptive immunity induced by live virus. Although both vaccines induced antibody- and T cell-mediated immune responses, our analysis revealed significant quantitative and qualitative differences between the two types of challenges. The BBIBP-CorV vaccine elicited antireceptor-binding domain (RBD) IgG, as well as anti-spike protein (S) IgG and IgA antibodies in healthy individuals, the levels of which were much lower than after BNT162b2 vaccination but still higher than in the convalescent patients. The cumulative IFNγ-positive T cell response, however, was only twofold higher in participants injected with BNT162b2 compared to those who were primed and boosted with BBIBP-CorV vaccine. Moreover, the inactivated virus vaccine induced T cell response that targets not only the S but also the nucleocapsid (N) and membrane (M) proteins, whereas the mRNA vaccine was able to elicit a much narrower response that targets the S protein epitopes only. Thus, the pattern of BBIBP-CorV-induced T cell response in virus-naive participants was similar to the cell-mediated anti-SARS-CoV-2 response observed in convalescent patients. Based on these data, we can conclude that the BBIBP-CorV inactivated virus vaccine is immunologically effective. However, the duration of BBIBP-CorV-induced integrated, antibody, and T cell-mediated, immune responses needs further investigation.

Oklahoma Nathan Shock Aging Center — assessing the basic biology of aging from genetics to protein and function - Holly Van Remmen; Willard M. Freeman; Benjamin F. Miller; Michael Kinter; Jonathan D. Wren; Ann Chiao; Rheal A. Towner; Timothy A. Snider; William E. Sonntag; Arlan Richardson (GeroScience, 2021)

Generation and characterization of a tractable C. elegans model of tauopathy - Joshua C. Russell; Haoyi Lei; Rahul K. Chaliparambil; Sarah Fish; Susan M. Markiewicz; Ting-I. Lee; Anushka Noori; Matt Kaeberlein (GeroScience, 2021)

Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity - Kyle M. Schachtschneider; Lawrence B. Schook; Jennifer J. Meudt; Dhanansayan Shanmuganayagam; Joseph A. Zoller; Amin Haghani; Caesar Z. Li; Joshua Zhang; Andrew Yang; Ken Raj; Steve Horvath (GeroScience, 2021)
DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs ( Sus scrofa domesticus ) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig’s increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation - Nidheesh Thadathil; Evan H. Nicklas; Sabira Mohammed; Tommy L. Lewis; Arlan Richardson; Sathyaseelan S. Deepa (GeroScience, 2021)
Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which cause membrane binding and permeabilization, were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl −/− mice reduced markers of neuroinflammation (Iba-1 and GFAP) in the brains of old mice, and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.

A COVID-19-association-dependent categorization of death causes in 100 autopsy cases - Krisztina Danics; Adrián Pesti; Klára Törő; Noémi Kiss-Dala; János Szlávik; Botond Lakatos; Andrea Radnai; Tamás Balázs; Miklós Bacskai; Deján Dobi; Tibor Várkonyi; Tibor Glasz; et al. (GeroScience, 2021)
From March through December 2020, 100 autopsies were performed (Semmelweis University, Budapest, Hungary), with chart review, of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection demonstrated by real-time reverse-transcription polymerase chain reaction testing (mean age, 74.73 years, range 40–102 years; 50 males, mean age 71.96 years, and 50 females, mean age 77.5 years). Classified by the date of death, 21 cases were from the pandemic’s “first wave” (March through July) and 79 from the “second wave” (August through December). Three mortality categories were defined by relevance of SARS-CoV-2 infection: (1) “strong” association ( n =57), in which COVID-19 was primary responsible for death; (2) “contributive” association ( n =27), in which a pre-existing condition independent of COVID-19 was primary responsible for death, albeit with substantial COVID-19 co-morbidity; (3) “weak” association ( n =16), in which COVID-19 was minimally or not at all responsible for death. Distributions among categories differed between the first wave, in which the “contributive” association cases dominated (strong: 24%, contributive: 48% , weak: 28%), and the second wave, in which the “strong” association cases dominated (strong: 66% , contributive: 21%, weak: 13%). Charted co-morbidities included hypertension (85 %), cardiovascular diseases (71 %), diabetes (40 %), cerebrovascular diseases (31 %), chronic respiratory diseases (30 %), malignant tumors (20 %), renal diseases (19 %), diseases of the central nervous system (15 %), and liver diseases (6 %). Autopsy evaluation analyzed alterations on macroscopy as well as findings on microscopy of scanned and scored sections of formalin-fixed, paraffin-embedded tissue samples (50–80 blocks/case). Severity of histological abnormalities in the lung differed significantly between “strong” and “contributive” ( p <0.0001) and between “strong” and “weak” categories ( p <0.0001). Abnormalities included diffuse alveolar damage, macrophage infiltration, and vascular and alveolar fibrin aggregates (lung), with macro- and microvascular thrombi and thromboemboli (lung, kidney, liver). In conclusion, autopsies clarified in what extent COVID-19 was responsible for death, demonstrated the pathological background of clinical signs and symptoms, and identified organ alterations that led to the death. Clinicopathologic correlation, with conference discussions of severity of co-morbidities and of direct pathological signs of disease, permitted accurate categorization of cause of death and COVID-19 association as “strong,” “contributive,” or “weak.” Lung involvement, with reduced ventilatory capacity, was the primary cause of death in the “strong” and “contributive” categories. Shifts in distribution among categories, with “strong” association between COVID-19 and death dominating in the second wave, may reflect improved clinical management of COVID-19 as expertise grew.

Cognitive decrement in older adults with symptomatic peripheral artery disease - Andrew W. Gardner; Polly S. Montgomery; Ming Wang; Biyi Shen; Ana I. Casanegra; Federico Silva-Palacios; Zoltan Ungvari; Andriy Yabluchanskiy; Anna Csiszar; Shari R. Waldstein (GeroScience, 2021)

Epigenetic clock and methylation studies in the rhesus macaque - Steve Horvath; Joseph A. Zoller; Amin Haghani; Anna J. Jasinska; Ken Raj; Charles E. Breeze; Jason Ernst; Kelli L. Vaughan; Julie A. Mattison (GeroScience, 2021)
Methylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque ( Macaca mulatta ), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n = 281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regard to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation ( R = 0.89) with the vervet monkey ( Chlorocebus sabaeus ), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). Future studies will be needed to evaluate whether these epigenetic clocks predict age-related conditions in the rhesus macaque.

DNA methylation age analysis of rapamycin in common marmosets - Steve Horvath; Joseph A. Zoller; Amin Haghani; Ake T. Lu; Ken Raj; Anna J. Jasinska; Julie A. Mattison; Adam B. Salmon (GeroScience, 2021)
Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging (“epigenetic clocks”). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets ( Callithrix jacchus ) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here two epigenetic clocks for marmosets that are applicable to whole blood samples. We find that the human-marmoset clock for relative age exhibits moderately high age correlations in two other non-human primate species: vervet monkeys and rhesus macaques. In a separate cohort of marmosets, we tested whether intervention with rapamycin, a drug shown to extend lifespan in mice, would alter the epigenetic age of marmosets, as measured by the marmoset epigenetic clocks. These clocks did not detect significant effects of rapamycin on the epigenetic age of marmoset blood. The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). Overall, the epigenetic clocks developed here for the common marmoset are expected to be useful for age estimation of wild-born animals and for anti-aging studies in this species.

Elamipretide (SS-31) treatment attenuates age-associated post-translational modifications of heart proteins - Jeremy A. Whitson; Miguel Martín-Pérez; Tong Zhang; Matthew J. Gaffrey; Gennifer E. Merrihew; Eric Huang; Collin C. White; Terrance J. Kavanagh; Wei-Jun Qian; Matthew D. Campbell; Michael J. MacCoss; David J. Marcinek; et al. (GeroScience, 2021)

Favipiravir treatment does not influence disease progression among adult patients hospitalized with moderate-to-severe COVID-19: a prospective, sequential cohort study from Hungary - Balint Gergely Szabo; Katalin Szidonia Lenart; Borisz Petrik; Zsofia Gaspar; Noemi Kiss-Dala; Janos Szlavik; Istvan Valyi-Nagy; Botond Lakatos (GeroScience, 2021)
Data suggests that favipiravir (FVP) could be used against SARS-CoV-2. Our aim was to investigate the role of FVP in COVID-19 treatment. A prospective sequential cohort study was performed among adults hospitalized at our center between March and August 2020 with moderate-to-severe, PCR-confirmed COVID-19. For diagnosis and severity, ECDC and WHO definitions were utilized. Patients were screened for inclusion by a priori criteria and included in the FVP cohort if standard-of-care (SOC) + FVP or the non-FVP cohort if SOC ± other antivirals without FVP were administered for > 48 h from diagnosis. Treatment allocation was done per national guidelines, based on severity and drug availability. Primary endpoint was disease progression, a composite of 14-day all-cause death, need for mechanical ventilation, or immunomodulatory therapy. The impact of FVP exposure on disease progression was analyzed by binomial logistic regression. In all, 150 patients were included, 75 in each cohort. Disease progression (17/75, 22.7% vs. 10/75, 13.3%, p = 0.13), 14-day all-cause death (9/75, 12.0% vs. 10/75, 13.3%, p = 0.8), and need for mechanical ventilation (8/75, 10.7% vs. 4/75, 5.3%, p = 0.22) were similar, while immunomodulatory therapies were required more frequently among patients receiving FVP (10/75, 13.3% vs. 1/75, 1.3%, p < 0.01). The use of favipiravir was not retained as a protective factor against disease progression in multivatiate analysis. Time to antiviral therapy from PCR positivity, disease severity, need for oxygen supportation, and ICU admittance rates did not differ statistically between cohorts. In this study, favipiravir did not seem to positively affect disease progression.

Serological and viral genetic features of patients with COVID-19 in a selected German patient cohort—correlation with disease characteristics - Jonas Schmidt; Sandro Berghaus; Frithjof Blessing; Folker Wenzel; Holger Herbeck; Josef Blessing; Peter Schierack; Stefan Rödiger; Dirk Roggenbuck (GeroScience, 2021)
To study host-virus interactions after SARS coronavirus-2 (SARS-CoV-2) infection, genetic virus characteristics and the ensued humoral immune response were investigated for the first time. Fifty-five SARS-CoV-2-infected patients from the early pandemic phase were followed up including serological testing and whole genome sequencing. Anti-spike and nucleocapsid protein (S/N) IgG and IgM levels were determined by screening ELISA and IgG was further characterized by reactivity to S-subunit 1 (anti-S1), S-subunit 2 (anti-S2) and anti-N. In 55 patients, 90 genetic SARS-CoV-2 changes including 48 non-synonymous single nucleotide variants were identified. Phylogenetic analysis of the sequencing data showed a cluster representing a local outbreak and various family clusters. Anti-S/N and anti-N IgG were detected in 49 patients at an average of 83 days after blood collection. Anti-S/N IgM occurred significantly less frequently than IgG whereas anti-S2 was the least prevalent IgG reactivity ( P < 0.05, respectively). Age and overweight were significantly associated with higher anti-S/N and anti-S1 IgG levels while age only with anti-N IgG (multiple regression, P < 0.05, respectively). Anti-S/N IgG/IgM levels, blood group A + , cardiovascular and tumour disease, NSP12 Q444H and ORF3a S177I were independent predictors of clinical characteristics with anti-S/N IgM being associated with the need for hospitalization (multivariate regression, P < 0.05, respectively). Anti-SARS-CoV-2 antibody generation was mainly affected by higher age and overweight in the present cohort. COVID-19 traits were associated with genetic SARS-CoV-2 variants, anti-S/N IgG/IgM levels, blood group A + and concomitant disease. Anti-S/N IgM was the only antibody associated with the need for hospitalization.

Einstein-Nathan Shock Center: translating the hallmarks of aging to extend human health span - Ana Maria Cuervo; Derek M. Huffman; Jan Vijg; Sofiya Milman; Rajat Singh; Nir Barzilai (GeroScience, 2021)

Epigenetic clock and methylation studies in cats - Ken Raj; Balazs Szladovits; Amin Haghani; Joseph A. Zoller; Caesar Z. Li; Pete Black; Dewey Maddox; Todd R. Robeck; Steve Horvath (GeroScience, 2021)
Human DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging (“epigenetic clocks”). Although these human epigenetic clocks are not immediately applicable to all species of the animal kingdom, the principles underpinning them appear to be conserved even in animals that are evolutionarily far removed from humans. This is exemplified by recent development of epigenetic clocks for mice and other mammalian species. Here, we describe epigenetic clocks for the domestic cat ( Felis catus ), based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs are measured using a custom-designed Infinium array (HorvathMammalMethylChip40). From these, we present 3 epigenetic clocks for cats; of which, one applies only to blood samples from cats, while the remaining two dual-species human-cat clocks apply both to cats and humans. We demonstrate that these domestic cat clocks also lead to high age correlations in cheetahs, tigers, and lions. It is expected that these epigenetic clocks for cats possess the potential to be further developed for monitoring feline health as well as being used for identifying and validating anti-aging interventions.

Animal reservoirs of SARS-CoV-2: calculable COVID-19 risk for older adults from animal to human transmission - Teresa G. Valencak; Anna Csiszar; Gabor Szalai; Andrej Podlutsky; Stefano Tarantini; Vince Fazekas-Pongor; Magor Papp; Zoltan Ungvari (GeroScience, 2021)
The current COVID-19 pandemic, caused by the highly contagious respiratory pathogen SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has already claimed close to three million lives. SARS-CoV-2 is a zoonotic disease: it emerged from a bat reservoir and it can infect a number of agricultural and companion animal species. SARS-CoV-2 can cause respiratory and intestinal infections, and potentially systemic multi-organ disease, in both humans and animals. The risk for severe illness and death with COVID-19 significantly increases with age, with older adults at highest risk. To combat the pandemic and protect the most susceptible group of older adults, understanding the human-animal interface and its relevance to disease transmission is vitally important. Currently high infection numbers are being sustained via human-to-human transmission of SARS-CoV-2. Yet, identifying potential animal reservoirs and potential vectors of the disease will contribute to stronger risk assessment strategies. In this review, the current information about SARS-CoV-2 infection in animals and the potential spread of SARS-CoV-2 to humans through contact with domestic animals (including dogs, cats, ferrets, hamsters), agricultural animals (e.g., farmed minks), laboratory animals, wild animals (e.g., deer mice), and zoo animals (felines, non-human primates) are discussed with a special focus on reducing mortality in older adults.

Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice - Stefano Tarantini; Priya Balasubramanian; Jordan Delfavero; Tamas Csipo; Andriy Yabluchanskiy; Tamas Kiss; Ádám Nyúl-Tóth; Peter Mukli; Peter Toth; Chetan Ahire; Anna Ungvari; Zoltan Benyo; et al. (GeroScience, 2021)

Canine Cognitive Dysfunction (CCD) scores correlate with amyloid beta 42 levels in dog brain tissue - Silvan R. Urfer; Martin Darvas; Kálmán Czeibert; Sára Sándor; Daniel E. L. Promislow; Kate E. Creevy; Enikő Kubinyi; Matt Kaeberlein (GeroScience, 2021)

Effect of genetic depletion of MMP-9 on neurological manifestations of hypertension-induced intracerebral hemorrhages in aged mice - Stefano Tarantini; Andriy Yabluchanskiy; Merry L. Lindsey; Anna Csiszar; Zoltan Ungvari (GeroScience, 2021)

Impact of COVID-19 on ischemic stroke care in Hungary - Péter Pál Böjti; Géza Szilágyi; Balázs Dobi; Rita Stang; István Szikora; Balázs Kis; Ákos Kornfeld; Csaba Óváry; Lóránd Erőss; Péter Banczerowski; Wojciech Kuczyński; Dániel Bereczki (GeroScience, 2021)
Data about the coronavirus disease 2019 (COVID-19) pandemic’s collateral damage on ischemic stroke (IS) care during the second epidemic wave in Central Europe are limited. We sought to evaluate the impact of the COVID-19 outbreak on Hungarian IS care during the two epidemic waves. This retrospective observational study was based on a nationwide reimbursement database that encompasses all IS admissions and all reperfusion interventions, i.e., intravenous thrombolysis (IVT) and endovascular therapy (EVT) from 2 January 2017 to 31 December 2020 in Hungary. COVID-19 pandemic’s effect on the number of IS admissions and reperfusion interventions were analyzed using different statistics: means, medians, trends, relative rates, and linear relationships. The mean and median values of IS admissions and reperfusion interventions decreased only in some measure during the COVID-periods. However, trend analysis demonstrated a significant decline from the trends. The decline’s dynamic and amplitude have differed for each variable. In contrast to IVT, the number of IS admissions and EVTs negatively correlated with the epidemic waves’ amplitude. Besides, the decrease in the number of IS admissions was more pronounced than the decrease in the number of reperfusion interventions. Our study demonstrated a significant disruption in IS care during the COVID-19 epidemic in Hungary, in which multiple different factors might play a role. The disproportionate reduction of IS admission numbers could partially be explained by the effect of health emergency operative measures and changes in patients’ social behavior. Further studies are needed to evaluate the causes of our observations.

Correction to: Temporal emergence of age-associated changes in cognitive and physical function in vervets (Chlorocebus aethiops sabaeus) - Brett M. Frye; Payton M. Valure; Suzanne Craft; Mark G. Baxter; Christie Scott; Shanna Wise-Walden; David W. Bissinger; Hannah M. Register; Carson Copeland; Matthew J. Jorgensen; Jamie N. Justice; Stephen B. Kritchevsky; et al. (GeroScience, 2021)

Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype - Stefano Tarantini; Ádám Nyúl-Tóth; Andriy Yabluchanskiy; Tamas Csipo; Peter Mukli; Priya Balasubramanian; Anna Ungvari; Peter Toth; Zoltan Benyo; William E. Sonntag; Zoltan Ungvari; Anna Csiszar (GeroScience, 2021)

The Nathan Shock Centers - Steven N. Austad; Odette van der Willik; Stephanie Lederman; Candace Kerr (GeroScience, 2021)

The San Diego Nathan Shock Center: tackling the heterogeneity of aging - Gerald S. Shadel; Peter D. Adams; W. Travis Berggren; Jolene K. Diedrich; Kenneth E. Diffenderfer; Fred H. Gage; Nasun Hah; Malene Hansen; Martin W. Hetzer; Anthony J. A. Molina; Uri Manor; Kurt Marek; et al. (GeroScience, 2021)

Children’s education and level of health care utilization among parents: a pooled cross-sectional study from national population-based survey in India - Mayanka Ambade; William Joe; S. V. Subramanian (GeroScience, 2021)

University of Alabama at Birmingham Nathan Shock Center: comparative energetics of aging - Steven N. Austad; Thomas W. Buford; David B. Allison; Scott. W. Ballinger; Andrew W. Brown; Christy S. Carter; Victor M. Darley-Usmar; John L. Hartman; Timothy R. Nagy; Daniel L. Smith; Liou Sun; Jianhua Zhang (GeroScience, 2021)

Pterocarpus marsupium extract extends replicative lifespan in budding yeast - Mitchell B. Lee; Michael G. Kiflezghi; Mitsuhiro Tsuchiya; Brian Wasko; Daniel T. Carr; Priya A. Uppal; Katherine A. Grayden; Yordanos C. Elala; Tu Anh Nguyen; Jesse Wang; Priya Ragosti; Sunny Nguyen; et al. (GeroScience, 2021)

The Jackson Laboratory Nathan Shock Center: impact of genetic diversity on aging - Ron Korstanje; Luanne L. Peters; Laura L. Robinson; Stephen D. Krasinski; Gary A. Churchill (GeroScience, 2021)

Eat like an athlete: insights of sports nutrition science to support active aging in healthy older adults - Sara Y. Oikawa; Tristin D. Brisbois; Luc J. C. van Loon; Ian Rollo (GeroScience, 2021)
Skeletal muscle mass losses with age are associated with negative health consequences, including an increased risk of developing metabolic disease and the loss of independence. Athletes adopt numerous nutritional strategies to maximize the benefits of exercise training and enhance recovery in pursuit of improving skeletal muscle quality, mass, or function. Importantly, many of the principles applied to enhance skeletal muscle health in athletes may be applicable to support active aging and prevent sarcopenia in the healthy (non-clinical) aging population. Here, we discuss the anabolic properties of protein supplementation in addition to ingredients that may enhance the anabolic effects of protein (e.g. omega 3 s, creatine, inorganic nitrate) in older persons. We conclude that nutritional strategies used in pursuit of performance enhancement in athletes are often applicable to improve skeletal muscle health in the healthy older population when implemented as part of a healthy active lifestyle. Further research is required to elucidate the mechanisms by which these nutrients may induce favourable changes in skeletal muscle and to determine the appropriate dosing and timing of nutrient intakes to support active aging.

Therapeutic prevention of COVID-19 in elderly: a case–control study - Frederic Blanc; Cedric Waechter; Thomas Vogel; Benoit Schorr; Catherine Demuynck; Catherine Martin Hunyadi; Maxence Meyer; Denata Mutelica; Nadjiba Bougaa; Samira Fafi-Kremer; Lidia Calabrese; Elise Schmitt; et al. (GeroScience, 2021)

University of Southern California and buck institute nathan shock center: multidimensional models of aging - Sean P. Curran; Gordon J. Lithgow; Eric Verdin; Cohen P (GeroScience, 2021)

The hidden interplay between sex and COVID-19 mortality: the role of cardiovascular calcification - Alberto Cereda; Marco Toselli; Anna Palmisano; Davide Vignale; Riccardo Leone; Valeria Nicoletti; Chiara Gnasso; Antonio Mangieri; Arif Khokhar; Gianluca Campo; Alessandra Scoccia; Matteo Bertini; et al. (GeroScience, 2021)
Recent clinical and demographical studies on COVID-19 patients have demonstrated that men experience worse outcomes than women. However, in most cases, the data were not stratified according to gender, limiting the understanding of the real impact of gender on outcomes. This study aimed to evaluate the disaggregated in-hospital outcomes and explore the possible interactions between gender and cardiovascular calcifications. Data was derived from the sCORE-COVID-19 registry, an Italian multicentre registry that enrolled COVID-19 patients who had undergone a chest computer tomography scan on admission. A total of 1683 hospitalized patients (mean age 67±14 years) were included. Men had a higher prevalence of cardiovascular comorbidities, a higher pneumonia extension, more coronary calcifications (63% vs.50.9%, p<0.001), and a higher coronary calcium score (391±847 vs. 171±479 mm 3 , p <0.001). Men experienced a significantly higher mortality rate (24.4% vs. 17%, p =0.001), but the death event tended to occur earlier in women (15±7 vs. 8±7 days, p = 0.07). Non-survivors had a higher coronary, thoracic aorta, and aortic valve calcium score. Female sex, a known independent predictor of a favorable outcome in SARS-CoV2 infection, was not protective in women with a coronary calcification volume greater than 100 mm 3 . There were significant differences in cardiovascular comorbidities and vascular calcifications between men and women with SARS-CoV2 pneumonia. The differences in outcomes can be at least partially explained by the different cardiovascular profiles. However, women with poor outcomes had the same coronary calcific burden as men. The presumed favorable female sex bias in COVID-19 must therefore be reviewed in the context of comorbidities, especially cardiovascular ones.

A quantitative yeast aging proteomics analysis reveals novel aging regulators - Yu Sun; Ruofan Yu; Hao-Bo Guo; Hong Qin; Weiwei Dang (GeroScience, 2021)

Role of heat shock proteins in aging and chronic inflammatory diseases - Christian R. Gomez (GeroScience, 2021)

Learning from machine learning: prediction of age-related athletic performance decline trajectories - Christoph Hoog Antink; Anne K. Braczynski; Bergita Ganse (GeroScience, 2021)
Factors that determine individual age-related decline rates in physical performance are poorly understood and prediction poses a challenge. Linear and quadratic regression models are usually applied, but often show high prediction errors for individual athletes. Machine learning approaches may deliver more accurate predictions and help to identify factors that determine performance decline rates. We hypothesized that it is possible to predict the performance development of a master athlete from a single measurement, that prediction by a machine learning approach is superior to prediction by the average decline curve or an individually shifted decline curve, and that athletes with a higher starting performance show a slower performance decline than those with a lower performance. The machine learning approach was implemented using a multilayer neuronal network. Results showed that performance prediction from a single measurement is possible and that the prediction by a machine learning approach was superior to the other models. The estimated performance decline rate was highest in athletes with a high starting performance and a low starting age, as well as in those with a low starting performance and high starting age, while the lowest decline rate was found for athletes with a high starting performance and a high starting age. Machine learning was superior and predicted trajectories with significantly lower prediction errors compared to conventional approaches. New insights into factors determining decline trajectories were identified by visualization of the model outputs. Machine learning models may be useful in revealing unknown factors that determine the age-related performance decline.

San Antonio Nathan Shock Center: your one-stop shop for aging research - Adam B. Salmon; James F. Nelson; Jonathan A. L. Gelfond; Martin Javors; Brett Ginsburg; Marisa Lopez-Cruzan; Veronica Galvan; Elizabeth Fernandez; Nicolas Musi; Yuji Ikeno; Gene Hubbard; James Lechleiter; et al. (GeroScience, 2021)

University of Washington Nathan Shock Center: innovation to advance aging research - Matt Kaeberlein; Alessandro Bitto; Maitreya J. Dunham; Warren Ladiges; Su-In Lee; Michael J. MacCoss; Alexander Mendenhall; Daniel E. L. Promislow; Peter S. Rabinovitch; Judit Villén; Lu Wang; Yuliang Wang; et al. (GeroScience, 2021)

Grip strength performance from 9431 participants of the GenoFit study: normative data and associated factors - Jedd Pratt; Giuseppe De Vito; Marco Narici; Ricardo Segurado; Jackie Dolan; Judith Conroy; Colin Boreham (GeroScience, 2021)
Weak grip strength is a strong predictor of multiple adverse health outcomes and an integral diagnostic component of sarcopenia. However, the limited availability of normative data for certain populations impedes the interpretation of grip performance across adulthood. This study aimed to establish normative data and low grip strength thresholds in a large adult population, and to examine associations between grip strength and clinically relevant health variables. A total of 9431 adults aged between 18 and 92 years participated in this study (mean age: 44.8 ± 13.4 years; 57% females). Grip strength, body composition, and cardiorespiratory (CR) fitness were assessed using hand dynamometry, dual-energy x-ray absorptiometry and physical work capacity tests, respectively. Low grip strength was established according to criteria of the European Working Group on Sarcopenia in Older People. Normative data and t-scores, stratified by sex and age groups, are presented. Grip performance was associated with lean mass, skeletal muscle index (SMI), fat mass, CR fitness, bone mineral density (BMD), android/gynoid ratio, disease prevalence and physical activity levels (all p < 0.001) after controlling for multiple potential confounders. Individuals with weak grip strength had lower lean mass, SMI, CR fitness (all p < 0.001) and BMD ( p = 0.001), and higher disease prevalence ( p < 0.001), compared to healthy controls, although sex-specific differences were observed. Grip strength has practical screening utility across a range of health domains. The normative data and grip strength thresholds established in this study can guide the clinical interpretation of grip performance and facilitate timely therapeutic strategies targeting sarcopenia.

Prognosis of the non-ST elevation myocardial infarction complicated with early ventricular fibrillation at higher age - Réka Skoda; György Bárczi; Hajnalka Vágó; Attila Nemes; Liliána Szabó; Gábor Fülöp; István Hizoh; Dominika Domokos; Klára Törő; Elek Dinya; Béla Merkely; Dávid Becker (GeroScience, 2021)
Early ventricular fibrillation (EVF) predicts mortality in ST-segment elevation myocardial infarction (STEMI) patients. Data are lacking about prognosis and management of non-ST-segment elevation myocardial infarction (NSTEMI) EMI with EVF, especially at higher age. In the daily clinical practice, there is no clear prognosis of patients surviving EVF. The present study aimed to investigate the risk factors and factors influencing the prognosis of NSTEMI patients surviving EVF, especially at higher age. Clinical data, including 30-day and 1-year mortality of 6179 NSTEMI patients, were examined; 2.44% ( n =151) survived EVF and were further analyzed using chi-square test and uni- and multivariate analyses. Patients were divided into two age groups below and above the age of 70 years. Survival time was compared with Kaplan-Meier analysis. EVF was an independent risk factor for mortality in NSTEMI patients below (HR: 2.4) and above the age of 70 (HR: 2.1). Mortality rates between the two age groups of NSTEMI patients with EVF did not differ significantly: 30-day mortality was 24% vs 40% ( p =0.2709) and 1-year mortality was 39% vs 55% ( p =0.2085). Additional mortality after 30 days to 1 year was 15% vs 14.6% ( p =0.9728). Clinical characteristics of patients with EVF differed significantly from those without in both age groups. EVF after revascularization—within 48 h—had 11.2 OR for 30-day mortality above the age of 70. EVF in NSTEMI was an independent risk factor for mortality in both age groups. Invasive management and revascularization of NSTEMI patients with EVF is highly recommended. Closer follow-up and selection of patients (independent of age) for ICD implantation in the critical first month is essential.

Muscle and tendon adaptations to moderate load eccentric vs. concentric resistance exercise in young and older males - Jonathan Iain Quinlan; Martino Vladimiro Franchi; Nima Gharahdaghi; Francesca Badiali; Susan Francis; Andrew Hale; Bethan Eileen Phillips; Nathaniel Szewczyk; Paul Leonard Greenhaff; Kenneth Smith; Constantinos Maganaris; Phillip James Atherton; et al. (GeroScience, 2021)
Resistance exercise training (RET) is well-known to counteract negative age-related changes in both muscle and tendon tissue. Traditional RET consists of both concentric (CON) and eccentric (ECC) contractions; nevertheless, isolated ECC contractions are metabolically less demanding and, thus, may be more suitable for older populations. However, whether submaximal (60% 1RM) CON or ECC contractions differ in their effectiveness is relatively unknown. Further, whether the time course of muscle and tendon adaptations differs to the above is also unknown. Therefore, this study aimed to establish the time course of muscle and tendon adaptations to submaximal CON and ECC RET. Twenty healthy young (24.5 ± 5.1 years) and 17 older males (68.1 ± 2.4 years) were randomly allocated to either isolated CON or ECC RET which took place 3/week for 8 weeks. Tendon biomechanical properties, muscle architecture and maximal voluntary contraction were assessed every 2 weeks and quadriceps muscle volume every 4 weeks. Positive changes in tendon Young’s modulus were observed after 4 weeks in all groups after which adaptations in young males plateaued but continued to increase in older males, suggesting a dampened rate of adaptation with age. However, both CON and ECC resulted in similar overall changes in tendon Young’s modulus, in all groups. Muscle hypertrophy and strength increases were similar between CON and ECC in all groups. However, pennation angle increases were greater in CON, and fascicle length changes were greater in ECC. Notably, muscle and tendon adaptations appeared to occur in synergy, presumably to maintain the efficacy of the muscle–tendon unit.

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease - Caitlin S. Latimer; Nicole F. Liachko (GeroScience, 2021)
Alzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

Prefrontal cortex activation during dual-task walking in older adults is moderated by thickness of several cortical regions - Daliah Ross; Mark E. Wagshul; Meltem Izzetoglu; Roee Holtzer (GeroScience, 2021)

Early manifestation of gait alterations in the Tg2576 mouse model of Alzheimer’s disease - Adam Nyul-Toth; Jordan DelFavero; Peter Mukli; Amber Tarantini; Anna Ungvari; Andriy Yabluchanskiy; Anna Csiszar; Zoltan Ungvari; Stefano Tarantini (GeroScience, 2021)

Blood–brain barrier leakage at baseline and cognitive decline in cerebral small vessel disease: a 2-year follow-up study - Danielle Kerkhofs; Sau May Wong; Eleana Zhang; Renske Uiterwijk; Erik I. Hoff; Jacobus F. A. Jansen; Julie Staals; Walter H. Backes; Robert J. van Oostenbrugge (GeroScience, 2021)
Blood–brain barrier (BBB) dysfunction is one of the pathophysiological mechanisms in cerebral small vessel disease (SVD). Previously, it was shown that BBB leakage volume is larger in patients with SVD compared with controls. In this study, we investigated the link between BBB leakage and cognitive decline over 2 years in patients with cSVD. At baseline, 51 patients with clinically overt cSVD (lacunar stroke or mild vascular cognitive impairment) received a dynamic contrast-enhanced MRI scan to quantify BBB permeability in the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical grey matter (CGM), and deep grey matter (DGM). Cognitive function in the domain executive function, information processing speed, and memory was measured in all patients at baseline and after 2 years. The association between baseline BBB leakage and cognitive decline over 2 years was determined with multivariable linear regression analysis, corrected for age, sex, educational level, baseline WMH volume, and baseline brain volume. Regression analyses showed that higher baseline leakage volume and rate in the NAWM and CGM were significantly associated with increased overall cognitive decline. Furthermore, higher baseline leakage volume in the NAWM and CGM, and higher baseline leakage rate in the CGM were significantly associated with increased decline in executive function. This longitudinal study showed that higher BBB leakage at baseline is associated with stronger cognitive decline, specifically in executive function, over 2 years of follow-up in patients with cSVD. These results emphasize the key role of BBB disruption in the pathophysiology and clinical progression of cSVD.

Correction to: Effect of longevity genetic variants on the molecular aging rate - Anastasia Gurinovich; Zeyuan Song; William Zhang; Anthony Federico; Stefano Monti; Stacy L. Andersen; Lori L. Jennings; David J. Glass; Nir Barzilai; Sofiya Millman; Thomas T. Perls; Paola Sebastiani (GeroScience, 2021)

Metabolomics of aging in primary fibroblasts from small and large breed dogs - Paul S. Brookes; Ana Gabriela Jimenez (GeroScience, 2021)
Among several animal groups (eutherian mammals, birds, reptiles), lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including the following: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in coenzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age-dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small vs. large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.

The AGE Presents Introduction to Geroscience video lecture series - Alessandro Bitto; Mitchell B. Lee; Cristal M. Hill; Ron Korstanje; Matt Kaeberlein (GeroScience, 2021)

Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging - Kamil Pabis; Ylenia Chiari; Claudia Sala; Elisabeth Straka; Robertina Giacconi; Mauro Provinciali; Xinna Li; Holly Brown-Borg; Karin Nowikovsky; Teresa G. Valencak; Claudia Gundacker; Paolo Garagnani; et al. (GeroScience, 2021)

Increased procoagulant platelet levels are predictive of death in COVID-19 - Mohamad H. Khattab; Calin I. Prodan; Andrea S. Vincent; Chao Xu; Kellie R. Jones; Sharanjeet Thind; Meheroz Rabadi; Shubhada Mithilesh; Eleanor Mathews; Leslie Guthery; George L. Dale; Angelia C. Kirkpatrick (GeroScience, 2021)

Are fat and sugar just as detrimental in old age? - Ana P. Valencia; Nitin Nagaraj; Deena H. Osman; Peter S. Rabinovitch; David J. Marcinek (GeroScience, 2021)

Imaging retinal microvascular manifestations of carotid artery disease in older adults: from diagnosis of ocular complications to understanding microvascular contributions to cognitive impairment - Lilla István; Cecilia Czakó; Ágnes Élő; Zsuzsanna Mihály; Péter Sótonyi; Andrea Varga; Zoltán Ungvári; Anna Csiszár; Andriy Yabluchanskiy; Shannon Conley; Tamás Csipő; Ágnes Lipecz; et al. (GeroScience, 2021)
Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation (including funduscopy, fluorescein angiography, Doppler sonography, optical coherence tomography [OCT] and optical coherence tomography angiography [OCTA]) are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered.

Age and sex modify cellular proliferation responses to oxidative stress and glucocorticoid challenges in baboon cells - Daniel A. Adekunbi; Cun Li; Peter W. Nathanielsz; Adam B. Salmon (GeroScience, 2021)

Regulation of TDP-43 phosphorylation in aging and disease - Randall J. Eck; Brian C. Kraemer; Nicole F. Liachko (GeroScience, 2021)
Insoluble inclusions of phosphorylated TDP-43 occur in disease-affected neurons of most patients with amyotrophic lateral sclerosis (ALS) and about half of patients with frontotemporal lobar degeneration (FTLD-TDP). Phosphorylated TDP-43 potentiates a number of neurotoxic effects including reduced liquid–liquid phase separation dynamicity, changes in splicing, cytoplasmic mislocalization, and aggregation. Accumulating evidence suggests a balance of kinase and phosphatase activities control TDP-43 phosphorylation. Dysregulation of these processes may lead to an increase in phosphorylated TDP-43, ultimately contributing to neurotoxicity and neurodegeneration in disease. Here we summarize the evolving understanding of major regulators of TDP-43 phosphorylation as well as downstream consequences of their activities. Interventions restoring kinase and phosphatase balance may be a generalizable therapeutic strategy for all TDP-43 proteinopathies including ALS and FTLD-TDP.

Acute-care hospital reencounters in COVID-19 patients - Jeffrey R. Clark; Ayush Batra; Nathan A. Shlobin; Steven C. Hoffman; Zachary S. Orban; Igor J. Koralnik; Eric M. Liotta (GeroScience, 2021)

The association of proBNPage with manifestations of age-related cardiovascular, physical, and psychological impairment in community-dwelling older adults - Antonio Muscari; Giampaolo Bianchi; Paola Forti; Donatella Magalotti; Paolo Pandolfi; Marco Zoli (GeroScience, 2021)
NT-proB-type natriuretic peptide (NT-proBNP) serum concentration can be transformed by simple formulas into proBNPage, a surrogate of biological age strongly associated with chronological age, all-cause mortality, and disease count. This cross-sectional study aimed to assess whether proBNPage is also associated with other manifestations of the aging process in comparison with other variables. The study included 1117 noninstitutionalized older adults (73.1 ± 5.6 years, 537 men). Baseline measurements of serum NT-proBNP, erythrocyte sedimentation rate, hemoglobin, lymphocytes, and creatinine, which have previously been shown to be highly associated with both age and all-cause mortality, were performed. These variables were compared between subjects with and without manifestations of cardiovascular impairment (myocardial infarction (MI), stroke, peripheral artery disease (PAD), arterial revascularizations (AR)), physical impairment (long step test duration (LSTD), walking problems, falls, deficit in one or more activities of daily living), and psychological impairment (poor self-rating of health (PSRH), anxiety/depression, Mini Mental State Examination (MMSE) score < 24). ProBNPage (years) was independently associated (OR, 95% CI) with MI (1.08, 1.07–1.10), stroke (1.02, 1.00–1.05), PAD (1.04, 1.01–1.06), AR (1.06, 1.04–1.08), LSTD (1.03, 1.02–1.04), walking problems (1.02, 1.01–1.03), and PSRH (1.02, 1.01–1.02). For 5 of these 7 associations, the relationship was stronger than that of chronological age. In addition, proBNPage was univariately associated with MMSE score < 24, anxiety/depression, and falls. None of the other variables provided comparable performances. Thus, in addition to the known associations with mortality and disease count, proBNPage is also associated with cardiovascular manifestations as well as noncardiovascular manifestations of the aging process.

Strategies and cognitive reserve to preserve lexical production in aging - Monica Baciu; Sonja Banjac; Elise Roger; Célise Haldin; Marcela Perrone-Bertolotti; Hélène Lœvenbruck; Jean-François Démonet (GeroScience, 2021)
In the absence of any neuropsychiatric condition, older adults may show declining performance in several cognitive processes and among them, in retrieving and producing words, reflected in slower responses and even reduced accuracy compared to younger adults. To overcome this difficulty, healthy older adults implement compensatory strategies, which are the focus of this paper. We provide a review of mainstream findings on deficient mechanisms and possible neurocognitive strategies used by older adults to overcome the deleterious effects of age on lexical production. Moreover, we present findings on genetic and lifestyle factors that might either be protective or risk factors of cognitive impairment in advanced age. We propose that “aging-modulating factors” (AMF) can be modified, offering prevention opportunities against aging effects. Based on our review and this proposition, we introduce an integrative neurocognitive model of mechanisms and compensatory strategies for lexical production in older adults (entitled Lexical Access and Retrieval in Aging, LARA). The main hypothesis defended in LARA is that cognitive aging evolves heterogeneously and involves complementary domain-general and domain-specific mechanisms, with substantial inter-individual variability, reflected at behavioral, cognitive, and brain levels. Furthermore, we argue that the ability to compensate for the effect of cognitive aging depends on the amount of reserve specific to each individual which is, in turn, modulated by the AMF. Our conclusion is that a variety of mechanisms and compensatory strategies coexist in the same individual to oppose the effect of age. The role of reserve is pivotal for a successful coping with age-related changes and future research should continue to explore the modulating role of AMF.

Man’s best friend in life and death: scientific perspectives and challenges of dog brain banking - Sára Sándor; Kálmán Czeibert; Attila Salamon; Enikő Kubinyi (GeroScience, 2021)
Biobanking refers to the systematic collection, storage, and distribution of pre- or post-mortem biological samples derived from volunteer donors. The demand for high-quality human specimens is clearly demonstrated by the number of newly emerging biobanking facilities and large international collaborative networks. Several animal species are relevant today in medical research; therefore, similar initiatives in comparative physiology could be fruitful. Dogs, in particular, are gaining increasing attention in translational research on complex phenomena, like aging, cancer, and neurodegenerative diseases. Therefore, biobanks gathering and storing dog biological materials together with related data could play a vital role in translational and veterinary research projects. To achieve these aims, a canine biobank should meet the same standards in sample quality and data management as human biobanks and should rely on well-designed collaborative networks between different professionals and dog owners. While efforts to create dog biobanks could face similar financial and technical challenges as their human counterparts, they can widen the spectrum of successful collaborative initiatives towards a better picture of dogs’ physiology, disease, evolution, and translational potential. In this review, we provide an overview about the current state of dog biobanking and introduce the “Canine Brain and Tissue Bank” (CBTB)—a new, large-scale collaborative endeavor in the field.

Acute cognitive impairment after traumatic brain injury predicts the occurrence of brain atrophy patterns similar to those observed in Alzheimer’s disease - Kenneth A. Rostowsky; Andrei Irimia (GeroScience, 2021)

Left-ventricular hypertrophy in 18-month-old donor rat hearts was not associated with graft dysfunction in the early phase of reperfusion after cardiac transplantation–gene expression profiling - Sevil Korkmaz-Icöz; Deniz Akca; Shiliang Li; Sivakkanan Loganathan; Paige Brlecic; Mihály Ruppert; Alex Ali Sayour; Andreas Simm; Maik Brune; Tamás Radovits; Matthias Karck; Gábor Szabó (GeroScience, 2021)
The use of hearts with left-ventricular (LV) hypertrophy (LVH) could offer an opportunity to extend the donor pool for cardiac transplantation. We assessed the effects of LVH in 18-month-old spontaneously hypertensive stroke-prone (SHRSP) donor rats and following transplantation. In donors, cardiac function and structural alterations were assessed. Then, the hearts were transplanted into young normotensive-rats. We evaluated LV graft function 1 h after transplantation. The myocardial expression of 92 genes involved in apoptosis, inflammation, and oxidative-stress was profiled using PCR-array. Compared to controls, SHRSP-rats developed LVH, had increased LV systolic performance (slope of the end-diastolic pressure-volume (PV) relationship: 1.6±0.2 vs 0.8±0.1mmHg/μl, p <0.05) accompanied by diastolic dysfunction [prolonged time constant of LV pressure decay (Tau: 15.8±0.6 vs 12.3±0.5ms) and augmented diastolic stiffness (LV end-diastolic PV relationship: 0.103±0.012 vs 0.045±0.006mmHg/ml), p <0.05]. They presented ECG changes, myocardial fibrosis, and increased nitrotyrosine immunoreactivity and plasma troponin-T and creatine kinase-CM levels. After transplantation, even though the graft contractility was better in SHRSP rats compared to controls, the adverse impact of ischemia/reperfusion-injury on contractility was not altered (E es ratio after versus before transplantation: 32% vs 29%, p >0.05). Whereas nitrotyrosine immunoreactivity was higher, myeloperoxidase-positive cell infiltration was decreased in the SHRSP+transplanted compared to control+transplanted. Among the tested genes, LVH was associated with altered expression of 38 genes in donors, while transplantation of these hearts resulted in the change of four genes. Alterations in 18-month-old donor hearts, as a consequence of hypertension and LVH, were not associated with graft dysfunction in the early phase of reperfusion after transplantation.

An energetics perspective on geroscience: mitochondrial protonmotive force and aging - Brandon J. Berry; Matt Kaeberlein (GeroScience, 2021)

Age-related expression of prominent regulatory elements in mouse brain: catastrophic decline of FOXO3a - C. D. Rollo; S. E. Marsh-Rollo; D. Boreham; J. A. Lemon (GeroScience, 2021)

Neurovascular-glymphatic dysfunction and white matter lesions - Behnam Sabayan; Rudi G. J. Westendorp (GeroScience, 2021)

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice - Rachana Trivedi; Bailey Knopf; Jitendra Kumar Tripathi; Shar Rakoczy; Gunjan D. Manocha; Holly Brown-Borg; Donald A. Jurivich (GeroScience, 2021)
How the heat shock axis, repair pathways, and proteostasis impact the rate of aging is not fully understood. Recent reports indicate that normal aging leads to a 50% change in several regulatory elements of the heat shock axis. Most notably is the age-dependent enhancement of inhibitory signals associated with accumulated heat shock proteins and hyper-acetylation associated with marked attenuation of heat shock factor 1 (HSF1)–DNA binding activity. Because exceptional longevity is associated with increased resistance to stress, this study evaluated regulatory check points of the heat shock axis in liver extracts from 12 months and 24 months long-lived Ames dwarf mice and compared these findings with aging wild-type mice. This analysis showed that 12M dwarf and wild-type mice have comparable stress responses, whereas old dwarf mice, unlike old wild-type mice, preserve and enhance activating elements of the heat shock axis. Old dwarf mice thwart negative regulation of the heat shock axis typically observed in usual aging such as noted in HSF1 phosphorylation at Ser307 residue, acetylation within its DNA binding domain, and reduction in proteins that attenuate HSF1–DNA binding. Unlike usual aging, dwarf HSF1 protein and mRNA levels increase with age and further enhance by stress. Together these observations suggest that exceptional longevity is associated with compensatory and enhanced HSF1 regulation as an adaptation to age-dependent forces that otherwise downregulate the heat shock axis.

Results of a hospitalization policy of asymptomatic and pre-symptomatic COVID-19-positive long-term care facility residents in the province of Salzburg—a report from the AGMT COVID-19 Registry - Florian Huemer; Gabriel Rinnerthaler; Benedikt Jörg; Patrick Morre; Birgit Stegbuchner; Elisabeth Proksch; Stefanie Fleimisch; Hannes Oberkofler; Iris Kremser; Richard Greil; Alexander Egle (GeroScience, 2021)
COVID-19-associated case fatality rates up to 48% were reported among nursing facility residents. During the first wave of the COVID-19 pandemic, routine SARS-CoV-2 testing in long-term care facilities in the Province of Salzburg and centralized hospitalization in the COVID-19 unit of the Paracelsus Medical University Salzburg (Austria) irrespective of symptoms was implemented. Baseline characteristics and the course of COVID-19 disease were assessed among hospitalized long-term care facility residents within the COVID-19 Registry of the Austrian Group Medical Tumor Therapy (AGMT; NCT04351529). Between the 24 th of March and the 20 th of April 2020, 50 COVID-19-positive residents were hospitalized. The median age was 84.5 years (range: 79–88) and the median number of comorbidities and baseline medication classes was 6 (IQR: 4–7) and 5 (IQR: 3–6), respectively. At admission, 31 residents (62%) were symptomatic, nine residents (18%) pre-symptomatic whereas ten residents (20%) remained asymptomatic. The 30-day mortality rate from hospitalization was 32% and significantly higher in symptomatic residents at admission when compared to asymptomatic residents including pre-symptomatic residents (48% [95% CI: 27–63%] versus 5% [95% CI: 0–15%], p= 0.006). The Early Warning Score (EWS) at admission was associated with 30-day mortality: high risk: 100%, intermediate risk: 50% (95% CI: 0–78%), and low risk: 21% (95% CI: 7-32%) ( p <0.001). In light of comparably low mortality rates between asymptomatic and pre-symptomatic hospitalized COVID-19-positive residents, we suggest the supply of comparable intensity and quality of monitoring and care in long-term care facilities as an alternative to immediate hospitalization upon a positive COVID-19 test in asymptomatic residents.

Sensory and memory processing in old female and male Wistar rat brain, and its relationship with the cortical and hippocampal redox state - Roberto Santín-Márquez; Belén Ramírez-Cordero; Rafael Toledo-Pérez; Armando Luna-López; Norma E. López-Diazguerrero; Ulalume Hernández-Arciga; Marcel Pérez-Morales; Juan José Ortíz-Retana; Martín García-Servín; Sarael Alcauter; Braulio Hernández-Godínez; Alejandra Ibañez-Contreras; et al. (GeroScience, 2021)

The trophocytes and oenocytes of worker and queen honey bees (Apis mellifera) exhibit distinct age-associated transcriptome profiles - Cheng-Yen Lu; Yu-Ting Weng; Bertrand Tan; Chin-Yuan Hsu (GeroScience, 2021)

In vivo proton magnetic resonance spectroscopy detection of metabolite abnormalities in aged Tat-transgenic mouse brain - Jason J. Paris; Xi Chen; Joseph Anderson; Alaa N. Qrareya; Fakhri Mahdi; Fei Du; Jay P. McLaughlin; Marc J. Kaufman (GeroScience, 2021)

Proceedings from the annual University of Washington Geroscience Symposium, October 23, 2020 - Mitchell B. Lee; Alessandro Bitto; Matt Kaeberlein (GeroScience, 2021)

Longitudinal course of GDF15 levels before acute hospitalization and death in the general population - Juliette Tavenier; Ove Andersen; Jan O. Nehlin; Janne Petersen (GeroScience, 2021)

Lifelong exercise is associated with more homogeneous motor unit potential features across deep and superficial areas of vastus lateralis - Eleanor J. Jones; Jessica Piasecki; Alex Ireland; Daniel W. Stashuk; Philip J. Atherton; Bethan E. Phillips; Jamie S. McPhee; Mathew Piasecki (GeroScience, 2021)
Motor unit (MU) expansion enables rescue of denervated muscle fibres helping to ameliorate age-related muscle atrophy, with evidence to suggest master athletes are more successful at this remodelling. Electrophysiological data has suggested MUs located superficially are larger than those located deeper within young muscle. However, the effects of ageing and exercise on MU heterogeneity across deep and superficial aspects of vastus lateralis (VL) remain unclear. Intramuscular electromyography was used to record individual MU potentials (MUPs) and near fibre MUPs (NFMs) from deep and superficial regions of the VL during 25% maximum voluntary contractions, in 83 males (15 young (Y), 17 young athletes (YA), 22 old (O) and 29 master athletes (MA)). MUP size and complexity were assessed using area and number of turns, respectively. Multilevel mixed effects linear regression models were performed to investigate the effects of depth in each group. MUP area was greater in deep compared with superficial MUs in Y ( p <0.001) and O ( p =0.012) but not in YA ( p =0.071) or MA ( p =0.653). MUP amplitude and NF MUP area were greater, and MUPs were more complex in deep MUPs from Y, YA and O (all p <0.05) but did not differ across depth in MA (all p >0.07). These data suggest MU characteristics differ according to depth within the VL which may be influenced by both ageing and exercise. A more homogenous distribution of MUP size and complexity across muscle depths in older athletes may be a result of a greater degree of age-related MU adaptations.

Effects of metformin, rapamycin, and resveratrol on cellular metabolism of canine primary fibroblast cells isolated from large and small breeds as they age - Ana Gabriela Jimenez; Sahil Lalwani; William Cipolli (GeroScience, 2021)

Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence - Yu Hu; Yun Zhu; Skyler D. Gerber; Jared M. Osland; Min Chen; Krishna A. Rao; Heng Gu; Rong Yuan (GeroScience, 2021)

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner - Yoko O. Henderson; Nazmin Bithi; Christopher Link; Jie Yang; Rebecca Schugar; Natalia Llarena; J. Mark Brown; Christopher Hine (GeroScience, 2021)
Global average life expectancy continues to rise. As aging increases the likelihood of frailty, which encompasses metabolic, musculoskeletal, and cognitive deficits, there is a need for effective anti-aging treatments. It is well established in model organisms that dietary restriction (DR), such as caloric restriction or protein restriction, enhances health and lifespan. However, DR is not widely implemented in the clinic due to patient compliance and its lack of mechanistic underpinnings. Thus, the present study tested the effects of a somewhat more clinically applicable and adoptable DR regimen, every-other-day (EOD) intermittent fasting, on frailty in 20-month-old male and female C57BL/6 mice. Frailty was determined by a series of metabolic, musculoskeletal, and cognitive tasks performed prior to and toward the end of the 2.5-month dietary intervention. Late-life EOD fasting attenuated overall energy intake, hypothalamic inflammatory gene expression, and frailty in males. However, it failed to reduce overall caloric intake and had a little positive effect in females. Given that the selected benefits of DR are dependent on augmented production of the gasotransmitter hydrogen sulfide (H 2 S) and that renal H 2 S production declines with age, we tested the effects of EOD fasting on renal H 2 S production capacity and its connection to frailty in males. EOD fasting boosted renal H 2 S production, which positively correlated with improvements in multiple components of frailty tasks. Therefore, late-life initiated EOD fasting is sufficient to reduce aging-related frailty, at least in males, and suggests that renal H 2 S production capacity may modulate the effects of late-life EOD fasting on frailty.

Cardiac response to adrenergic stress differs by sex and across the lifespan - Aykhan Yusifov; Vikram E. Chhatre; Jacob M. Zumo; Ross F. Cook; Benjamin D. McNair; Emily E. Schmitt; Kathleen C. Woulfe; Danielle R. Bruns (GeroScience, 2021)

Circulating fatty acids and endocannabinoidome-related mediator profiles associated to human longevity - Claudia Manca; Gianfranca Carta; Elisabetta Murru; Armita Abolghasemi; Hastimansooreh Ansar; Alessandra Errigo; Patrice D. Cani; Sebastiano Banni; Giovanni Mario Pes (GeroScience, 2021)
To evaluate whether a peculiar plasma profile of fatty acids and endocannabinoidome (eCBome)-related mediators may be associated to longevity, we assessed them in octogenarians (Old; n =42) living in the east-central mountain area of Sardinia, a High-Longevity Zone (HLZ), compared to sexagenarian (Young; n =21) subjects from the same area, and to Olds ( n =22) from the Northern Sardinia indicated as Lower-Longevity Zone (LLZ). We found significant increases in conjugated linoleic acid (CLA) and heptadecanoic acid (17:0) levels in Old-HLZ with respect to younger subjects and Old-LLZ subjects. Young-HLZ subjects exhibited higher circulating levels of pentadecanoic acid (15:0) and retinol. Palmitoleic acid (POA) was elevated in both Young and Old subjects from the HLZ. eCBome profile showed a significantly increased plasma level of the two endocannabinoids, N -arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in Old-HLZ subjects compared to Young-HLZ and Old-LLZ respectively. In addition, we found increased N -oleoyl-ethanolamine (OEA), 2-linoleoyl-glycerol (2-LG) and 2-oleoyl-glycerol (2-OG) levels in Old-HLZ group with respect to Young-HLZ (as for OEA an d 2-LG) and both the Old-LLZ and Young-HLZ for 2-OG. The endogenous metabolite of docosahexaenoic acid (DHA), N -docosahexaenoyl-ethanolamine (DHEA) was significantly increased in Old-HLZ subjects. In conclusion, our results suggest that in the HLZ area, Young and Old subjects exhibited a favourable, albeit distinctive, fatty acids and eCBome profile that may be indicative of a metabolic pattern potentially protective from adverse chronic conditions. These factors could point to a suitable physiological metabolic pattern that may counteract the adverse stimuli leading to age-related disorders such as neurodegenerative and metabolic diseases.

Age-related neuroendocrine and alerting responses to light - Sarah L. Chellappa; Vivien Bromundt; Sylvia Frey; Christian Cajochen (GeroScience, 2021)

Effect of longevity genetic variants on the molecular aging rate - Anastasia Gurinovich; Zeyuan Song; William Zhang; Anthony Federico; Stefano Monti; Stacy L. Andersen; Lori L. Jennings; David J. Glass; Nir Barzilai; Sofiya Millman; Thomas T. Perls; Paola Sebastiani (GeroScience, 2021)

Metabolic pathways and therapeutics to promote resilience, rehabilitation and delayed aging - William K. Smith; Donald K. Ingram; Rafael de Cabo; Paul Pasquina (GeroScience, 2021)

Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline - Carlos J. Padilla; Markus E. Harrigan; Hallie Harris; Jan M. Schwab; Seward B. Rutkove; Mark M. Rich; Brian C. Clark; W. David Arnold (GeroScience, 2021)

T lymphocyte depletion ameliorates age-related metabolic impairments in mice - Daniel W. Trott; Md Torikul Islam; David J. Buckley; Anthony J. Donato; Tavia Dutson; Eric S. Sorensen; Jinjin Cai; Venkateswara R. Gogulamudi; Tam T. T. Phuong; Lisa A. Lesniewski (GeroScience, 2021)

Beta-guanidinopropionic acid has age-specific effects on markers of health and function in mice - Jonathan D. Dorigatti; Kevin M. Thyne; Brett C. Ginsburg; Adam B. Salmon (GeroScience, 2021)

Ageing affects subtelomeric DNA methylation in blood cells from a large European population enrolled in the MARK-AGE study - Maria Giulia Bacalini; Anna Reale; Marco Malavolta; Fabio Ciccarone; María Moreno-Villanueva; Martijn E. T. Dollé; Eugène Jansen; Tilman Grune; Efstathios S. Gonos; Christiane Schön; Jürgen Bernhardt; Beatrix Grubeck-Loebenstein; et al. (GeroScience, 2021)
Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.

50 years of the “war on cancer”: lessons for public health and geroscience - Colin Farrelly (GeroScience, 2021)

Skeletal muscle mitochondrial DNA copy number and mitochondrial DNA deletion mutation frequency as predictors of physical performance in older men and women - Allen Herbst; Steven J. Prior; Cathy C. Lee; Judd M. Aiken; Debbie McKenzie; Austin Hoang; Nianjun Liu; Xiwei Chen; Pengcheng Xun; David B. Allison; Jonathan Wanagat (GeroScience, 2021)

Intermittent fasting: from calories to time restriction - Eleonora Duregon; Laura C.D. D. Pomatto-Watson; Michel Bernier; Nathan L. Price; Rafael de Cabo (GeroScience, 2021)

Temporal emergence of age-associated changes in cognitive and physical function in vervets (Chlorocebus aethiops sabaeus) - Brett M. Frye; Payton M. Valure; Suzanne Craft; Mark G. Baxter; Christie Scott; Shanna Wise-Walden; David W. Bissinger; Hannah M. Register; Carson Copeland; Matthew J. Jorgensen; Jamie N. Justice; Stephen B. Kritchevsky; et al. (GeroScience, 2021)

A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts - David Gomez-Cabrero; Stefan Walter; Imad Abugessaisa; Rebeca Miñambres-Herraiz; Lucia Bernad Palomares; Lee Butcher; Jorge D. Erusalimsky; Francisco Jose Garcia-Garcia; José Carnicero; Timothy C. Hardman; Harald Mischak; Petra Zürbig; et al. (GeroScience, 2021)

Longevity pathways in stress resistance: targeting NAD and sirtuins to treat the pathophysiology of hemorrhagic shock - Carrie A. Sims; Hanna E. Labiner; Sohini S. Shah; Joseph A. Baur (GeroScience, 2021)

Cerebral hemodynamics in obesity: relationship with sex, age, and adipokines in a cohort-based study - Oscar Ayo-Martin; Jorge García-García; Francisco Hernández-Fernández; Mercedes Gómez-Hontanilla; Isabel Gómez-Fernández; Carolina Andrés-Fernández; Cristina Lamas; José Joaquín Alfaro-Martínez; Francisco Botella; Tomás Segura (GeroScience, 2021)

Exogenous hydrogen sulfide and miR-21 antagonism attenuates macrophage-mediated inflammation in ischemia reperfusion injury of the aged kidney - Sathnur Pushpakumar; Sourav Kundu; Gregory Weber; Utpal Sen (GeroScience, 2021)

SMAD4 mutations and cross-talk between TGF-β/IFNγ signaling accelerate rates of DNA damage and cellular senescence, resulting in a segmental progeroid syndrome—the Myhre syndrome - Renuka Kandhaya-Pillai; Deyin Hou; Jiaming Zhang; Xiaomeng Yang; Goli Compoginis; Takayasu Mori; Tamara Tchkonia; George M. Martin; Fuki M. Hisama; James L. Kirkland; Junko Oshima (GeroScience, 2021)

T cell–depleted cultured pediatric thymus tissue as a model for some aspects of human age-related thymus involution - Laura P. Hale; Lynn Cheatham; Andrew N. Macintyre; Bonnie LaFleur; Brittany Sanders; Jesse Troy; Joanne Kurtzberg; Gregory D. Sempowski (GeroScience, 2021)

Access to females and early life castration individually extend maximal but not median lifespan in male mice - Michael Garratt; Heather Try; Robert C. Brooks (GeroScience, 2021)

Decreased parenchymal arteriolar tone uncouples vessel-to-neuronal communication in a mouse model of vascular cognitive impairment - Ki Jung Kim; Juan Ramiro Diaz; Jessica L. Presa; P. Robinson Muller; Michael W. Brands; Mohammad B. Khan; David C. Hess; Ferdinand Althammer; Javier E. Stern; Jessica A. Filosa (GeroScience, 2021)
Chronic hypoperfusion is a key contributor to cognitive decline and neurodegenerative conditions, but the cellular mechanisms remain ill-defined. Using a multidisciplinary approach, we sought to elucidate chronic hypoperfusion-evoked functional changes at the neurovascular unit. We used bilateral common carotid artery stenosis (BCAS), a well-established model of vascular cognitive impairment, combined with an ex vivo preparation that allows pressurization of parenchymal arterioles in a brain slice. Our results demonstrate that mild (~ 30%), chronic hypoperfusion significantly altered the functional integrity of the cortical neurovascular unit. Although pial cerebral perfusion recovered over time, parenchymal arterioles progressively lost tone, exhibiting significant reductions by day 28 post-surgery. We provide supportive evidence for reduced adenosine 1 receptor-mediated vasoconstriction as a potential mechanism in the adaptive response underlying the reduced baseline tone in parenchymal arterioles. In addition, we show that in response to the neuromodulator adenosine, the action potential frequency of cortical pyramidal neurons was significantly reduced in all groups. However, a significant decrease in adenosine-induced hyperpolarization was observed in BCAS 14 days. At the microvascular level, constriction-induced inhibition of pyramidal neurons was significantly compromised in BCAS mice. Collectively, these results suggest that BCAS uncouples vessel-to-neuron communication—vasculo-neuronal coupling—a potential early event in cognitive decline.

Fasting and fasting-mimicking diets for chemotherapy augmentation - Sebastian Brandhorst (GeroScience, 2021)

Endothelin B receptor dysfunction mediates elevated myogenic tone in cerebral arteries from aged male Fischer 344 rats - Alexander P. Young; Jiequan Zhu; Amina M. Bagher; Eileen M. Denovan-Wright; Susan E. Howlett; Melanie E.M. Kelly (GeroScience, 2021)

ACE2/ACE imbalance and impaired vasoreparative functions of stem/progenitor cells in aging - S. Joshi; K. Chittimalli; J. Jahan; G. Vasam; Y. P. Jarajapu (GeroScience, 2021)

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation - Megha Jhanji; Chintada Nageswara Rao; Mathew Sajish (GeroScience, 2021)

Is impaired dopaminergic function associated with mobility capacity in older adults? - Simon Moskowitz; David W. Russ; Leatha A. Clark; Nathan P. Wages; Dustin R. Grooms; Adam J. Woods; Julie Suhr; Janet E. Simon; Andrew O’Shea; Cody R. Criss; Paolo Fadda; Brian C. Clark (GeroScience, 2021)

Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics - Donald K. Ingram; George S. Roth (GeroScience, 2021)

Effect of rapamycin on aging and age-related diseases—past and future - Ramasamy Selvarani; Sabira Mohammed; Arlan Richardson (GeroScience, 2021)
In 2009, rapamycin was reported to increase the lifespan of mice when implemented later in life. This observation resulted in a sea-change in how researchers viewed aging. This was the first evidence that a pharmacological agent could have an impact on aging when administered later in life, i.e., an intervention that did not have to be implemented early in life before the negative impact of aging. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on various diseases, physiological functions, and biochemical processes in mice. In this review, we focus on those areas in which there is strong evidence for rapamycin’s effect on aging and age-related diseases in mice, e.g., lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence. We conclude that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer’s disease.

Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study - Yiqiang Zhan; Sara Hägg (GeroScience, 2021)
Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging ( β = − 0.02, 95% confidence interval: − 0.04, − 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.

From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience - Brianna J. Stubbs; Andrew P. Koutnik; Jeff S. Volek; John C. Newman (GeroScience, 2021)
Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, and other cellular processes. While these energy and signaling mechanisms of ketone bodies are currently being studied in a variety of aging-related diseases such as Alzheimer’s disease and type 2 diabetes mellitus, they may also be relevant to military service members undergoing stressors that mimic or accelerate aging pathways, particularly traumatic brain injury and muscle rehabilitation and recovery. Here we summarize the biology of ketone bodies relevant to resilience and rehabilitation, strategies for translational use of ketone bodies, and current clinical investigations in this area.

Diabetes medications as potential calorie restriction mimetics—a focus on the alpha-glucosidase inhibitor acarbose - Daniel L. Smith; Rachael M. Orlandella; David B. Allison; Lyse A. Norian (GeroScience, 2021)

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin - Jamie N. Justice; Sriram Gubbi; Ameya S. Kulkarni; Jenna M. Bartley; George A. Kuchel; Nir Barzilai (GeroScience, 2021)

Mitochondrial-derived peptides in aging and age-related diseases - Su-Jeong Kim; Brendan Miller; Hiroshi Kumagai; Ana R. Silverstein; Melanie Flores; Kelvin Yen (GeroScience, 2021)

High-intensity exercise training induces mitonuclear imbalance and activates the mitochondrial unfolded protein response in the skeletal muscle of aged mice - André Victor Cordeiro; Guilherme Francisco Peruca; Renata Rosseto Braga; Rafael Santos Brícola; Luciene Lenhare; Vagner Ramon Rodrigues Silva; Chadi Pellegrini Anaruma; Carlos Kiyoshi Katashima; Barbara Moreira Crisol; Lucas Torres Barbosa; Fernando Moreira Simabuco; Adelino Sanchez Ramos da Silva; et al. (GeroScience, 2021)

Rapamycin restores brain vasculature, metabolism, and blood-brain barrier in an inflammaging model - Rheal A. Towner; Rafal Gulej; Michelle Zalles; Debra Saunders; Nataliya Smith; Megan Lerner; Kathryn A. Morton; Arlan Richardson (GeroScience, 2021)

A ride through the epigenetic landscape: aging reversal by reprogramming - Lucas Paulo de Lima Camillo; Robert B. A. Quinlan (GeroScience, 2021)
Aging has become one of the fastest-growing research topics in biology. However, exactly how the aging process occurs remains unknown. Epigenetics plays a significant role, and several epigenetic interventions can modulate lifespan. This review will explore the interplay between epigenetics and aging, and how epigenetic reprogramming can be harnessed for age reversal. In vivo partial reprogramming holds great promise as a possible therapy, but several limitations remain. Rejuvenation by reprogramming is a young but rapidly expanding subfield in the biology of aging.

Reversal of cerebral hypoperfusion: a novel therapeutic target for the treatment of AD/ADRD? - Fan Fan; Richard J. Roman (GeroScience, 2021)

IGF1R signaling regulates astrocyte-mediated neurovascular coupling in mice: implications for brain aging - Stefano Tarantini; Priya Balasubramanian; Andriy Yabluchanskiy; Nicole M. Ashpole; Sreemathi Logan; Tamas Kiss; Anna Ungvari; Ádám Nyúl-Tóth; Michal L. Schwartzman; Zoltan Benyo; William E. Sonntag; Anna Csiszar; et al. (GeroScience, 2021)

Targeting mitochondrial dysfunction with small molecules in intervertebral disc aging and degeneration - Morteza Saberi; Xiaolei Zhang; Ali Mobasheri (GeroScience, 2021)
The prevalence of rheumatic and musculoskeletal diseases (RMDs) including osteoarthritis (OA) and low back pain (LBP) in aging societies present significant cost burdens to health and social care systems. Intervertebral disc (IVD) degeneration, which is characterized by disc dehydration, anatomical alterations, and extensive changes in extracellular matrix (ECM) composition, is an important contributor to LBP. IVD cell homeostasis can be disrupted by mitochondrial dysfunction. Mitochondria are the main source of energy supply in IVD cells and a major contributor to the production of reactive oxygen species (ROS). Therefore, mitochondria represent a double-edged sword in IVD cells. Mitochondrial dysfunction results in oxidative stress, cell death, and premature cell senescence, which are all implicated in IVD degeneration. Considering the importance of optimal mitochondrial function for the preservation of IVD cell homeostasis, extensive studies have been done in recent years to evaluate the efficacy of small molecules targeting mitochondrial dysfunction. In this article, we review the pathogenesis of mitochondrial dysfunction, aiming to highlight the role of small molecules and a selected number of biological growth factors that regulate mitochondrial function and maintain IVD cell homeostasis. Furthermore, molecules that target mitochondria and their mechanisms of action and potential for IVD regeneration are identified. Finally, we discuss mitophagy as a key mediator of many cellular events and the small molecules regulating its function.

Lack of resemblance between Myhre syndrome and other “segmental progeroid” syndromes warrants restraint in applying this classification - Angela E. Lin; Nicola Brunetti-Pierri; Bert Callewaert; Valérie Cormier-Daire; Sofia Douzgou; T. Bernard Kinane; Mark E. Lindsay; Lois J. Starr (GeroScience, 2021)

IL-6 can singlehandedly drive many features of frailty in mice - Mladen Jergović; Heather L. Thompson; Christine M. Bradshaw; Sandip Ashok Sonar; Arveen Ashgar; Niels Mohty; Bellal Joseph; Mindy J. Fain; Kristan Cleveland; Rick G. Schnellman; Janko Nikolich-Žugich (GeroScience, 2021)

Implication of post-translationally modified SOD1 in pathological aging - Kashfia Shafiq; Nitesh Sanghai; Ying Guo; Jiming Kong (GeroScience, 2021)

Longitudinal uncoupling of the heart and arteries with aging in a community-dwelling population - Majd AlGhatrif; Chris H. Morrell; Lewis C. Becker; Paul D. Chantler; Samer S. Najjar; Luigi Ferrucci; Gary Gerstenblith; Edward G. Lakatta (GeroScience, 2021)

A novel role of the mitochondrial iron-sulfur cluster assembly protein ISCU-1/ISCU in longevity and stress response - Yi Sheng; Guang Yang; Kaitlyn Casey; Shayla Curry; Mason Oliver; Sung Min Han; Christiaan Leeuwenburgh; Rui Xiao (GeroScience, 2021)

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length - Alexander Wirth; Bettina Wolf; Cheng-Kai Huang; Silke Glage; Sebastian J. Hofer; Marion Bankstahl; Christian Bär; Thomas Thum; Kai G. Kahl; Stephan J. Sigrist; Frank Madeo; Jens P. Bankstahl; et al. (GeroScience, 2021)
Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.

The relative contributions of behavioral, biological, and psychological risk factors in the association between psychosocial stress and all-cause mortality among middle- and older-aged adults in the USA - Justin Rodgers; Adolfo G. Cuevas; David R. Williams; Ichiro Kawachi; S.V. Subramanian (GeroScience, 2021)

Dynamics of leukocyte telomere length in adults aged 50 and older: a longitudinal population-based cohort study - Zhezhou Huang; Chazhen Liu; Ye Ruan; Yanfei Guo; Shuangyuan Sun; Yan Shi; Fan Wu (GeroScience, 2021)

Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin - Douglas E. Long; Bailey D. Peck; Steven C. Tuggle; Alejandro G. Villasante Tezanos; Samuel T. Windham; Marcas M. Bamman; Philip A. Kern; Charlotte A. Peterson; Rosicka G. Walton (GeroScience, 2021)

Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study - Majd AlGhatrif; Toshiko Tanaka; Ann Zenobia Moore; Stefania Bandinelli; Edward G. Lakatta; Luigi Ferrucci (GeroScience, 2021)

Effects of 16 months of high intensity resistance training on thigh muscle fat infiltration in elderly men with osteosarcopenia - Mansour Ghasemikaram; Oliver Chaudry; Armin M. Nagel; Michael Uder; Franz Jakob; Wolfgang Kemmler; Matthias Kohl; Klaus Engelke (GeroScience, 2021)

Thyroid hormone signaling is associated with physical performance, muscle mass, and strength in a cohort of oldest-old: results from the Mugello study - Angelo Di Iorio; Roberto Paganelli; Michele Abate; Giovanni Barassi; Alex Ireland; Claudio Macchi; Raffaele Molino-Lova; Francesca Cecchi (GeroScience, 2021)
Thyroid hormones (THs) play a crucial role in the homeostasis of muscle function, such as myogenesis and energy metabolism, suggesting that the thyroid may be also involved in the entropic processes of muscle aging. The aim of the present study is to evaluate the effect of TH signaling on physical performance, muscle mass, and strength in a cohort of community-dwelling oldest-old subjects (> 90 years). The study population was selected in a rural area of central Italy (Mugello, Tuscany), and the design was cross-sectional. Four hundred seventy-five subjects (130 males and 345 females) were enrolled, representing about 65% of all the nonagenarians living in the Mugello area. After adjusting for multiple confounding factors (sex, age, diabetes, and levothyroxine administration), the lowest quartile of FT3/FT4 ratio distribution showed lower physical performance compared to the other quartiles ( β ± SE: − 0.49 ± 0.12; p < 0.001), whereas the highest quartile of FT3/FT4 ratio was associated with higher skeletal muscle index ( β ± SE: 1.11 ± 0.42; p = 0.009). In addition, the lowest quartile of FT4 showed a statistically significant higher handgrip strength ( β ± SE: 1.78 ± 0.68; p = 0.009) compared to all other quartiles. This study demonstrates that nonagenarians with higher FT3/FT4 ratios had better preserved muscle function, therefore successfully overcoming the imbalance of homeostatic and entropic processes involved in muscle aging. However, we could not establish a cause-effect relationship due to the cross-sectional design of the study.

Biomarkers and phenotypic expression in Alzheimer’s disease: exploring the contribution of frailty in the Alzheimer’s Disease Neuroimaging Initiative - Marco Canevelli; Ivan Arisi; Ilaria Bacigalupo; Andrea Arighi; Daniela Galimberti; Nicola Vanacore; Mara D’Onofrio; Matteo Cesari; Giuseppe Bruno (GeroScience, 2021)
The present study aimed at investigating if the main biomarkers of Alzheimer’s disease (AD) neuropathology and their association with cognitive disturbances and dementia are modified by the individual’s frailty status. We performed a cross-sectional analysis of data from participants with normal cognition, mild cognitive impairment (MCI), and AD dementia enrolled in the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI2) study. Frailty was operationalized by computing a 40-item Frailty Index (FI). The following AD biomarkers were considered and analyzed according to the participants’ frailty status: CSF Aβ 1-42 , 181 P-tau, and T-tau; MRI-based hippocampus volume; cortical glucose metabolism at the FDG PET imaging; amyloid deposition at the 18 F-AV-45 PET imaging. Logistic regression models, adjusted for age, sex, and education, were performed to explore the association of biomarkers with cognitive status at different FI levels. Subjects with higher FI scores had lower CSF levels of Aβ 1-42 , hippocampus volumes at the MRI, and glucose metabolism at the FDG PET imaging, and a higher amyloid deposition at the 18 F-AV-45 PET. No significant differences were observed among the two frailty groups concerning ApoE genotype, CSF T-tau, and P-tau. Increasing frailty levels were associated with a weakened relationship between dementia and 18 F-AV-45 uptake and hippocampus volume and with a stronger relationship of dementia with FDG PET. Frailty contributes to the discrepancies between AD pathology and clinical manifestations and influences the association of AD pathological modifications with cognitive changes. AD and dementia should increasingly be conceived as “complex diseases of aging,” determined by multiple, simultaneous, and interacting pathophysiological processes.

Characterization of the plasma proteomic profile of frailty phenotype - Kristina Landino; Toshiko Tanaka; Giovanna Fantoni; Julián Candia; Stefania Bandinelli; Luigi Ferrucci (GeroScience, 2021)

Association between telomere length, frailty and death in older adults - Mariam El Assar; Javier Angulo; José A. Carnicero; Stefan Walter; Francisco J. García-García; Fernando Rodríguez-Artalejo; Leocadio Rodríguez-Mañas (GeroScience, 2021)

Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer’s disease in comparison with healthy aging - Maria Conte; Jacopo Sabbatinelli; Antonio Chiariello; Morena Martucci; Aurelia Santoro; Daniela Monti; Marina Arcaro; Daniela Galimberti; Elio Scarpini; Anna Rita Bonfigli; Angelica Giuliani; Fabiola Olivieri; et al. (GeroScience, 2021)
Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer’s disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian’ offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.

I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway - Foteini Vasilopoulou; Christian Griñán-Ferré; Sergio Rodríguez-Arévalo; Andrea Bagán; Sònia Abás; Carmen Escolano; Mercè Pallàs (GeroScience, 2021)

Late-onset depression is associated to age-related central auditory processing disorder in an older population in Southern Italy - Madia Lozupone; Rodolfo Sardone; Rossella Donghia; Francesca D’Urso; Carla Piccininni; Petronilla Battista; Ilaria Di Gioia; Emanuela Resta; Fabio Castellana; Luisa Lampignano; Roberta Zupo; Ilaria Bortone; et al. (GeroScience, 2021)

C60 in olive oil causes light-dependent toxicity and does not extend lifespan in mice - Kristopher J. Grohn; Brandon S. Moyer; Danique C. Wortel; Cheyanne M. Fisher; Ellie Lumen; Anthony H. Bianchi; Kathleen Kelly; Paul S. Campbell; Douglas E. Hagrman; Roger G. Bagg; James Clement; Aaron J. Wolfe; et al. (GeroScience, 2021)

High-resolution yeast quiescence profiling in human-like media reveals complex influences of auxotrophy and nutrient availability - Sean M. Santos; Samantha Laflin; Audrie Broadway; Cosby Burnet; Joline Hartheimer; John Rodgers; Daniel L. Smith; John L. Hartman (GeroScience, 2021)

Age-dependent modulation of bone metabolism in zebrafish scales as new model of male osteoporosis in lower vertebrates - Marta Carnovali; Giuseppe Banfi; Massimo Mariotti (GeroScience, 2021)
After middle age, in human bone, the resorption usually exceeds formation resulting in bone loss and increased risk of fractures in the aged population. Only few in vivo models in higher vertebrates are available for pathogenic and therapeutic studies about bone aging. Among these, male Danio rerio (zebrafish) can be successfully used as low vertebrate model to study degenerative alterations that affect the skeleton during aging, reducing the role of sex hormones. In this paper, we investigated the early bone aging mechanisms in male zebrafish (3, 6, 9 months old) scales evaluating the physiological changes and the effects of prednisolone, a pro-osteoporotic drug. The results evidentiated an age-dependent reduction of the mineralization rate in the fish scales, as highlighted by growing circle measurements. Indeed, the osteoblastic ALP activity at the matrix deposition site was found progressively downregulated. The higher TRAP activity was found in 63% of 9-month-old fish scales associated with resorption lacunae along the scale border. Gene expression analysis evidentiated that an increase of the tnfrsf1b (homolog of human rank ) in aging scales may be responsible for resorption stimulation. Interestingly, prednisolone inhibited the physiological growth of the scale and induced in aged scales a more significant bone resorption compared with untreated fish (3.8% vs 1.02%). Bone markers analysis shown a significant reduction of ALP/TRAP ratio due to a prednisolone-dependent stimulation of tnfsf11 (homolog of human rankl) in scales of older fish. The results evidentiated for the first time the presence of a senile male osteoporosis in lower vertebrate. This new model could be helpful to identify the early mechanisms of bone aging and new therapeutic strategies to prevent age-related bone alterations in humans.

The retention of fall-resisting behavior derived from treadmill slip-perturbation training in community-dwelling older adults - Xuan Liu; Tanvi Bhatt; Yiru Wang; Shuaijie Wang; Anna Lee; Yi-Chung Pai (GeroScience, 2021)

Protein signatures from blood plasma and urine suggest changes in vascular function and IL-12 signaling in elderly with a history of chronic diseases compared with an age-matched healthy cohort - Yanbao Yu; Harinder Singh; Keehwan Kwon; Tamara Tsitrin; Joann Petrini; Karen E. Nelson; Rembert Pieper (GeroScience, 2021)

Treatment with a DC-SIGN ligand reduces macrophage polarization and diastolic dysfunction in the aging female but not male mouse hearts - JoAnn Trial; Rodrigo Diaz Lankenau; Aude Angelini; Jorge E. Tovar Perez; George E. Taffet; Mark L. Entman; Katarzyna A. Cieslik (GeroScience, 2021)
Cardiac diastolic dysfunction in aging arises from increased ventricular stiffness caused by inflammation and interstitial fibrosis. The diastolic dysfunction contributes to heart failure with preserved ejection fraction (HFpEF), which in the aging population is more common in women. This report examines its progression over 12 weeks in aging C57BL/6J mice and correlates its development with changes in macrophage polarization and collagen deposition. Aged C57BL/6J mice were injected with dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) ligand 1 (DCSL1, an anti-inflammatory agent) or saline for 12 weeks. Echo and Doppler measurements were performed before and after 4 and 12 weeks of treatment. DCSL1 prevented the worsening of diastolic dysfunction over time in females but not in males. Cardiac single cell suspensions analyzed by flow cytometry revealed changes in the inflammatory infiltrate: (1) in males, there was an increased total number of leukocytes with an increased pro-inflammatory profile compared with females and they did not respond to DCSL1; (2) by contrast, DCSL1 treatment resulted in a shift in macrophage polarization to an anti-inflammatory phenotype in females. Notably, DCSL1 preferentially targeted tumor necrosis factor-α (TNFα + ) pro-inflammatory macrophages. The reduction in pro-inflammatory macrophage polarization was accompanied by a decrease in collagen content in the heart. Age-associated diastolic dysfunction in mice is more severe in females and is associated with unique changes in macrophage polarization in cardiac tissue. Treatment with DCSL1 mitigates the changes in inflammation, cardiac function, and fibrosis. The characteristics of diastolic dysfunction in aging female mice mimic similar changes in aging women.

Handgrip strength—a risk indicator for future fractures in the general population: findings from a prospective study and meta-analysis of 19 prospective cohort studies - Setor K. Kunutsor; Samuel Seidu; Ari Voutilainen; Ashley W. Blom; Jari A. Laukkanen (GeroScience, 2021)
Evolving debate suggests that handgrip strength, a measure of muscular strength, might be associated with the risk of fractures; however, the evidence is conflicting. We aimed to assess the association of handgrip strength with the risk of fracture in the general population. Handgrip strength, measured using a dynamometer, was assessed at baseline in a population-based sample of 853 men and women aged 61–73 years in the Kuopio Ischemic Heart Disease prospective cohort. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for incident fractures. Incident fractures (hip, humeral, or wrist) ( n = 159) occurred during a median follow-up of 16.7 years. Comparing extreme tertiles of handgrip strength, the age- and sex-adjusted hazard ratio (95% CI) for fractures was 0.80 (0.55–1.18). The association remained similar on further adjustment for other potential confounders: HR (95% CI) of 0.82 (0.55–1.21). In a meta-analysis of 19 population-based prospective cohort studies (including the current study) comprising 220,757 participants and 9199 fractures (including 1302 hip fractures), the fully adjusted relative risk (RR) (95% confidence interval, CI) for incident fractures was 0.70 (0.61–0.80) comparing the top versus bottom thirds of handgrip strength. The association remained significant after trim-and-fill correction for publication bias. The corresponding RR (95% CI) for hip fractures (9 studies) was 0.61 (0.54–0.70). Handgrip was only modestly associated with fracture risk in the primary analysis, which may be driven by the low event rate. Pooled prospective cohort evidence suggests that elevated handgrip strength is associated with reduced future fracture risk.

Ageing human bone marrow mesenchymal stem cells have depleted NAD(P)H and distinct multispectral autofluorescence - Jared M. Campbell; Saabah Mahbub; Abbas Habibalahi; Sharon Paton; Stan Gronthos; Ewa Goldys (GeroScience, 2021)

Mapping the multicausality of Alzheimer’s disease through group model building - Jeroen F. Uleman; René J. F. Melis; Rick Quax; Eddy A. van der Zee; Dick Thijssen; Martin Dresler; Ondine van de Rest; Isabelle F. van der Velpen; Hieab H. H. Adams; Ben Schmand; Inge M. C. M. de Kok; Jeroen de Bresser; et al. (GeroScience, 2021)
Alzheimer’s disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. In this work, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD. We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts. As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders. Furthermore, the CLD is the first step in the development of a computational model for simulating the effects of risk factors on AD.

N-terminal pro B-type natriuretic peptide (NT-proBNP): a possible surrogate of biological age in the elderly people - Antonio Muscari; Giampaolo Bianchi; Paola Forti; Donatella Magalotti; Paolo Pandolfi; Marco Zoli (GeroScience, 2021)
NT-proB-type natriuretic peptide (NT-proBNP) increases with age and is associated with all-cause mortality. With this study, we assessed its possible utilization as a marker of biological age in comparison with other variables. The study included 1079 non-institutionalized elderly subjects (mean age 72.8 ± 5.5 years, 561 women). Baseline measurements were performed of serum NT-proBNP and of some laboratory variables previously utilized to estimate biological age (creatinine, albumin, C-reactive protein, cholesterol, blood glucose, leukocytes, lymphocytes, hemoglobin, mean cell volume). During 7 years of follow-up, 114 all-cause deaths occurred. The logarithm of NT-proBNP was the most age-related parameter ( r = 0.35, P < 0.0001). Its relationship with mortality, according to Cox regression and ROC curve (AUC = 0.707, 95% CI 0.654–0.759), was stronger than that of all other variables, including age. In multivariate analysis, only NT-proBNP and age remained independently associated with mortality. The regression lines between age and NT-proBNP (pg/ml) allowed a separate estimation of biological age (“proBNPage”) for men (= [log(NT-proBNP) + 1.2068]/0.0827) and for women (= [log(NT-proBNP) − 1.5258]/0.0478). The hazard ratio of all-cause mortality for the fifth quintile of proBNP age (≥ 85 years) compared with the first quintile (< 61 years) was 7.9 (95% CI 3.6–17.5). Similarly, the difference between pro-BNPage and chronological age was associated with a hazard ratio of 3.5 in the fifth quintile (95% CI 1.9–6.4) and was associated with disease count ( P for trend = 0.0002). In conclusion, NT-proBNP was the best indicator of biological age, which can be estimated by simple formulas and might be used for prognostic purposes or as a surrogate end point in epidemiological and intervention studies.

Sex differences in changes of protein synthesis with rapamycin treatment are minimized when metformin is added to rapamycin - Christopher A. Wolff; Marcus M. Lawrence; Hunter Porter; Qian Zhang; Justin J. Reid; Jaime L. Laurin; Robert V. Musci; Melissa A. Linden; Frederick F. Peelor; Jonathan D. Wren; Joseph S. Creery; Kyle J. Cutler; et al. (GeroScience, 2021)

Hemiterpene compound, 3,3-dimethylallyl alcohol promotes longevity and neuroprotection in Caenorhabditis elegans - Suresh Chandra Phulara; Swapnil Pandey; Anubhuti Jha; Puneet Singh Chauhan; Pratima Gupta; Virendra Shukla (GeroScience, 2021)

Plasma exosomes characterization reveals a perioperative protein signature in older patients undergoing different types of on-pump cardiac surgery - Alessandro Carrozzo; Valentina Casieri; Dario Di Silvestre; Francesca Brambilla; Emanuele De Nitto; Nicola Sardaro; Gaia Papini; Simona Storti; Giuseppina Settanni; Marco Solinas; Pierluigi Mauri; Domenico Paparella; et al. (GeroScience, 2021)

5′-Hydroxy-6, 7, 8, 3′, 4′-pentamethoxyflavone extends longevity mediated by DR-induced autophagy and oxidative stress resistance in C. elegans - Shalini Trivedi; Rakesh Pandey (GeroScience, 2021)

Regular endurance exercise of overloaded muscle of young and old male mice does not attenuate hypertrophy and improves fatigue resistance - Paul William Hendrickse; Raulas Krusnauskas; Emma Hodson-Tole; Tomas Venckunas; Hans Degens (GeroScience, 2021)
It has been observed that there is an inverse relationship between fiber size and oxidative capacity due to oxygen, ADP, and ATP diffusion limitations. We aimed to see if regular endurance exercise alongside a hypertrophic stimulus would lead to compromised adaptations to both, particularly in older animals. Here we investigated the effects of combining overload with regular endurance exercise in young (12 months) and old (26 months) male mice. The plantaris muscles of these mice were overloaded through denervation of synergists to induce hypertrophy and the mice ran on a treadmill for 30 min per day for 6 weeks. The hypertrophic response to overload was not blunted by endurance exercise, and the increase in fatigue resistance with endurance exercise was not reduced by overload. Old mice demonstrated less hypertrophy than young mice, which was associated with impaired angiogenesis and a reduction in specific tension. The data of this study suggest that combining endurance exercise and overload induces the benefits of both types of exercise without compromising adaptations to either. Additionally, the attenuated hypertrophic response to overload in old animals may be due to a diminished capacity for capillary growth.

Current perspectives on the clinical implications of oxidative RNA damage in aging research: challenges and opportunities - Zhijie Xu; Jinzhou Huang; Ming Gao; Guijie Guo; Shuangshuang Zeng; Xi Chen; Xiang Wang; Zhicheng Gong; Yuanliang Yan (GeroScience, 2021)

Identification of biomarkers for physical frailty and sarcopenia through a new multi-marker approach: results from the BIOSPHERE study - Riccardo Calvani; Anna Picca; Federico Marini; Alessandra Biancolillo; Jacopo Gervasoni; Silvia Persichilli; Aniello Primiano; Hélio J. Coelho-Junior; Matteo Cesari; Maurizio Bossola; Andrea Urbani; Graziano Onder; et al. (GeroScience, 2021)

Age-related compositional changes and correlations of gut microbiome, serum metabolome, and immune factor in rats - Xia Zhang; Yuping Yang; Juan Su; Xiaojiao Zheng; Chongchong Wang; Shaoqiu Chen; Jiajian Liu; Yingfang Lv; Shihao Fan; Aihua Zhao; Tianlu Chen; Wei Jia; et al. (GeroScience, 2021)