Aging
Abstract
Background. Neuronal hyper-excitability characterizes the early stages of Alzheimer’s disease (AD). In animals, early misfolded tau and amyloid-beta (Aβ) protein accumulation, both central to AD neuropathology, promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau, and its associated neuroinflammation, and cortical Aβ aggregations remains unknown. Methods. We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late middle-aged individuals (50-69 y; 45 women). We assessed whole-brain [18F]THK5351 positron emission tomography (PET) uptake as a proxy measure of tau/neuroinflammation, and whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers. Results. We find that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment is associated with increased cortical excitability (r = .29, p = .02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (pFWE-corrected < .001), was not significantly associated with cortical excitability (r = .14, p = .25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = -.20, p = .11). Conclusion. These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans. Trial registration. EudraCT 2016-001436-35. Funding. F.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.
Authors
Maxime Van Egroo, Daphne O. Chylinski, Justinas Narbutas, Gabriel Besson, Vincenzo Muto, Christina Schmidt, Davide Marzoli, Paolo Cardone, Nora Vandeleene, Martin Grignard, André Luxen, Eric Salmon, Christian Lambert, Christine Bastin, Fabienne Collette, Christophe Phillips, Pierre Maquet, Mohamed Ali Bahri, Evelyne Balteau, Gilles Vandewalle
Abstract
Cardiac fibrosis is a pathophysiologic hallmark of the aging heart. In the uninjured heart, cardiac fibroblasts exist in the quiescent state, but little is known about how proliferation rates and fibroblast transcriptional programs change throughout the lifespan of the organism from the immediate postnatal period to adult life and old age. Using EdU pulse labeling, we demonstrate that more than 50% of cardiac fibroblasts are actively proliferating in the first day of post-natal life. However, within 4 weeks of birth in the juvenile animal, only 10% of cardiac fibroblasts are proliferating. By early adulthood, the fraction of proliferating cardiac fibroblasts further decreases to approximately 2%, where it so remains throughout the rest of the organism’s life span. Examination of absolute cardiac fibroblast numbers demonstrated concordance with age related changes in fibroblast proliferation with no significant differences in absolute cardiac fibroblast numbers between animals 14 weeks and 1.5 years of age. We demonstrate that the maximal changes in cardiac fibroblast transcriptional programs and in particular collagen expression occur within the first weeks of life from the immediate postnatal to the juvenile period. We show that even though the aging heart exhibits an increase in the total amount of accumulated collagen, transcription of various collagens and ECM genes both in the heart and cardiac fibroblast is maximal in the newly born and juvenile animal and decreases with organismal aging. Examination of DNA methylation changes both in the heart and in cardiac fibroblasts did not demonstrate significant changes in differentially methylated regions between young and old mice. Our observations demonstrate that cardiac fibroblasts attain a stable proliferation rate and transcriptional program early in the life span of the organism and suggest a model of cardiac aging where phenotypic changes in the aging heart are not directly attributable to changes in proliferation rate or altered collagen expression in cardiac fibroblasts.
Authors
Rimao Wu, Feiyang Ma, Anela Tosevska, Colin Farrell, Matteo Pellegrini, Arjun Deb
Abstract
Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e. slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
Authors
Richard A. Miller, David E. Harrison, David B. Allison, Molly A. Bogue, Lucas K. Debarba, Vivian Diaz, Elizabeth Fernandez, Andrzej T. Galecki, W. Timothy Garvey, Hashan Jayarathne, Navasuja Kumar, Martin Javors, Warren Ladiges, Francesca Macchiarini, James F. Nelson, Peter C. Reifsnyder, Nadia Rosenthal, Marianna Sadagurski, Adam B. Salmon, Daniel L. Smith, Jr., Jessica M. Snyder, David B. Lombard, Randy Strong
Abstract
With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat Type 2 diabetes (T2DM) can extend mouse lifespan, with greater effect in males than in females. Utilizing a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological and biochemical changes that occur during aging, and determined which of the effects of age and drug were sex-dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids – changes which have previously been associated with aging, cardiac dysfunction and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging anti-aging effects in multiple tissues, and may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.
Authors
Jonathan J Herrera, Sean Louzon, Kaitlyn Pifer, Danielle Leander, Gennifer E. Merrihew, Jea H. Park, Kate Szczesniak, Jeremy A. Whitson, John E. Wilkinson, Oliver Fiehn, Michael J. MacCoss, Sharlene M. Day, Richard A. Miller, Michael Garratt
Abstract
Background: Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies, but their presence or link to EI in the frail older adult is unknown. Methods: Three groups of ambulatory, community-dwelling adults with no history of significant coronary disease were studied: frail, older individuals (FO, 81±2.7 years, mean±SEM), non-frail, older individuals (NFO, 79±2.0 years), and healthy middle-aged controls (CONT, 51±2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded, multistage plantar flexion exercise (PFE). EI was quantified by six-minute walk and peak oxygen consumption during cardiopulmonary testing (peak-VO2). Results: During graded exercise, frail older (FO), non-frail older (NFO), and healthy middle-aged individuals all fatigued at similar SM HEP levels measured by 31P MR. However, FO fatigued fastest with several-fold higher rates of PFE-induced HEP decline, which correlated closely with shorter exercise duration in the MR scanner and with six-minute walk distance and lower peak oxygen consumption on cardiopulmonary testing (p<0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI. Conclusions: Several-fold faster skeletal muscle energetic decline during exercise occurs in frail older individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.
Authors
Sabra C. Lewsey, Kilian Weiss, Michael Schär, Yi Zhang, Paul A. Bottomley, T. Jake Samuel, Qian-Li Xue, Angela Steinberg, Jeremy Walston, Gary Gerstenblith, Robert G. Weiss
Abstract
In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) for 6 weeks or vehicle. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria and increases in uro-damaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural and physiological abnormalities toward that of a younger state. 8-AG, is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uro-protective effects of 8-AG are mediated by increased bladder levels of uro-protective inosine and guanosine and reductions in uro-damaging hypoxanthine and xanthine. These findings demonstrate 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.
Authors
Lori A. Birder, Amanda Wolf-Johnston, Alan J. Wein, Fangzhou Cheng, Mara Grove-Sullivan, Anthony J. Kanai, Alan M. Watson, Donna Stolz, Simon C. Watkins, Anne M. Robertson, Diane Newman, Roger R. Dmochowski, Edwin K. Jackson
Abstract
Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.
Authors
Reyhan Westbrook, Tae Chung, Jacqueline Lovett, Chris Ward, Humberto Joca, Huanle Yang, Mohammed Khadeer, Jing Tian, Qian-Li Xue, Anne Le, Luigi Ferrucci, Ruin Moaddel, Rafa de Cabo, Ahmet Hoke, Jeremy Walston, Peter M. Abadir
Abstract
Age-associated systemic, chronic inflammation is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can partially rescue age-related thymic involution. Given the findings that TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected naturally young TECs can lead to middle-aged thymus regrowth, we attempted to extend these two findings by combining them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated FOXN1-reprogrammed embryonic fibroblasts (FREFs). We engrafted these two-types of FREFs directly into the aged murine thymus. We found significant regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and auto-reactive T cell-mediated inflammation in old mice. Therefore, this strategy has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to significantly, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in the elderly.
Authors
Jiyoung Oh, Weikan Wang, Rachel Thomas, Dong-Ming Su
Abstract
Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20–90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60–90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.
Authors
Marissa J. Schafer, Xu Zhang, Amanika Kumar, Elizabeth J. Atkinson, Yi Zhu, Sarah Jachim, Daniel L. Mazula, Ashley K. Brown, Michelle Berning, Zaira Aversa, Brian Kotajarvi, Charles J. Bruce, Kevin L. Greason, Rakesh M. Suri, Russell P. Tracy, Steven R. Cummings, Thomas A. White, Nathan K. LeBrasseur
Abstract
Tissue regeneration capacity declines with aging in association with heightened oxidative stress. Expression of the oxidant-generating enzyme, NADPH oxidase 4 (Nox4) is elevated in aged mice with diminished capacity for fibrosis resolution. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal (BET) family of proteins that function as epigenetic “readers” of acetylated lysine groups on histones. In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4, and the in-vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. BET inhibition interferes with the association of Brd4, p300, and acetylated histone H4K16 with the Nox4 promoter in lung fibroblasts stimulated with the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-β1). This Brd4-Nox4 epigenetic axis is constitutively upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. A number of BET inhibitors, including I-BET-762, JQ1, and OTX015, downregulate Nox4 gene expression and activity. Aged mice with established and persistent lung fibrosis recovered capacity for fibrosis resolution with OTX015 treatment. This study implicates epigenetic regulation of Nox4 by Brd4 and p300, and supports BET/Brd4 inhibition as an effective strategy for the treatment of age-related fibrotic lung disease.
Authors
Yan Y. Sanders, Xing Lyu, Q. Jennifer Zhou, Zheyi Xiang, Denise Stanford, Sandeep Bodduluri, Steven M. Rowe, Victor J. Thannickal
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