Brain aging-dependent glioma traits reversible by NAD+/BDNF-mediated neuronal reactivation

SummaryThe rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD+) with aging, as old mice exposed to young blood via parabiosis or supplemented with the NAD+ precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF+/- young mice and in BDNF+/- mice undergoing tumor challenge, supporting the notion that the lower NAD+-BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD+ worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.

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TAMI-39. AGE-DEPENDENT PHENOTYPIC CONVERSION FROM NEURONAL ACTIVITY TO NEURO-INFLAMMATION IN GLIOBLASTOMA PROGRESSION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.927 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii221-ii221

Author(s):

Daisuke Yamashita ◽

Victoria Flanary ◽

Rachel Munk ◽

Kazuhiro Sonomura ◽

Saya Ozaki ◽

...

Keyword(s):

Population Aging ◽

Survival Rates ◽

The Elderly ◽

Synaptic Activity ◽

Synaptic Signaling ◽

Nicotinamide Mononucleotide ◽

Improved Outcomes ◽

Age Dependent ◽

Neuro Inflammation ◽

The Impact

Abstract The rise in population aging worldwide is causing an unparalleled increase in death from many cancers, including glioblastoma (GBM). Here, we have explored the impact of aging and rejuvenation on GBM tumorigenesis. Compared with neuro-inflammatory old GBM, young GBM displayed elevated neuronal/synaptic signaling via brain-derived neurotrophic factor (BDNF) and SLIT and NTRK like-family member 6 (SLITRK6), promoting favorable survival rates. These effects were attributed to the rise in nicotinamide adenine dinucleotide (NAD+) levels, as brain rejuvenation by parabiosis or administration of nicotinamide mononucleotide (NMN) in mice elicited a younger phenotype with activated neuronal/synaptic signaling and improved outcomes. Our data indicate that age-associated NAD+ loss contributes to the highly aggressive GBM by the shift from neuronal/synaptic activity to neuro-inflammation in the elderly brain. These findings have therapeutic and preventive implications in GBM and provide mechanistic insights into the exacerbation of GBM tumorigenesis by aging.

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Aspirin treatment does not increase microhemorrhage size in young or aged mice

10.1101/411710 ◽

2018 ◽

Author(s):

Sandy Chan ◽

Morgan Brophy ◽

Nozomi Nishimura ◽

Chris B. Schaffer

Keyword(s):

Femtosecond Laser Ablation ◽

Surrounding Tissue ◽

Aging Brain ◽

Older Individuals ◽

Aged Mice ◽

Intravenous Heparin ◽

The Impact ◽

Old Mice ◽

The Brain ◽

Vessel Rupture

AbstractMicrohemorrhages are common in the aging brain and are thought to contribute to cognitive decline and the development of neurodegenerative diseases, such as Alzheimer’s disease. Chronic aspirin therapy is widespread in older individuals and decreases the risk of coronary artery occlusions and stroke. There remains a concern that such aspirin usage may prolong bleeding after a vessel rupture in the brain, leading to larger bleeds that cause more damage to the surrounding tissue. Here, we aimed to understand the influence of aspirin usage on the size of cortical microhemorrhages and explored the impact of age. We used femtosecond laser ablation to rupture arterioles in the cortex of both young (2-5 months old) and aged (18-29 months old) mice dosed on aspirin in their drinking water and measured the extent of penetration of both red blood cells and blood plasma into the surrounding tissue. We found no difference in microhemorrhage size for both young and aged mice dosed on aspirin, as compared to controls (hematoma diameter = 104 +/- 39 (97 +/- 38) μm in controls and 109 +/- 25 (101 +/- 28) μm in aspirin-treated young (aged) mice; mean +/- SD). In contrast, young mice treated with intravenous heparin had an increased hematoma diameter of 136 +/- 44 μm. These data suggest that aspirin does not increase the size of microhemorrhages, supporting the safety of aspirin usage.

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Diet modulates brain network stability, a biomarker for brain aging, in young adults

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1913042117 ◽

2020 ◽

Vol 117 (11) ◽

pp. 6170-6177 ◽

Cited By ~ 12

Author(s):

Lilianne R. Mujica-Parodi ◽

Anar Amgalan ◽

Syed Fahad Sultan ◽

Botond Antal ◽

Xiaofei Sun ◽

...

Keyword(s):

Ketogenic Diet ◽

Large Scale ◽

Brain Aging ◽

Brain Network ◽

Detection Sensitivity ◽

Aging Brain ◽

Standard Diet ◽

Network Stability ◽

The Impact ◽

Ketone Ester

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n= 292, ages 20 to 85 y;n= 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

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Social isolation and the aging brain. Social isolation is linked to declining grey matter structure and cognitive functions in the LIFE-Adult panel study

10.1101/2021.12.14.21267787 ◽

2021 ◽

Author(s):

Laurenz Lammer ◽

Frauke Beyer ◽

Melanie Luppa ◽

Christian Sander ◽

Ronny Baber ◽

...

Keyword(s):

Social Isolation ◽

Cortical Thickness ◽

Cognitive Functions ◽

Grey Matter ◽

Brain Aging ◽

Panel Study ◽

Hippocampal Volume ◽

Cortical Atrophy ◽

Aging Brain ◽

The Impact

Background Social isolation is a risk factor for dementia, a devastating disease with a rapidly growing global prevalence. However, the link between social isolation and changes in brain structure and function is poorly understood, as studies are scarce in number, methodologically inconsistent and small in size. In this pre-registered analysis of a large population-based panel study, we aimed to determine the impact of social isolation on brain structures and cognitive functions central to age associated decline and dementia. Methods and findings We analysed data of 1992 cognitively healthy participants of the LIFE-Adult study at baseline (age range: 50-82 years) and of 1409 particpants at follow-up (average change in age: 5.89 years). We measured social isolation using the 30-point Lubben Social Network Scale (LSNS) and derived measures of grey matter structure from anatomical 3T MRIs. We employed covariate adjusted linear mixed models to test the associations of baseline social isolation and change in social isolation with hippocampal volume, cognitive functions (executive functions, memory, processing speed) and cortical thickness. We found stronger baseline social isolation to be significantly associated with smaller hippocampal volumes (β = −5.5 mm3/LSNS point(pt), FDR q = 0.004, BF = 14.6) and lower cognitive functions (all β < −0.014 SD/pt, FDR q < 0.003, BF > 49). Increases in social isolation over time were linked to hippocampal volume decline (β = −4.9 mm3/pt, FDR q = 0.01, BF = 2.9) and worse memory performance (β = −0.013 SD/pt, FDR q = 0.04, BF = 1.1). Furthermore, we detected a significant interaction of baseline social isolation with change in age on hippocampal volume (β = −0.556 mm3/pt*a, q = 0.04, BF = 0.5), indicating accelerated brain aging in more isolated individuals. Moreover, social isolation cross-sectionally and longitudinally correlated with lower cortical thickness in multiple clusters in the orbitofrontal cortex, precuneus and other areas (FDR q < 0.05). Conclusions Here, we provide evidence that social isolation contributes to hippocampal and cortical atrophy and subtle cognitive decline in non-demented mid- to late-life adults. Importantly, within-subject effects of social isolation were similar to between-subject effects, indicating an opportunity for targeting social isolation to reduce dementia risk.

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The Oxford Handbook of Adult Cognitive Disorders

10.1093/oxfordhb/9780190664121.001.0001 ◽

2019 ◽

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

Neurodevelopmental Disorders ◽

Brain Aging ◽

Cognitive Disorders ◽

Diverse Range ◽

Medical Specialties ◽

Psychiatric Illnesses ◽

Medical Disorders ◽

The Impact

The prevalence of cognitive impairment caused by neurodegenerative diseases and other neurologic disorders associated with aging is expected to rise dramatically between now and year 2050, when the population of Americans aged 65 or older will nearly double. Cognitive impairment also commonly occurs in other neurologic conditions, as well as in non-neurologic medical disorders (and their treatments), idiopathic psychiatric illnesses, and adult neurodevelopmental disorders. Cognitive impairment can thus infiltrate all aspects of healthcare, making it necessary for clinicians and clinical researchers to have an integrated knowledge of the spectrum of adult cognitive disorders. The Oxford Handbook of Adult Cognitive Disorders is meant to serve as an up-to-date, scholarly, and comprehensive volume covering most diseases, conditions, and injuries resulting in impairments in cognitive function in adults. Topics covered include normal cognitive and brain aging, the impact of medical disorders (e.g., cardiovascular, liver, pulmonary) and psychiatric illnesses (e.g., depression and bipolar disorder) on cognitive function, adult neurodevelopmental disorders (e.g., Down Syndrome, Attention Deficit/Hyperactivity Disorder), as well as the various neurological conditions (e.g., Alzheimer’s disease, chronic traumatic encephalopathy, concussion). A section of the Handbook is also dedicated to unique perspectives and special considerations for the clinicians and clinical researchers, covering topics such as cognitive reserve, genetics, diversity, and neuroethics. The target audience of this Handbook includes: (1) clinicians, particularly psychologists, neuropsychologists, neurologists (including behavioral and cognitive neurologists), geriatricians, and psychiatrists (including neuropsychiatrists), who provide clinical care and management for adults with a diverse range of cognitive disorders; (2) clinical researchers who investigate cognitive outcomes and functioning in adult populations; and (3) graduate level students and post-doctoral trainees studying psychology, clinical neuroscience, and various medical specialties.

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Chromosome Instability, Aging and Brain Diseases

Cells ◽

10.3390/cells10051256 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1256

Author(s):

Ivan Y. Iourov ◽

Yuri B. Yurov ◽

Svetlana G. Vorsanova ◽

Sergei I. Kutsev

Keyword(s):

Brain Aging ◽

Chromosome Instability ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Accelerated Aging ◽

Brain Diseases ◽

Aging Brain ◽

Ontogenetic Changes ◽

Health And Disease

Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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Impact of pretreatment anemia on upfront abiraterone acetate therapy for metastatic hormone-sensitive prostate cancer: a multicenter retrospective study

BMC Cancer ◽

10.1186/s12885-021-08206-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Teppei Okamoto ◽

Daisuke Noro ◽

Shingo Hatakeyama ◽

Shintaro Narita ◽

Koji Mitsuzuka ◽

...

Keyword(s):

Prostate Cancer ◽

Prognostic Factor ◽

Abiraterone Acetate ◽

Tumor Burden ◽

Hazard Ratio ◽

Historical Cohort ◽

High Tumor Burden ◽

Significant Difference ◽

Hormone Sensitive ◽

The Impact

Abstract Background Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC. Methods We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019). Results We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia. Conclusion Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.

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Impact of aging on gene expression response to x-ray irradiation using mouse blood

Scientific Reports ◽

10.1038/s41598-021-89682-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Constantinos G. Broustas ◽

Axel J. Duval ◽

Sally A. Amundson

Keyword(s):

Gene Expression ◽

Differentially Expressed Genes ◽

Differentially Expressed ◽

X Rays ◽

Gene Expression Response ◽

X Ray ◽

The Impact ◽

Old Mice ◽

Radiation Biodosimetry ◽

Young Mice

AbstractAs a radiation biodosimetry tool, gene expression profiling is being developed using mouse and human peripheral blood models. The impact of dose, dose-rate, and radiation quality has been studied with the goal of predicting radiological tissue injury. In this study, we determined the impact of aging on the gene expression profile of blood from mice exposed to radiation. Young (2 mo) and old (21 mo) male mice were irradiated with 4 Gy x-rays, total RNA was isolated from whole blood 24 h later, and subjected to whole genome microarray analysis. Pathway analysis of differentially expressed genes revealed young mice responded to x-ray exposure by significantly upregulating pathways involved in apoptosis and phagocytosis, a process that eliminates apoptotic cells and preserves tissue homeostasis. In contrast, the functional annotation of senescence was overrepresented among differentially expressed genes from irradiated old mice without enrichment of phagocytosis pathways. Pathways associated with hematologic malignancies were enriched in irradiated old mice compared with irradiated young mice. The fibroblast growth factor signaling pathway was underrepresented in older mice under basal conditions. Similarly, brain-related functions were underrepresented in unirradiated old mice. Thus, age-dependent gene expression differences should be considered when developing gene signatures for use in radiation biodosimetry.

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Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

Science Advances ◽

10.1126/sciadv.abe4601 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabe4601

Author(s):

Sandro Da Mesquita ◽

Jasmin Herz ◽

Morgan Wall ◽

Taitea Dykstra ◽

Kalil Alves de Lima ◽

...

Keyword(s):

T Cells ◽

Cognitive Decline ◽

Brain Aging ◽

Therapeutic Potential ◽

T Cell Response ◽

Age Related ◽

Lymphatic Vasculature ◽

Amyloid Aβ ◽

Β Amyloid ◽

Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

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Aging Brain, Aging Mind

Scientific American ◽

10.1038/scientificamerican0992-134 ◽

1992 ◽

Vol 267 (3) ◽

pp. 134-142 ◽

Cited By ~ 56

Author(s):

Dennis J. Selkoe

Keyword(s):

Brain Aging ◽

Aging Brain

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