Normal Aging
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2021 ◽  
Vol 12 ◽  
Magdalena Orzylowski ◽  
Esther Fujiwara ◽  
Darrell D. Mousseau ◽  
Glen B. Baker

Dementia, of which Alzheimer's disease (AD) is the most common form, is characterized by progressive cognitive deterioration, including profound memory loss, which affects functioning in many aspects of life. Although cognitive deterioration is relatively common in aging and aging is a risk factor for AD, the condition is not necessarily a part of the aging process. The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-Serine is necessary for activation of the NMDAR and in maintenance of long-term potentiation (LTP) and is involved in brain development, neuronal connectivity, synaptic plasticity and regulation of learning and memory. In this paper, we review evidence, from both preclinical and human studies, on the involvement of D-serine (and the enzymes involved in its metabolism) in regulation of cognition. Potential mechanisms of action of D-serine are discussed in the context of normal aging and in dementia, as is the potential for using D-serine as a potential biomarker and/or therapeutic agent in dementia. Although there is some controversy in the literature, it has been proposed that in normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.

Cell Stress ◽  
2021 ◽  
Vol 5 (10) ◽  
pp. 146-166
Emmanouela Kallergi ◽  
Vassiliki Nikoletopoulou

Aging represents a cumulative form of cellular stress, which is thought to challenge many aspects of proteostasis. The non-dividing, long-lived neurons are particularly vulnerable to stress, and, not sur-prisingly, even normal aging is highly associated with a decline in brain function in humans, as well as in other animals. Macroautophagy is a fundamental arm of the proteostasis network, safeguarding proper protein turnover during different cellular states and against diverse cellular stressors. An intricate interplay between macroautophagy and aging is beginning to unravel, with the emergence of new tools, including those for monitoring autophagy in cultured neurons and in the nervous system of different organisms in vivo. Here, we review recent findings on the impact of aging on neuronal integrity and on neuronal macroautophagy, as they emerge from studies in inverte-brate and mammalian models.

2021 ◽  
Sophia I Thomopoulos ◽  
Talia M Nir ◽  
Julio E Villalon-Reina ◽  
Artemis Zavaliangos-Petropulu ◽  
Piyush Maiti ◽  

Diffusion-weighted magnetic resonance imaging (dMRI) is sensitive to microstructural changes in the brain that occur with normal aging and Alzheimer's disease (AD). There is much interest in which dMRI measures are most strongly correlated with clinical measures of AD severity, such as the clinical dementia rating (CDR), and biological processes that may be disrupted in AD, such as brain amyloid load measured using PET. Of these processes, some can be targeted using novel drugs. Since 2016, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has collected dMRI data from three scanner manufacturers across 58 sites using 7 different protocols that vary in angular resolution, scan duration, and in the number and distribution of diffusion-weighted gradients. Here, we assessed dMRI data from 730 of those individuals (447 cognitively normal controls, 214 with mild cognitive impairment, 69 with dementia; age: 74.1±7.9 years; 381 female/349 male). To harmonize data from different protocols, we applied ComBat, ComBat-GAM, and CovBat to dMRI metrics from 28 white matter regions of interest. We ranked all dMRI metrics in order of the strength of clinically relevant associations, and assessed how this depended on the harmonization methods employed. dMRI metrics were associated with age and clinical impairment, but also with amyloid positivity. All harmonization methods gave comparable results while enabling data integration across multiple scanners and protocols.

2021 ◽  
Vol 15 ◽  
Daniela Marín-Pardo ◽  
Lydia Giménez-Llort

The temporal course and the severity of the involution of sensory systems through aging can be critical since they ensure the ability to perceive and recognize the world. In older people, sensory impairments significantly increase their risk of biological, psychological, and social impoverishment. Besides this, olfactory loss is considered an early biomarker in Alzheimer’s disease (AD) neurodegenerative process. Here we studied olfactory ethograms in middle-aged male and female gold-standard C57BL/6 mice and 3xTg-AD mice, a genetic model of AD that presents cognitive dysfunction and a conspicuous neuropsychiatric-like phenotype. A paradigm involving 1-day food deprivation was used to investigate the ethological patterns shown in the olfactory inspection of a new cage and the sniffing, finding, and eating of hidden food pellets. The sniffing–find–eat temporal patterns were independent of the loss of weight and unveiled (fast) olfactory signatures in Alzheimer’s disease, differing from those (slow progressive) in normal aging. Male 3xTg-AD mice exhibited an early signature than female mice, opposite to animals with normal aging. The sequence of actions was correlated in male and female 3xTg-AD mice in contrast to control mice. Social isolation, naturally occurring in male 3xTg-AD due to the death of cage mates, emphasized their olfactory patterns and disrupted the behavioral correlates. The paradigm provided distinct contextual, sex, and genotype olfactory ethogram signatures useful to investigate olfactory function in normal and AD-pathological aging. Isolation had an impact on enhancing the changes in the olfactory signature here described, for the first time, in the 3xTg-AD model of Alzheimer’s disease.

Nature Aging ◽  
2021 ◽  
Vol 1 (10) ◽  
pp. 919-931
Alberto Serrano-Pozo ◽  
Zhaozhi Li ◽  
Ayush Noori ◽  
Huong N. Nguyen ◽  
Aziz Mezlini ◽  

Caitlin Fowler ◽  
Dana Goerzen ◽  
Dan Madularu ◽  
Gabriel A. Devenyi ◽  
M. Mallar Chakravarty ◽  

2021 ◽  
Vol 18 ◽  
François R. Herrmann ◽  
Marie-Louise Montandon ◽  
Valentina Garibotto ◽  
Cristelle Rodriguez ◽  
Sven Haller ◽  

Background: The determinants of the progressive decrement of cognition in normal aging are still a matter of debate. Alzheimer disease (AD)-signature markers and vascular lesions, but also psychological variables such as personality factors, are thought to have an impact on the longitudinal trajectories of neuropsychological performances in healthy elderly individuals. Objective: The current research aimed to identify the main determinants associated with cognitive trajectories in normal aging. Methods: We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, medial temporal atrophy (MTA), number of cerebral mi- crobleeds (CMB), and white matter hyperintensities (WMH) at inclusion, visual rating of amyloid and FDG PET at follow-up, and APOE genotyping. Personality factors were assessed at baseline using the NEO-PI-R. Univariate and backward stepwise regression models were built to explore the association between the continuous cognitive score (CCS) and both imaging and personality variables. Results: The number of strictly lobar CMB at baseline (4 or more) was related to a significant in- crease in the risk of cognitive decrement. In multivariable models, amyloid positivity was associat- ed with a 1.73 unit decrease of the CCS at follow-up. MTA, WMH and abnormal FDG PET were not related to the cognitive outcome. Among personality factors, only higher agreeableness was re- lated to better preservation of neuropsychological performances. Conclusion: CMB and amyloid positivity are the only imaging determinants of cognitive trajecto- ries in this highly selected series of healthy controls. Among personality factors, higher agreeable- ness confers a modest but significant protection against the decline of cognitive performances.

eNeuro ◽  
2021 ◽  
pp. ENEURO.0527-20.2021
Guneet Bindra ◽  
Rylee Brower ◽  
Ryan North ◽  
Weiwei Zhou ◽  
Wilsaan M. Joiner

Diseases ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 67
Cassandra Millet-Boureima ◽  
Caroline C. Ennis ◽  
Jurnee Jamison ◽  
Shana McSweeney ◽  
Anna Park ◽  

Melatonin functions as a central regulator of cell and organismal function as well as a neurohormone involved in several processes, e.g., the regulation of the circadian rhythm, sleep, aging, oxidative response, and more. As such, it holds immense pharmacological potential. Receptor-mediated melatonin function mainly occurs through MT1 and MT2, conserved amongst mammals. Other melatonin-binding proteins exist. Non-receptor-mediated activities involve regulating the mitochondrial function and antioxidant cascade, which are frequently affected by normal aging as well as disease. Several pathologies display diseased or dysfunctional mitochondria, suggesting melatonin may be used therapeutically. Drosophila models have extensively been employed to study disease pathogenesis and discover new drugs. Here, we review the multiple functions of melatonin through the lens of functional conservation and model organism research to empower potential melatonin therapeutics to treat neurodegenerative and renal diseases.

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