Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain.

Is it possible to enhance neural and cognitive function with cognitive training techniques? Can we delay age-related decline in cognitive function with interventions and stave off Alzheimer's disease? Does an aged brain really have the capacity to change in response to stimulation? In the present paper, we consider the neuroplasticity of the aging brain, that is, the brain's ability to increase capacity in response to sustained experience. We argue that, although there is some neural deterioration that occurs with age, the brain has the capacity to increase neural activity and develop neural scaffolding to regulate cognitive function. We suggest that increase in neural volume in response to cognitive training or experience is a clear indicator of change, but that changes in activation in response to cognitive training may be evidence of strategy change rather than indicative of neural plasticity. We note that the effect of cognitive training is surprisingly durable over time, but that the evidence that training effects transfer to other cognitive domains is relatively limited. We review evidence which suggests that engagement in an environment that requires sustained cognitive effort may facilitate cognitive function.

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Exercise Impacts Age-Related Changes in Cognitive Function and Neural Complexity

Kinesiology Review ◽

10.1123/kr.2015-0050 ◽

2016 ◽

Vol 5 (1) ◽

pp. 30-38 ◽

Cited By ~ 1

Author(s):

Jennifer J. Heisz ◽

Ana Kovacevic

Keyword(s):

Older Adults ◽

Cognitive Function ◽

Executive Functions ◽

Cognitive Outcomes ◽

Physically Active ◽

Age Related ◽

The Neural Network ◽

Future Work ◽

The Brain ◽

Age Related Changes

Age-related changes in the brain can compromise cognitive function. However, in some cases, the brain is able to functionally reorganize to compensate for some of this loss. The present paper reviews the benefits of exercise on executive functions in older adults and discusses a potential mechanism through which exercise may change the way the brain processes information for better cognitive outcomes. Specifically, older adults who are more physically active demonstrate a shift toward local neural processing that is associated with better executive functions. We discuss the use of neural complexity as a sensitive measure of the neural network plasticity that is enhanced through exercise. We conclude by highlighting the future work needed to improve exercise prescriptions that help older adults maintain their cognitive and physical functions for longer into their lifespan.

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Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

Molecular Neurobiology ◽

10.1007/s12035-019-01821-4 ◽

2019 ◽

Vol 57 (3) ◽

pp. 1317-1331 ◽

Cited By ~ 2

Author(s):

Gavin Pharaoh ◽

Daniel Owen ◽

Alexander Yeganeh ◽

Pavithra Premkumar ◽

Julie Farley ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Function ◽

Spatial Learning ◽

Mitochondrial Function ◽

Coupling Efficiency ◽

Redox Status ◽

Cellular Aging ◽

Age Related ◽

The Brain ◽

Circulating Levels

AbstractAge-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.

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Protein damage, ageing and age-related diseases

Open Biology ◽

10.1098/rsob.180249 ◽

2019 ◽

Vol 9 (3) ◽

pp. 180249 ◽

Cited By ~ 16

Author(s):

Anita Krisko ◽

Miroslav Radman

Keyword(s):

Oxidative Damage ◽

Protein Damage ◽

Death Studies ◽

Root Cause ◽

Age Related ◽

Oxidative Protein Damage ◽

Gompertz Law ◽

Radiation Induced ◽

Folded Proteins

Ageing is considered as a snowballing phenotype of the accumulation of damaged dysfunctional or toxic proteins and silent mutations (polymorphisms) that sensitize relevant proteins to oxidative damage as inborn predispositions to age-related diseases. Ageing is not a disease, but it causes (or shares common cause with) age-related diseases as suggested by similar slopes of age-related increase in the incidence of diseases and death. Studies of robust and more standard species revealed that dysfunctional oxidatively damaged proteins are the root cause of radiation-induced morbidity and mortality. Oxidized proteins accumulate with age and cause reversible ageing-like phenotypes with some irreversible consequences (e.g. mutations). Here, we observe in yeast that aggregation rate of damaged proteins follows the Gompertz law of mortality and review arguments for a causal relationship between oxidative protein damage, ageing and disease. Aerobes evolved proteomes remarkably resistant to oxidative damage, but imperfectly folded proteins become sensitive to oxidation. We show that α-synuclein mutations that predispose to early-onset Parkinson's disease bestow an increased intrinsic sensitivity of α-synuclein to in vitro oxidation. Considering how initially silent protein polymorphism becomes phenotypic while causing age-related diseases and how protein damage leads to genome alterations inspires a vision of predictive diagnostic, prognostic, prevention and treatment of degenerative diseases.

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CORRELATION OF MORNING SALIVARY CORTISOL-MELATONIN RATIO WITH QEEG AND DELAYED RECALL IN AGING

Acta Neuropsychologica ◽

10.5604/01.3001.0012.1971 ◽

2018 ◽

Vol 16 (2) ◽

pp. 177-188

Author(s):

Watchara Sroykham ◽

Yodchanan Wongsawat

Keyword(s):

Circadian Rhythm ◽

Cognitive Function ◽

Temporal Lobe ◽

Brain Activity ◽

High Ratio ◽

Left Temporal Lobe ◽

Delayed Recall ◽

Age Related ◽

Eyes Open ◽

The Brain

Melatonin and cortisol are the main hormones of the circadian rhythm, which effect cognitive decline during aging. An imbalance of circadian rhythm hormones serves as an early sign of the progress of age-related disease and brain pathology in aging. The aim of this study was to determine the cortisol-melatonin ratio in relation to brain activity and cognitive function in aging. Sixty-four aging subjects were recruited from the brain healthy project. The morning salivary of all subjects was collected for cortisol and melatonin levels analysis. The brain activity was recorded for 5 minutes in the eyes open condition and seven cognitive functions were assessed by the MoCA. The results were divided into a low ratio group and a high ratio group of cortisol-melatonin ratio. The low ratio group and the high ratio group differed in the delta-beta ratio at the left temporal lope (p < .05), and the delayed recall in the high ratio group was markedly higher than in the low ratio group. Moreover, the cortisol-melatonin ratio was strongly correlated with delayed recall (p < .05), the delta-beta ratio in the left temporal lope (p <.05), the theta alpha ratio in the left temporal lope (p < .05), and right temporal lope (p < .05). We found that a low cortisol-melatonin ratio corresponded to a high delta-beta ratio and a high thetaalpha ratio at the left temporal lobe with a low score of delayed recall function, but a high cortisol-melatonin ratio corresponded to a low delta-beta ratio and a low theta-alpha ratio at the left temporal lobe with a high score of delayed recall. The imbalance of the circadian hormone related to cognitive function and brain activity in aging could serve as a biomarker of age-related diseases.

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Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice

The Journal of Lipid Research ◽

10.1194/jlr.ra119000479 ◽

2020 ◽

Vol 61 (10) ◽

pp. 1308-1319

Author(s):

Eileen E. Parks ◽

Sreemathi Logan ◽

Alexander Yeganeh ◽

Julie A. Farley ◽

Daniel B. Owen ◽

...

Keyword(s):

Cognitive Function ◽

Cognitive Decline ◽

Inflammatory Cytokines ◽

Interleukin 6 ◽

Age Related ◽

Natural Inhibitor ◽

Age Related Cognitive Decline ◽

The Brain

Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

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Effects of Reactive Oxygen and Nitrogen Species on TrkA Expression and Signalling: Implications for proNGF in Aging and Alzheimer’s Disease

Cells ◽

10.3390/cells10081983 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1983

Author(s):

Erika Kropf ◽

Margaret Fahnestock

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Basal Forebrain ◽

Memory Loss ◽

Reactive Oxygen ◽

Neurotrophin Receptor ◽

Nitrogen Species ◽

Age Related ◽

The Brain

Nerve growth factor (NGF) and its precursor form, proNGF, are critical for neuronal survival and cognitive function. In the brain, proNGF is the only detectable form of NGF. Dysregulation of proNGF in the brain is implicated in age-related memory loss and Alzheimer’s disease (AD). AD is characterized by early and progressive degeneration of the basal forebrain, an area critical for learning, memory, and attention. Learning and memory deficits in AD are associated with loss of proNGF survival signalling and impaired retrograde transport of proNGF to the basal forebrain. ProNGF transport and signalling may be impaired by the increased reactive oxygen and nitrogen species (ROS/RNS) observed in the aged and AD brain. The current literature suggests that ROS/RNS nitrate proNGF and reduce the expression of the proNGF receptor tropomyosin-related kinase A (TrkA), disrupting its downstream survival signalling. ROS/RNS-induced reductions in TrkA expression reduce cell viability, as proNGF loses its neurotrophic function in the absence of TrkA and instead generates apoptotic signalling via the pan-neurotrophin receptor p75NTR. ROS/RNS also interfere with kinesin and dynein motor functions, causing transport deficits. ROS/RNS-induced deficits in microtubule motor function and TrkA expression and signalling may contribute to the vulnerability of the basal forebrain in AD. Antioxidant treatments may be beneficial in restoring proNGF signalling and axonal transport and reducing basal forebrain neurodegeneration and related deficits in cognitive function.

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The Effects of Age-Related Hearing Loss on the Brain and Cognitive Function

Trends in Neurosciences ◽

10.1016/j.tins.2020.07.005 ◽

2020 ◽

Vol 43 (10) ◽

pp. 810-821

Author(s):

Kate Slade ◽

Christopher J. Plack ◽

Helen E. Nuttall

Keyword(s):

Hearing Loss ◽

Cognitive Function ◽

Age Related ◽

Age Related Hearing Loss ◽

The Brain

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What do we GANE with age?

Behavioral and Brain Sciences ◽

10.1017/s0140525x15001892 ◽

2016 ◽

Vol 39 ◽

Cited By ~ 1

Author(s):

Matthew R. Nassar ◽

Rasmus Bruckner ◽

Ben Eppinger

Keyword(s):

Cognitive Function ◽

Age Related ◽

Receptor Pharmacology ◽

The Brain ◽

Age Related Changes

AbstractMather and colleagues provide an impressive cross-level account of how arousal levels modulate behavior, and they support it with data ranging from receptor pharmacology to measures of cognitive function. Here we consider two related questions: (1) Why should the brain engage in different arousal levels? and (2) What are the predicted consequences of age-related changes in norepinephrine signaling for cognitive function?

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Age-related Shift in Neural Complexity Related to Task Performance and Physical Activity

Journal of Cognitive Neuroscience ◽

10.1162/jocn_a_00725 ◽

2015 ◽

Vol 27 (3) ◽

pp. 605-613 ◽

Cited By ~ 15

Author(s):

Jennifer J. Heisz ◽

Michelle Gould ◽

Anthony R. McIntosh

Keyword(s):

Physical Activity ◽

Older Adults ◽

Information Processing ◽

Cognitive Function ◽

Neural Plasticity ◽

Structural Changes ◽

Local Information ◽

Multiscale Entropy ◽

Age Related ◽

The Brain

The human brain undergoes marked structural changes with age including cortical thinning and reduced connectivity because of the degradation of myelin. Although these changes can compromise cognitive function, the brain is able to functionally reorganize to compensate for some of this structural loss. However, there are interesting individual differences in outcome: When comparing individuals of similar age, those who engage in regular physical activity are less affected by the typical age-related decline in cognitive function. This study used multiscale entropy to reveal a shift in the way the brain processes information in older adults that is related to physical activity. Specifically, older adults who were more physically active engaged in more local neural information processing. Interestingly, this shift toward local information processing was also associated with improved executive function performance in older adults, suggesting that physical activity may help to improve aspects of cognitive function in older adults by biasing the neural system toward local information processing. In the face of age-related structural decline, the neural plasticity that is enhanced through physical activity may help older adults maintain cognitive health longer into their lifespan.

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