Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

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Arginine behaviour after arginine or citrulline administration in older subjects

British Journal Of Nutrition ◽

10.1017/s0007114515004638 ◽

2015 ◽

Vol 115 (3) ◽

pp. 399-404 ◽

Cited By ~ 20

Author(s):

C. Moinard ◽

J. Maccario ◽

S. Walrand ◽

V. Lasserre ◽

J. Marc ◽

...

Keyword(s):

Plasma Concentrations ◽

The Elderly ◽

Volume Of Distribution ◽

Elderly Subjects ◽

Healthy Elderly ◽

Age Related ◽

Loading Tests ◽

Kinetics Of ◽

Healthy Elderly Subjects

AbstractArginine (ARG) and its precursor citrulline (CIT) are popular dietary supplements, especially for the elderly. However, age-related reductions in lean body mass and alterations in organ functions could change their bioavailability. Pharmacokinetics and tolerance to amino acid (AA) loads are poorly documented in elderly subjects. The objective here was to characterise the plasma kinetics of CIT and ARG in a single-dosing study design. Eight fasting elderly men underwent two separate isomolar oral loading tests (10 g of CIT or 9·94 g of ARG). Blood was withdrawn over an 8-h period to measure plasma AA concentrations. Only CIT, ornithine and ARG plasma concentrations were changed. Volume of distribution was not dependent on AA administered. Conversely, parameters related to ARG kinetics were strongly dependent on AA administered: after ARG load, elimination was higher (ARG>CIT; P=0·041) and admission period+time at peak concentration was lower (ARG<CIT; P=0·033), and the combination of both phenomena results in a marked increase in ARG availability when CIT was administered (ARG<CIT; P=0·033) compared with ARG administration itself. In conclusion, a single CIT administration in the elderly is safe and well tolerated, and CIT proves to be a better in vivo ARG precursor than ARG itself in healthy elderly subjects.

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A Walnut-Enriched Diet Modifies the Oxylipin Profile in Liver and Brain of Aged Mice — Impact on Inflammation Markers

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_019 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1203-1203

Author(s):

Gunter Eckert ◽

Gunter Esselun ◽

Elisabeth Koch ◽

Nils Schebb

Keyword(s):

Physical Activity ◽

Fatty Acids ◽

Brain Aging ◽

Inflammatory Marker ◽

Inflammation Markers ◽

Aged Mice ◽

Funding Sources ◽

Age Related ◽

The Brain ◽

Related Increase

Abstract Objectives Neuroinflammation contributes to brain-aging which may be mitigated by anti-inflammatory oxylipins. Based on our previous findings that a 6% walnut-enriched diet alone, and additional physical activity (PA), enhanced cognition in 18 months old NMRI, we now investigated the effects of this diet on oxylipin- and inflammatory marker levels in liver and brain. Methods 18 months and 3 months old female NMRI mice were fed with a 6% walnut-enriched diet. Oxylipins were determined in brain and liver sections using LC-MS. Expression of IL1β gene was determined by qRT-PCR. Results The walnut diet compensates for the age related increase in IL1β gene expression in the liver of mice, whereas expression in the brain was not affected. Basal levels of oxylipins in brain and liver samples isolated from young mice were generally lower compared to aged mice. The walnut diet further increased oxylipin levels of walnut specific fatty acids in liver and brain of aged mice. Enrichment of linoleic acid (LA) and α-linolenic acid (ALA) derived oxylipin levels were quantitatively higher in the liver compared to the brain (P < 0.0001). Hydroxy-oxylipins (HO) based on fatty acid LA were significantly increased in brain (P < 0.001) and liver (P < 0.0001) compared to control mice, while ALA based HO were only detected in the brains of walnut fed mice. The walnut diet in combination with physical activity (PA) reduced ARA based oxylipin levels (P < 0.05). Across all groups, concentrations of prostanoids were higher in the brain as compared to liver (P < 0.001). In the liver, walnuts tended to decrease PGD2 and TxB2 levels while increasing 6-keto PGF1α. The latter, as well as TxB2 tended to be decreased in the brain. Other ARA based prostanoids were unaffected. Effects of PA were contrary to each other, tending to increase ARA based prostanoids in the liver while decreasing them in the brain. PA further enhanced this effect in the brain, but tended to increase the inflammatory response in the liver. Conclusions A walnut diet differentially affects the oxylipin profile of liver and brain in aged mice. Production of oxylipins based on walnut fatty acids is generally increased. Attenuation of age-related, chronic inflammation in might be one of walnut's benefits and may contribute to a healthier aging of the brain. Funding Sources Research was supported by grants from California Walnut Commission.

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Hazelnut modulates neurobehaviour and ameliorates ageing-induced oxidative stress, and caspase-3-mediated apoptosis in mice

Current Aging Science ◽

10.2174/1874609813666201228112349 ◽

2020 ◽

Vol 13 ◽

Author(s):

Anthony Tope Olofinnade ◽

Adejoke Yetunde Onaolapo ◽

Olakunle James Onaolapo ◽

Olugbenga Adekunle Olowe

Keyword(s):

Weight Gain ◽

Caspase 3 ◽

Standard Diet ◽

Dopamine Level ◽

Biochemical Tests ◽

Aged Mice ◽

Beneficial Effects ◽

Body Tissues ◽

Age Related ◽

The Brain

Background: Organismal aging has been associated with deleterious effects in different body tissues and organs, including the brain. There have been reports from ancient medicinal scripts of the beneficial effects of nuts like hazelnut in preventing aging induced-brain atrophy and memory loss. Objectives: This study examined the potential beneficial effects of a diet supplemented with two different (Italian and Turkish) cultivars of hazelnut on the brain of aged mice. Methods: Aged (24 months old) mice were randomly assigned into 7 groups of ten mice each. Mice were grouped as standard diet (SD) control, three groups of Turkish and three groups of Italian hazelnut incorporated into SD at 2, 4 and 8% respectively. Animals were fed standard or hazelnut diet for 8 weeks. On day 56, behaviours in the elevated plus maze, radial-arm maze, open field, and Y-maze paradigms were monitored and scored, following which animals were euthanized. The brains were removed, weighed and homogenized for the assessment of specific biochemical tests. Result: Results showed that hazelnut-supplemented diet was associated with significantly increased weight gain, with the Italian hazelnut being associated with greater weight gain. Hazelnut-supplemented diet also increased behavioural parameters such as horizontal locomotion and grooming, while it decreased rearing activity. Working-memory also improved significantly with both cultivars of hazelnut, while anxiety indices were reduced at lower concentrations of Italian, and higher concentrations of Turkish hazelnut. Both hazelnut varieties were associated with reduction in acetylcholinesterase activity, reduction in superoxide dismutase activity, reduction in nitric oxide levels, reduction in caspase-3 level, but increased dopamine level. Conclusion: Overall hazelnut cultivars have beneficial effects on the brain in aged mice; suggesting a possible role in the prevention or management of age-related neurodegenerative changes.

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Noninvasive Brain Stimulation for the Study of Memory Enhancement in Aging

European Psychologist ◽

10.1027/1016-9040/a000241 ◽

2016 ◽

Vol 21 (1) ◽

pp. 41-54 ◽

Cited By ~ 10

Author(s):

David Bartrés-Faz ◽

Didac Vidal-Piñeiro

Keyword(s):

Brain Stimulation ◽

Early Stage ◽

Synergistic Effects ◽

The Elderly ◽

Clear Understanding ◽

Noninvasive Brain Stimulation ◽

Beneficial Effects ◽

Healthy Elderly ◽

Age Related ◽

Potential Benefits

Abstract. Noninvasive brain stimulation (NIBS) techniques have recently attracted interest due to their potential for transiently improving cognition. This may prove particularly valuable in aging, given the known impact of age-related cognitive dysfunction on quality of life. The present review summarizes the currently available evidence of working and episodic memory enhancements achieved using NIBS in healthy elderly people. The evidence reviewed indicates that research is still at an early stage and that there is a need to define the best procedures for operating and performing multicentre characterization of protocols. However, a limited number of sham-controlled studies have reported improvements in both cognitive domains. Furthermore, evidences of long-term beneficial effects opens up the possibility of using NIBS as an adjuvant therapeutic strategy. However, the relevance of certain variables involved and approaches used remains to be elucidated, including the potential benefits of single versus multiple NIBS sessions, the putative synergistic effects of using NIBS in combination with cognitive training, and the importance of individual differences. Overall, NIBS techniques represent a promising opportunity for psychologists seeking strategies to improve memory functions in the elderly. Nevertheless, their use requires appropriate technical knowledge coupled with a clear understanding of the neurophysiology and cognitive neuroscience of aging.

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Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00705-3 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Debora Cutuli ◽

Eugenia Landolfo ◽

Annalisa Nobili ◽

Paola De Bartolo ◽

Stefano Sacchetti ◽

...

Keyword(s):

Fatty Acids ◽

Basal Forebrain ◽

Brain Aging ◽

Life Quality ◽

Cholinergic Neurons ◽

Hippocampal Neurogenesis ◽

Omega 3 ◽

Pufa Supplementation ◽

Aged Mice ◽

Age Related

Abstract Background In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer’s disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology. Methods Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out. Results The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities. Conclusions The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD.

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Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice

Scientific Reports ◽

10.1038/s41598-021-83910-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Angie K. Torres ◽

Claudia Jara ◽

Margrethe A. Olesen ◽

Cheril Tapia-Rojas

Keyword(s):

Mitochondrial Dysfunction ◽

Brain Aging ◽

Memory Loss ◽

Proteinase K ◽

Immunogold Electron Microscopy ◽

Phosphorylated Tau ◽

Aged Mice ◽

Age Related ◽

Synaptic Failure ◽

Synaptic Mitochondria

AbstractBrain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.

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Aged BALB/c Mice as a Model for Increased Severity of Severe Acute Respiratory Syndrome in Elderly Humans

Journal of Virology ◽

10.1128/jvi.79.9.5833-5838.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5833-5838 ◽

Cited By ~ 138

Author(s):

Anjeanette Roberts ◽

Christopher Paddock ◽

Leatrice Vogel ◽

Emily Butler ◽

Sherif Zaki ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Viral Replication ◽

Adverse Outcome ◽

The Elderly ◽

Advanced Age ◽

Sars Coronavirus ◽

Aged Mice ◽

Age Related ◽

Clinical Illness ◽

Elderly Humans

ABSTRACT Advanced age has repeatedly been identified as an independent correlate of adverse outcome and a predictor of mortality in cases of severe acute respiratory syndrome (SARS). SARS-associated mortality may exceed 50% for persons aged 60 years or older. Heightened susceptibility of the elderly to severe SARS and the ability of SARS coronavirus to replicate in mice led us to examine whether aged mice might be susceptible to disease. We report here that viral replication in aged mice was associated with clinical illness and pneumonia, demonstrating an age-related susceptibility to SARS disease in animals that parallels the human experience.

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Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation

10.1101/175810 ◽

2017 ◽

Cited By ~ 1

Author(s):

Niran Hadad ◽

Archana Unnikrishnan ◽

Jordan A. Jackson ◽

Dustin R. Masser ◽

Laura Otalora ◽

...

Keyword(s):

Dna Methylation ◽

Caloric Restriction ◽

Brain Aging ◽

Regulatory Element ◽

Memory Function ◽

Promoter Hypermethylation ◽

Epigenetic Mechanism ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Age Related

AbstractBrain aging is marked by cognitive decline and susceptibility to neurodegeneration. Caloric-restriction (CR) increases neurogenesis, improves memory function, and protects from age-associated neurological disorders. Epigenetic mechanisms, including DNA methylation, are vital to normal CNS cellular and memory functions, and are dysregulated with aging. The beneficial effects of CR have been proposed to work through epigenetic processes, but this is largely unexplored. We therefore tested whether life-long CR prevents age-related DNA methylation changes in the brain. Hippocampal DNA from young (3 months) and old (24 months) male mice fed ad libitum and 24 month old mice fed a 40% calorierestricted diet from 3 months of age were examined by genome-wide bisulfite sequencing to measure methylation with base-specificity. Over 27 million CG and CH (non-CG) sites were examined. Of the ~40,000 differentially methylated CGs (dmCGs) and ~80,000 CHs (dmCHs) with aging, >1/3 were prevented by CR and were found across genomic regulatory regions and gene pathways. CR also caused alterations to CG and CH methylation at sites not differentially methylated with aging, and these CR-specific changes demonstrated a different pattern of regulatory element and gene pathway enrichment than those affected by aging. CR-specific DNMT1 and TET3 promoter hypermethylation corresponded to reduced gene expression. These findings demonstrate that CR attenuates age-related CG and CH hippocampal methylation changes, in combination with CR-specific methylation that may also contribute to the neuroprotective effects of CR. The prevention of age-related methylation alterations is also consistent with the pro-longevity effects of CR working through an epigenetic mechanism.

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AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice

Communications Biology ◽

10.1038/s42003-021-02837-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Madelene Ericsson ◽

Pär Steneberg ◽

Rakel Nyrén ◽

Helena Edlund

Keyword(s):

Quality Of Life ◽

Cardiac Function ◽

Exercise Capacity ◽

Vascular Function ◽

Metabolic Dysfunction ◽

Aged Mice ◽

Beneficial Effects ◽

Positive Effects ◽

Age Related

AbstractAge is associated with progressively impaired, metabolic, cardiac and vascular function, as well as reduced work/exercise capacity, mobility, and hence quality of life. Exercise exhibit positive effects on age-related dysfunctions and diseases. However, for a variety of reasons many aged individuals are unable to engage in regular physical activity, making the development of pharmacological treatments that mimics the beneficial effects of exercise highly desirable. Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.

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Electroencephalographic Rhythms in Alzheimer’s Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/927573 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 28

Author(s):

Roberta Lizio ◽

Fabrizio Vecchio ◽

Giovanni B. Frisoni ◽

Raffaele Ferri ◽

Guido Rodriguez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Aging ◽

Event Related Potentials ◽

Brain Regions ◽

Elderly Subjects ◽

Single Individual ◽

Healthy Elderly ◽

Age Related ◽

Related Potentials

Physiological brain aging is characterized by synapses loss and neurodegeneration that slowly lead to an age-related decline of cognition. Neural/synaptic redundancy and plastic remodelling of brain networking, also due to mental and physical training, promotes maintenance of brain activity in healthy elderly subjects for everyday life and good social behaviour and intellectual capabilities. However, age is the major risk factor for most common neurodegenerative disorders that impact on cognition, like Alzheimer's disease (AD). Brain electromagnetic activity is a feature of neuronal network function in various brain regions. Modern neurophysiological techniques, such as electroencephalography (EEG) and event-related potentials (ERPs), are useful tools in the investigation of brain cognitive function in normal and pathological aging with an excellent time resolution. These techniques can index normal and abnormal brain aging analysis of corticocortical connectivity and neuronal synchronization of rhythmic oscillations at various frequencies. The present review suggests that discrimination between physiological and pathological brain aging clearly emerges at the group level, with suggested applications also at the level of single individual. The possibility of combining the use of EEG together with biological/neuropsychological markers and structural/functional imaging is promising for a low-cost, non-invasive, and widely available assessment of groups of individuals at-risk.

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