Papers by Marshall G Miller
European journal of nutrition, Jan 10, 2017
As populations shift to include a larger proportion of older adults, the necessity of research ta... more As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been associated with positive outcomes in cell and rodent models of aging. We hypothesized that dietary blueberry would improve mobility and cognition among older adults. In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equivalent to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention. Significant supplement group by study visit interactions were observed on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal L...
Health Promotion and Therapeutic Potential, 2012
Life sciences in space research, 2017
The protective effects of anthocyanin-rich blueberries (BB) on brain health are well documented a... more The protective effects of anthocyanin-rich blueberries (BB) on brain health are well documented and are particularly important under conditions of high oxidative stress, which can lead to "accelerated aging." One such scenario is exposure to space radiation, consisting of high-energy and -charge particles (HZE), which are known to cause cognitive dysfunction and deleterious neurochemical alterations. We recently tested the behavioral and neurochemical effects of acute exposure to HZE particles such as (56)Fe, within 24-48h after exposure, and found that radiation primarily affects memory and not learning. Importantly, we observed that specific brain regions failed to upregulate antioxidant and anti-inflammatory mechanisms in response to this insult. To further examine these endogenous response mechanisms, we have supplemented young rats with diets rich in BB, which are known to contain high amounts of antioxidant-phytochemicals, prior to irradiation. Exposure to (56)Fe cau...
The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 21, 2017
Frailty is a clinical syndrome that is increasingly prevalent during aging. Frailty involves the ... more Frailty is a clinical syndrome that is increasingly prevalent during aging. Frailty involves the confluence of reduced strength, speed, physical activity, and endurance and is associated with adverse health outcomes. The present study adapts existing clinical and preclinical indices of frailty to the Fischer (F344) rat. Male F344 rats (n = 133; 17 mo) completed a battery of behavioral tasks, including forelimb wire suspension (strength), rotarod (speed), open field (physical activity), and inclined screen (endurance). Rats that performed poorly (lowest quintile) on two tasks were considered mildly frail (17.29%, n = 23), and rats that performed poorly on 3-4 tasks were considered frail (2.26%, n = 3). Logistic regression of 100-day survival revealed that mildly frail rats were 3.8 times and frail rats were 27.5 times more likely to die during that period than nonfrail rats (p = .038; 95% confidence interval: 2.030, 372.564). The selected criterion tests, cutoff points, and index pro...
Experimental Gerontology, 2016
Population aging is leading to an increase in the incidence of age-related cognitive dysfunction ... more Population aging is leading to an increase in the incidence of age-related cognitive dysfunction and, with it, the health care burden of caring for older adults. Epidemiological studies have shown that consumption of fruits, nuts, and vegetables is positively associated with cognitive ability; however, these foods, which contain a variety of neuroprotective phytochemicals, are widely under-consumed. Surprisingly few studies have investigated the effects of individual plant foods on cognitive health but recent clinical trials have shown that dietary supplementation with individual foods, or switching to a diet rich in several of these foods, can improve cognitive ability. While additional research is needed, increasing fruit, nut, and vegetable intake may be an effective strategy to prevent or delay the onset of cognitive dysfunction during aging.
AGE, 2016
High consumption of fruits and vegetables has been associated with reduced risk of debilitating d... more High consumption of fruits and vegetables has been associated with reduced risk of debilitating diseases and improved cognition in aged populations. These beneficial effects have been attributed to the phytochemicals found in fruits and vegetables, which have previously been shown to be anti-inflammatory and modulate autophagy. Tart cherries contain a variety of potentially beneficial phytochemicals; however, little research has been done to investigate the effects of tart cherry on the aging brain. Therefore, the purpose of this study was to determine if tart cherry supplementation can improve cognitive and motor function of aged rats via modulation of inflammation and autophagy in the brain. Thirty 19-month-old male Fischer 344 rats were weight-matched and assigned to receive either a control diet or a diet supplemented with 2 % Montmorency tart cherry. After 6 weeks on the diet, rats were given a battery of behavioral tests to assess for strength, stamina, balance, and coordination, as well as learning and working memory. Although no significant effects were observed on tests of motor performance, tart cherry improved working memory of aged rats. Following behavioral testing, the hippocampus was collected for western/densitometric analysis of inflammatory (GFAP, NOX-2, and COX-2) and autophagy (phosphorylated mTOR, Beclin 1, and p62/SQSTM) markers. Tart cherry supplementation significantly reduced inflammatory markers and improved autophagy function. Daily consumption of tart cherry reduced age-associated inflammation and promoted protein/cellular homeostasis in the hippocampus, along with improvements in working memory. Therefore, addition of tart cherry to the diet may promote healthy aging and/or delay the onset of neurodegenerative diseases.
The Faseb Journal, Apr 1, 2015
Neuromolecular medicine, Jan 11, 2016
Advanced glycation end products (AGEs) are naturally occurring macromolecules that are formed in ... more Advanced glycation end products (AGEs) are naturally occurring macromolecules that are formed in vivo by the non-enzymatic modification of proteins, lipids, or nucleic acids by sugar, even in the absence of hyperglycemia. In the diet, AGEs are found in animal products, and additional AGEs are produced when those foods are cooked at high temperatures. Studies have linked AGEs to various age-related physiological changes, including wrinkles, diabetic complications, and neurodegenerative disease, including Alzheimer's disease. Dietary berry fruits have been shown to reduce the severity or slow the progression of many physiological changes and disease pathologies that accompany aging. Emerging evidence has shown that the phytochemicals found in berry fruits exhibit anti-glycative activity. In this review, we briefly summarize the current evidence supporting the neuroprotective anti-glycative activity of berry fruits and their potential to preserve cognitive function during aging.
Nutrition Research, 2015
Decline in brain function during normal aging is partly due to the long-term effects of oxidative... more Decline in brain function during normal aging is partly due to the long-term effects of oxidative stress and inflammation. Several fruits and vegetables have been shown to possess antioxidant and anti-inflammatory properties. The present study investigated the effects of dietary mushroom intervention on mobility and memory in aged Fischer 344 rats. We hypothesized that daily supplementation of mushroom would have beneficial effects on behavioral outcomes in a dose-dependent manner. Rats were randomly assigned to receive a diet containing either 0%, 0.5%, 1%, 2%, or 5% lyophilized white button mushroom (Agaricus bisporus); after 8 weeks on the diet, a battery of behavioral tasks was given to assess balance, coordination, and cognition. Rats on the 2% or 5% mushroom-supplemented diet consumed more food, without gaining weight, than rats in the other diet groups. Rats in the 0.5% and 1% group stayed on a narrow beam longer, indicating an improvement in balance. Only rats on the 0.5% mushroom diet showed improved performance in a working memory version of the Morris water maze. When taken together, the most effective mushroom dose that produced improvements in both balance and working memory was 0.5%, equivalent to about 1.5 ounces of fresh mushrooms for humans. Therefore, the results suggest that the inclusion of mushroom in the daily diet may have beneficial effects on age-related deficits in cognitive and motor function.
Neurochemistry International, 2015
Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these con... more Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 4'-trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and anti-inflammatory signaling and behavioral outcomes.
Neurobiology of Aging, 2012
We have previously reported that a modified Stone T-maze (STM), using escape from water as motiva... more We have previously reported that a modified Stone T-maze (STM), using escape from water as motivation, was effective in evaluating learning and memory ability in young C57/BL6 mice. Here we report on the effectiveness and sensitivity of the STM in the assessment of age-related learning and memory deficits in mice using either escape from foot shock or water as the motivational manipulations. C57BL/6Nia mice 7-, 12-, 20- and 24-months old received 15 massed trials in the escape from foot shock motivated STM while C57BL/6Nia mice 5-, 12-, and 25-months old were tested in the escape from water STM. Analysis of errors, the main performance variable, revealed similar results in both versions of the task with younger mice making fewer errors. Notably, mice of all ages in the water-motivated version moved quickly through the maze, while all ages of mice in the shock-motivated version tended to wait for shock to be initiated to move forward. Overall, both versions of the STM appear to be sensitive to age-related changes in learning and memory and provide an alternative to other testing paradigms such as the Morris water maze which are susceptible to performance confounds which can lead to uninterpretable results.
Neurobiology of aging, 2012
Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates--are stress-induc... more Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates--are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (A...
Calorie Restriction, Aging and Longevity, 2010
... J Neurosci 27, 1018510195. Freemantle, E., Vandal, M., Tremblay-Mercier, J., Tremblay, S., B... more ... J Neurosci 27, 1018510195. Freemantle, E., Vandal, M., Tremblay-Mercier, J., Tremblay, S., Blachere, JC, Begin, ME, Brenna, JT, Windust, A. and Cunnane, SC, 2006. ... Neurobiol Aging 10, 317322. Mouton, PR, Chachich, ME, Quigley, C., Spangler, E. and Ingram, DK, 2009. ...
Plant Secondary Metabolites and Health, 2011
Page 1. Chapter 4 Teas, Tisanes and Health Diane L. McKay1, Marshall G. Miller2 and Jeffrey B. Bl... more Page 1. Chapter 4 Teas, Tisanes and Health Diane L. McKay1, Marshall G. Miller2 and Jeffrey B. Blumberg1 1Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA ...
Journal of Nutrition, 2014
Because of the combination of population growth and population aging, increases in the incidence ... more Because of the combination of population growth and population aging, increases in the incidence of chronic neurodegenerative disorders have become a societal concern, both in terms of decreased quality of life and increased financial burden. Clinical manifestation of many of these disorders takes years, with the initiation of mild cognitive symptoms leading to behavioral problems, dementia and loss of motor functions, the need for assisted living, and eventual death. Lifestyle factors greatly affect the progression of cognitive decline, with high-risk behaviors including unhealthy diet, lack of exercise, smoking, and exposure to environmental toxins leading to enhanced oxidative stress and inflammation. Although there exists an urgent need to develop effective treatments for age-related cognitive decline and neurodegenerative disease, prevention strategies have been underdeveloped. Primary prevention in many of these neurodegenerative diseases could be achieved earlier in life by consuming a healthy diet, rich in antioxidant and anti-inflammatory phytochemicals, which offers one of the most effective and least expensive ways to address the crisis. English walnuts (Juglans regia L.) are rich in numerous phytochemicals, including high amounts of polyunsaturated fatty acids, and offer potential benefits to brain health. Polyphenolic compounds found in walnuts not only reduce the oxidant and inflammatory load on brain cells but also improve interneuronal signaling, increase neurogenesis, and enhance sequestration of insoluble toxic protein aggregates. Evidence for the beneficial effects of consuming a walnut-rich diet is reviewed in this article.
Journal of Neuroscience, 2010
Conservation of normal cognitive functions relies on the proper performance of the nervous system... more Conservation of normal cognitive functions relies on the proper performance of the nervous system at the cellular and molecular level. The mammalian NAD + -dependent deacetylase, SIRT1, impacts different processes potentially involved in the maintenance of brain integrity such as chromatin remodeling, DNA repair, cell survival and neurogenesis. Here we show that SIRT1 is expressed in neurons of the hippocampus, a key structure in learning and memory. Using a combination of behavioral and electrophysiological paradigms we analyzed the effects of SIRT1 deficiency and overexpression on mouse learning and memory as well as on synaptic plasticity. We demonstrated that the absence of SIRT1 impaired cognitive abilities, including immediate memory, classical conditioning and spatial learning. In addition, we found that the cognitive deficits in SIRT1 knockout mice were associated with defects in synaptic plasticity without alterations in basal synaptic transmission or NMDA receptor function. Brains of SIRT1-KO mice exhibited normal morphology and dendritic spine structure but display a decrease in dendritic branching, branch length and complexity of neuronal dendritic arbors. Also, a decrease in ERK1/2 phosphorylation and altered expression of hippocampal genes involved in synaptic function, lipid metabolism and myelination were detected in SIRT1-KO mice. In contrast, mice with high levels of SIRT1 expression in brain exhibited regular synaptic plasticity and memory. We conclude that SIRT1 is indispensable for normal learning, memory and synaptic plasticity in mice.
Nucleic Acids Research, 2011
Oxidative DNA damage plays a role in disease development and the aging process. A prominent parti... more Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of $26 months and a nearly identical maximal life expectancy of $37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated-weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity-HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.
Neurobiology of Learning and Memory, 2008
Journal of Agricultural and Food Chemistry, 2012
Increased lifespans have led to population aging and brought attention to healthcare concerns ass... more Increased lifespans have led to population aging and brought attention to healthcare concerns associated with old age. A growing body of preclinical and clinical research has identified neurological benefits associated with the consumption of berry fruits. In addition to their now well-known antioxidant effects, dietary supplementation with berry fruits also has direct effects on the brain. Intake of these fruits may help to prevent age-related neurodegeneration and resulting changes in cognitive and motor function. In cell and animal models, berry fruits mediate signaling pathways involved in inflammation and cell survival in addition to enhancing neuroplasticity, neurotransmission, and calcium buffering, all of which lead to attenuation of age- and pathology-related deficits in behavior. Recent clinical trials have extended these antioxidant, anti-inflammatory, and cognition-sparing effects to humans. This paper reviews recent evidence for the beneficial signaling effects of berry fruits on the brain and behavior.
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Papers by Marshall G Miller