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Diet may influence the risk for cognitive decline and neurodegenerative disorders, including Alzheimer’s disease (AD), but these relationships are difficult to study in humans. Cynomolgus macaques (Macaca fascicularis) are appropriate models for investigations of diet effects on the brain because, like humans, they are omnivorous, have complex central nervous systems, are susceptible to diet-induced diseases, and accumulate amyloid and tauopathies with age. Using structural magnetic resonance imaging, we examined diet effects on brain anatomy by measuring thickness and volume of several areas relevant to AD in 38 middle-aged females, at baseline and after Mediterranean or Western diet consumption for 36 months (equivalent to a 9-year follow-up in humans). Using repeated measures analysis, cortical thicknesses generally increased in the Western diet group. Western diets also resulted in increases in total brain volume and cortical gray matter and decreases in cerebrospinal fluid, white matter, and deep gray matter (striatum and thalamus) (all p’s≤0.05). In contrast, thicknesses and volumes generally remained unchanged in animals consuming Mediterranean diets. Taken together, these findings demonstrate that Western diets induce widespread structural shifts which may increase risk of cognitive decline and neuropathology, whereas Mediterranean diets may exert a stabilizing influence on the brain. This study provides important insights about the significance of diet on brain structure and lays the groundwork for future investigations to uncover the molecular underpinnings of diet-induced changes in the brain. Mediterranean diet may protect against structural changes in brain that occur with age in those consuming a Western diet.

Age-related neurodegeneration associated with Alzheimer’s (AD) disease begins in middle age, well before the onset of symptoms. Therefore, translational models to identify modifiable risk factors in middle-age are needed to understand etiology and identify therapeutic targets. Vervet monkeys (Chlorocebus aethiops sabaeus), like humans, naturally develop several risk factors for AD with age, including obesity, prediabetes, and hypertension. Furthermore, older vervets exhibit accumulation of amyloid and tauopathies, decreased brain volumes, and physical declines in gait speed, suggesting that these NHPs may be useful models of early AD-like neuropathology. Currently, we are investigating the extent to which cognitive and physical decline co-occur in 20 elder (mean age=23 years, ~equivalent to a human age of 80 years) and 10 middle-aged (mean age=11 years) females through assessments of physical performance, executive function, social cognition, and short-term memory. These measures are part of a larger study to integrate physical, social, and cognitive function with measures of body composition, metabolic profiles, CSF, blood, neuroimages, and neuropathology. While tests of social cognition and short-term memory are ongoing, assessments of executive function indicate that performance declines with age (N=26; p

Diet modifications are some of the most well-established aging interventions. For decades we have known that caloric restriction can dramatically increase lifespan and healthspan in organisms ranging from yeast to primates. More recently, other dietary modifications, including varying nutrient composition, have been experimentally shown to alter healthspan and lifespan. However, limitations inherent in human trials, such as diet adherence and heterogeneity of other lifestyle factors, mitigate our ability to identify the mechanisms through which diet alters healthspan and lifespan. Here, we conducted a randomized, long-term, whole-diet manipulation in a nonhuman primate, where cynomolgus macaques consumed either a Mediterranean or Western diet for 15 months. We hypothesized that individuals fed a Western diet would exhibit accelerated rates of cellular and physiological aging relative to their Mediterranean-fed counterparts. Indeed, we found that Western diet-fed animals exhibited increases in physiological measures that also increase with age, including body weight, fasting insulin, and triglycerides. Animals eating a Mediterranean diet, on the other hand, had a more sensitive and tuned autonomic response, and reduced HPA responses to an acute stress challenge. Probing further, we found that diet strongly affected monocyte function, altering the expression of 40% of expressed genes, leading to a more proinflammatory monocyte phenotype in Western diet fed animals. Experiments are underway to explore effects of diet on other markers of biological aging. Together, these data provide the first controlled evidence that Western and Mediterranean diets can alter aging-associated function in a species with clear biological similarity and relevance to humans.

Social status is a powerful correlate of aging-related health decline. Observational data in humans suggest that disadvantaged social status may be associated with accelerated biological aging. But establishing causality in this relationship poses challenges; experimental manipulation of human social status is not possible. In contrast, social status can be experimentally manipulated non-human primates (e.g. Snyder-Mackler 2016 Science). We conducted analysis to reverse-translate blood-chemistry of biological aging to cynomolgus monkeys using data from several hundred animals in the Wake Primate Center breeding colony. We are applying these measures in an independent sample of monkeys with ascertained dominance rank to test replication in the non-human primate model of the human social gradient in biological aging. Parallel analysis of DNA methylation-based measures of biological aging are ongoing and should be available to present by Fall 2019. Results will inform potential to use this non-human primate model to study social determinants of biological aging.