Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlated with lifespan extension, though it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

Elevated branched-chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA per se or hepatic mammalian target of rapamycin activation, but instead are due to a shift in the relative quantity of dietary BCAAs and other amino acids, notably tryptophan and threonine. Increasing the ratio of BCAAs to these amino acids results in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high-BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but instead are a consequence of hyperphagia driven by amino acid imbalance.

Fibroblast growth factor 21 (FGF21) is the first known endocrine signal activated by protein restriction. Although FGF21 is robustly elevated in low-protein environments, increased FGF21 is also seen in various other contexts such as fasting, overfeeding, ketogenic diets, and high-carbohydrate diets, leaving its nutritional context and physiological role unresolved and controversial. Here, we use the Geometric Framework, a nutritional modeling platform, to help reconcile these apparently conflicting findings in mice confined to one of 25 diets that varied in protein, carbohydrate, and fat content. We show that FGF21 was elevated under low protein intakes and maximally when low protein was coupled with high carbohydrate intakes. Our results explain how elevation of FGF21 occurs both under starvation and hyperphagia, and show that the metabolic outcomes associated with elevated FGF21 depend on the nutritional context, differing according to whether the animal is in a state of under- or overfeeding.

Pre-clinical findings have provided mounting evidence that resveratrol, a dietary polyphenol, may confer health benefits and protect against a variety of medical conditions and age-related complications. However, there is no consistent evidence of an increased protection against metabolic disorders and other ailments when comparing studies in laboratory animals and humans. A number of extraneous and potential confounding variables can affect the outcome of clinical research. To date, most of the studies that have investigated the effect of resveratrol administration on patient outcomes have been limited by their sample sizes. In this review we will survey the latest advances regarding the timing, dosage, formulation, bioavailability, and toxicity of resveratrol, and resveratrol-drug interactions in human studies. Moreover, the present report focuses on the actions of resveratrol treatment in combatting diseases, such as cancer, diabetes, neurodegeneration, cardiovascular disease, and other age-related ailments.

Old age is the greatest risk factor for most neurodegenerative diseases. During recent decades there have been major advances in understanding the biology of aging, and the development of nutritional interventions that delay aging including calorie restriction (CR) and intermittent fasting (IF), and chemicals that influence pathways linking nutrition and aging processes. CR influences brain aging in many animal models and recent findings suggest that dietary interventions can influence brain health and dementia in older humans. The role of individual macronutrients in brain aging also has been studied, with conflicting results about the effects of dietary protein and carbohydrates. A new approach known as the Geometric Framework (GF) has been used to unravel the complex interactions between macronutrients (protein, fat, and carbohydrate) and total energy on outcomes such as aging. These studies have shown that low-protein, high-carbohydrate (LPHC) diets are optimal for lifespan in ad libitum fed animals, while total calories have minimal effect once macronutrients are taken into account. One of the primary purposes of this review is to explore the notion that macronutrients may have a more translational potential than CR and IF in humans, and therefore there is a pressing need to use GF to study the impact of diet on brain aging. Furthermore, given the growing recognition of the role of aging biology in dementia, such studies might provide a new approach for dietary interventions for optimizing brain health and preventing dementia in older people.

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In Brief Calorie restriction (CR) and ad libitum low-protein, high-carbohydrate (LPHC) diets improve cardiometabolic health in mice. Wahl et al. show that, like healthspan, CR and LPHC diets positively affect hippocampus biology in mice by influencing hippocampus gene expression, nutrient-sensing pathways, dendritic morphology, and cognition.

Although the basic morphological characteristics of neurons in the cerebellar cortex have been documented in several species, virtually nothing is known about the quantitative morphological characteristics of these neurons across different taxa. To that end, the present study investigated cerebellar neuronal morphology among eight different, large-brained mammalian species comprising a broad phylogenetic range: afrotherians (African elephant, Florida manatee), carnivores (Siberian tiger, clouded leopard), cetartiodactyls (humpback whale, giraffe) and primates (human, common chimpanzee). Specifically, several neuron types (e.g., stellate, basket, Lugaro, Golgi, and granule neurons; N = 317) of the cerebellar cortex were stained with a modified rapid Golgi technique and quantified on a computer-assisted microscopy system. There was a 64-fold variation in brain mass across species in our sample (from clouded leopard to the elephant) and a 103-fold variation in cerebellar volume. Most dendritic measures tended to increase with cerebellar volume. The cerebellar cortex in these species exhibited the trilaminate pattern common to all mammals. Morphologically, neuron types in the cerebellar cortex were generally consistent with those described in primates (Fox et al., 1967) and rodents (Palay and Chan-Palay, 1974), although there was substantial quantitative variation across species. In particular, Lugaro neurons in the elephant appeared to be disproportionately larger than those in other species. To explore potential quantitative differences in dendritic measures across species, MARSplines analyses were used to evaluate whether species could be differentiated from each other based on dendritic characteristics alone. Results of these analyses indicated that there were significant differences among all species in dendritic measures.