Devin Wahl

Resveratrol supplementation: Where are we now and where should we go?

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, toxicity of resveratrol, and resveratrol-drug interactions in human studies. Moreover, the present report focuses on the actions of resveratrol treatment in combating diseases, such as cancer, diabetes, neurodegeneration, cardiovascular disease, and other age-related ailments.

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

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 correlate with lifespan extension, although 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.

Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework

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.

Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress.

Nutritional strategies to optimise cognitive function in the aging brain

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.

New Horizons: Dietary protein, ageing and the Okinawan ratio

Nutrition has profound effects on ageing and lifespan. Caloric restriction is the major nutritional intervention that historically has been shown to influence lifespan and/or healthspan in many animal models. Studies have suggested that a reduction in protein intake can also increase lifespan, albeit not as dramatically as caloric restriction. More recent research based on nutritional geometry has attempted to define the effects of nutrition on ageing over a broad landscape of dietary macronutrients and energy content. Such studies in insects and mice indicate that animals with ad libitum access to low-protein, high-carbohydrate diets have longest lifespans. Remarkably, the optimum content and ratio of dietary protein to carbohydrates for ageing in experimental animals are almost identical to those in the traditional diets of the long-lived people on the island of Okinawa.

Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia

Evaluation of behavior and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially dementia. Commonly used tests include Morris water maze, Barnes maze, object recognition, fear conditioning, radial arm water maze, and Y maze. Each of these tests reflects some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory, and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting, and manipulation of macronutrients. Dietary interventions have been shown to influence various cognitive and behavioral tests in rodents indicating that nutrition can influence brain aging and possibly neurodegeneration.

The Relationship Between Dietary Macronutrients and Hepatic Telomere Length in Aging Mice

Macronutrients and dietary energy influence aging, age-related health, and life span. Reduction in telomere length has been proposed as one mechanism for aging. Therefore, this study investigated the effects of varying ratios of dietary macronutrients and energy on telomere length in older adult mice. C57Bl/6 mice were fed ad libitum their entire life on one of 25 diets varying in protein, carbohydrates, fat, and energy. Average telomere length ratio (ATLR) was measured by polymerase chain reaction in livers of a subset of 161 mice aged 15 months. There was a significant positive relationship between ATLR and carbohydrate intake and a negative relationship with protein intake, but no relationships with fat or energy intake. Analysis using the Geometric Framework and Generalized Additive Models confirmed that carbohydrate intake was positively associated with ATLR, while the longest ATLR was achieved by mice restricted to low protein, high carbohydrate diets. ATLR distribution across the diets was parallel to median life-span results previously published. ATLR was associated with blood levels of some amino acids (asparagine, glutamate, taurine) but not with blood levels of fatty acids, hepatic mitochondrial function, or nutrient sensing pathways. In conclusion, mice on low protein, high carbohydrate diets have the longest hepatic telomeres and longest life span.

Long-term Dietary Macronutrients and Hepatic Gene Expression in Aging Mice

Nutrition influences both hepatic function and aging, but mechanisms are poorly understood. Here, the effects of lifelong, ad libitum-fed diets varying in macronutrients and energy on hepatic gene expression were studied. Gene expression was measured using Affymetrix mouse arrays in livers of 46 mice aged 15 months fed one of 25 diets varying in protein, carbohydrates, fat, and energy density from 3 weeks of age. Gene expression was almost entirely influenced by protein intake. Carbohydrate and fat intake had few effects on gene expression compared with protein. Pathways and processes associated with protein intake included those involved with mitochondrial function, metabolic signaling (PI3K-Akt, AMPK, mTOR) and metabolism of protein and amino acids. Protein intake had variable effects on genes associated with regulation of longevity and influenced by caloric restriction. Among the genes of interest with expression that were significantly associated with protein intake are Cth, Gls2, Igf1, and Nnmt, which were increased with higher protein intake, and Igf2bp2, Fgf21, Prkab2, and Mtor, which were increased with lower protein intake. Dietary protein has a powerful impact on hepatic gene expression in older mice, with some overlap with genes previously reported to be involved with regulation of longevity or caloric restriction.

Comorbidity and vascular cognitive impairment-no dementia (VCI-ND)

The clinical and pathological definitions of vascular-related cognitive impairment and dementia have undergone many changes over the decades, and today still remain nebulous. Until the 1960s, most dementia, particularly in older people, was thought to be secondary to cerebral arteriosclerosis. This view of dementia changed in the second half of last century with the ascendency of the Alzheimer’s disease neuropathology paradigm for dementia and the consequent de-emphasis of vascular causes of dementia. In the 1970s, Hachinski and colleagues put forward the proposal that non-Alzheimers dementia secondary to vascular disease was secondary to multiple infarcts (multi-infarct dementia) but there was debate as to whether vascular dementia was related to ischaemic subcortical white matter changes or cortical infarcts. Multiple attempts to precisely define vascular dementia ensued including those by Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases and Related Health Problems (ICD) and NINDS-AIREN [1]. Key to all these definitions are the presence of vascular risk factors and/or vascular changes on pathology and/or imaging associated with various cognitive deficits [2]. Many publications about vascular cognitive impairment (VCI) emphasise the importance of making an early diagnosis before the onset of dementia because of the potential—but still unproven—benefits of treating the vascular risk factors to delay cognitive decline. The first mention of the term ‘vascular cognitive impairment’ was in 1993 when Hachinski and Bowler argued that the different types of VCI should be grouped by underlying vascular cause, rather than symptoms. They also recognised that VCI is likely to progress from an ‘at-risk’ stage, to a ‘peri-symptomatic’ stage then to symptomatic dementia, thus showing that they believed there was a vascular equivalent of mild cognitive impairment seen in Alzheimer’s disease [3]. In 2000, Rockwood et al. [4] in a study of the prevalence and outcomes of VCI from the Canadian Study of Health and Aging, reported that ‘vascular cognitive impairment with no dementia’ (vascular CIND or VCIND) was the most common form of VCI amongst older subjects. In this study, VCI-ND was defined using a combination of DSM-III-R and ICD-10 criteria for dementia and vascular dementia, respectively. VCI-ND was diagnosed in 2.4% of people over 65 years and was associated with increased risks of institutionalisation and mortality, confirming its clinical importance. They concluded that there was a need for large studies to decipher how VCI and VCI-ND vary according to underlying cause. Today the ‘variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment’ remains unresolved and the absence of well-accepted diagnostic criteria impacts on research and clinical diagnosis [5]. International consortiums such as ‘VICCCS’ and ‘STROKOG’ have been formed recently in an attempt to develop operational criteria and harmonise the field of VCI research [5, 6]. The recent study by Stephan et al. [7] in Age and Ageing is particularly important because it provides some explanation for the difficulties in defining VCI-ND to date and a way forward in improving the diagnosis of VCI-ND in the future. Data were obtained from a subset of the Cognitive Function and Ageing Study who underwent cognitive assessment using MMSE and CAMCOG then followed up over 2 years. More than half of the participants without dementia at baseline had one or more underlying cardiometabolic diagnoses including hypertension, coronary heart disease (CHD), stroke, diabetes and peripheral vascular disease (PVD). At baseline, hypertension, CHD and PVD were not associated with any cognitive deficits. Diabetes was associated with global impairment while participants with a history of stroke had a range of focal cognitive deficits. The risk of dementia at 2 years was associated with different cognitive deficits at baseline depending upon the underlying cardiometabolic disorder. The results indicate that comorbidity influences the pattern of cognitive deficits, and how these deficits impact on the risk of progression to dementia. This is no surprise for those involved with the healthcare of older people where the challenges of comorbidity are very familiar [8]. It emphasises the importance of person-based approaches in the clinical practice of geriatric medicine, rather than fixation with individual diagnoses such as dementia. Most dementia occurs in older people where multimorbidity is the norm and where dementia rarely occurs as a standalone single diagnosis [9]. Clinicians and researchers involved in health issues of older people including dementia need to be aware of the interactions between comorbidities, and of course, in many cases their treatments. This is particularly important for VCI where the treatments for the underlying vascular disorders may either reduce or increase the risk of