Donald Ingram

• Pennington Biomedical Research Center

Background: Unripe avocados (Persea americana) are naturally enriched in mannoheptulose (MH), which is a candidate caloric restriction mimetic. Objectives: To evaluate the effects of a diet supplement made from unripe avocado on glucose tolerance, and cardiometabolic risk factors in free-living nondiabetic adults with obesity. Methods: In a double-...

Identifying neurobiological mechanisms of aging-related parkinsonism, and lifestyle interventions that mitigate them, remain critical knowledge gaps. No aging study, from rodent to human, has reported loss of any dopamine (DA) signaling marker near the magnitude associated with onset of parkinsonian signs in Parkinson's disease (PD). However, in su...

Beginning at 16 weeks of age and continuing for 44 weeks, male C57BL/6J were fed either a control (CON) diet; a high-fat (HF) diet (60% unsaturated); or the HF diet containing an extract of unripe avocados (AvX) enriched in the 7-carbon sugar mannoheptulose (MH), designed to act as a glycolytic inhibitor (HF + MH). Compared to the CON diet, mice on...

As human lifespan increases and the population ages, diseases of aging such as Alzheimer’s disease (AD) are a major cause for concern. Although calorie restriction (CR) as an intervention has been shown to increase healthspan in many species, few studies have examined the effects of CR on brain aging in primates. Using postmortem tissue from a coho...

The degeneration in the locus coeruleus associated with Alzheimer’s disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer’s disease interventions. Monkeys were injected with the norad...

The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), w...

Emerging evidence from both preclinical and clinical studies have generated evidence of the potential health benefits of consuming blueberries (BBs). This fruit contains among the highest levels of polyphenols identified that provide highly effective antioxidant protection in addition to activating a wide range of other stress signaling pathways di...

The escalating increase in retirees living beyond their 8th decade brings increased prevalence of aging-related impairments, including locomotor impairment (Parkinsonism) which may affect ~50% of those reaching age 80, but has no confirmed neurobiological mechanism. Lifestyle strategies that attenuate motor decline, and its allied mechanisms, must...

The calorie restriction paradigm has provided one of the most widely used and most useful tools for investigating mechanisms of aging and longevity. By far, rodent models have been employed most often in these endeavors. Over decades of investigation, claims have been made that the paradigm produces the most robust demonstration that aging is malle...

In this study we examined the 24-hour plasma melatonin patterns of young adult (∼11 years of age) and old (∼24 years of age) rhesus macaques, and to determine how they would be influenced by 30% calorie restriction (CR). Well-defined 24-hour plasma melatonin rhythms were observed in all the males but only the old animals showed significant attenuat...

Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant posit...

Supplementary figures and supplementary tables.

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 h...

Aging-related bradykinesia affects ∼15% of those reaching age 65 and 50% of those reaching their 80s. Given this high risk and lack of pharmacologic therapeutics, noninvasive lifestyle strategies should be identified to diminish its risk and identify the neurobiological targets to reduce aging-related bradykinesia. Early-life, long-term calorie res...

Dietary resistant starch impact on intestinal microbiome and improving healthspan is the topic of this review. In the elderly population, dietary fiber intake is lower than recommended. Dietary resistant starch as a source of fiber produces a profound change in gut microbiota and fermentation in animal models of aging. Dietary resistant starch has...

Over the past decade, a large number of discoveries have shown that interventions (genetic, pharmacological, and nutritional) increase the lifespan of invertebrates and laboratory rodents. Therefore, the possibility of developing antiaging interventions for humans has gone from a dream to a reality. However, it has also become apparent that we need...

After nearly a century of rigorous investigation and testing, dietary caloric restriction (CR) remains the most robust and reproducible method for slowing aging and maintaining health, function, and vitality. This intervention has been applied to species across the evolutionary spectrum, but for a number of reasons, practical applicability to human...

The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was co...

Much has been written in recent years on the emerging field of calorie restriction mimetics (CRM), which appears to be the most efficient strategy for translating the huge body of research on the beneficial health and longevity promoting effects of actual calorie restriction (CR) into practice. While the latter has been shown to maintain, health, v...

Beginning in 1987 a long-term study was initiated by the National Institute on Aging to evaluate the effects on health, disease, and aging of a regimen of calorie restriction (CR) in nonhuman primates. Specifically, different age groups of rhesus monkeys (Macaca mulatta) were gradually introduced to a nutritionally balanced diet that represented ab...

Objective Metabolic syndrome (MetS) risk increases significantly during menopause and remains elevated postmenopause. Several botanicals, including blueberries (BB), have been shown to delay MetS progression, but few studies have been conducted in postmenopausal animal models. Here, the effects of BB supplementation on obese postmenopausal mice usi...

Strong consensus exists regarding the most robust environmental intervention for attenuating aging processes and increasing healthspan and lifespan: calorie restriction (CR). Over several decades, this paradigm has been replicated in numerous nonhuman models, and has been expanded over the last decade to formal, controlled human studies of CR. Give...

Objectives: The aim of this review was to provide an overview of studies conducted to determine the effects of chlorogenic acid (CGA) on cognition and neurological health. Methods: A literature search was conducted using PubMed and various search terms including chlorogenic acid, CGA, memory, neuroscience, cognition, nutrition, antioxidant, phar...

Heme oxygenase-1 (HO-1) encoded by the HMOX1 gene is a 32 kDa stress protein that catabolizes heme to biliverdin, free iron and carbon monoxide. Glial HO-1 is over-expressed in the CNS of subjects with Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The HMOX1 gene is exquisitely sensitive to oxidative stress and is i...

The present invention provides compounds and methods of administering compounds to a subject that can reduce βAPP production and that is not toxic in a wide range of dosages. The present invention also provides non-carbamate compounds and methods of administering such compounds to a subject that can reduce βAPP production and that is not toxic in a...

We previously reported that moderate calorie restriction (CR) has minimal impact on testicular gene expression in young adult rhesus macaques, and no obvious negative impact on semen quality or plasma testosterone levels. We now extend these findings by examining the influence of CR on various aspects of the reproductive axis of older males, includ...

Previous studies have shown that cyclic nucleotide phosphodiesterase type 5 (PDE5) inhibition with the drugs sildenafil and vardenafil can enhance spatial performance and object recognition in rodent models of learning and memory. We review recent studies on PDE5 inhibition and report novel data that specifically tests the systemic effects of both...

Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK...

Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related "sterile" inflammation in both periphery and...

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as impr...

Data S1 Material and methods. Table S1 Major gross pathologies identified at necropsy. Table S2 Blinded histopathological analysis. Table S3 Effect of SRT2104 on various biomarkers in serum. Table S4 Body composition. Table S5 The ten most highly upregulated and downregulated genes, based on Z-ratio in liver and muscles of SRT2104-treated mice comp...

This chapter highlights the health benefits of blueberries. The blueberry's nutritional value has recently been emphasized, as its polyphenolic compounds can exert benefits to human health. Metabolic syndrome is a pre-diabetic state characterized by phenotypes including insulin resistance, hyperlipidemia, inflammation and obesity, all of which are...

This chapter addresses the potential health benefits of avocados and avocado bioactives. Research using in vitro and in vivo animal models has shown potential health benefits associated with avocado consumption that includes reductions in cardiovascular disease (CVD) risk factors, osteoporosis, cancer, and inflammation. Clinical trials have been li...

Activity patterns and sleep-wake cycles are among the physiological processes that change most prominently as animals age, and are often good indicators of healthspan. In this study, we used the video-based high-resolution Behavioral Monitoring System (BMS) to monitor the daily activity cycle of tephritid fruit flies Anastrepha ludens over their li...

Experimental infection of Ad36 increases adiposity, yet improves glycemic control in rodents. In humans, natural Ad36 infection is temporally associated with gain in adiposity and better glycemic control. We determined associations of natural Ad36 infection with changes in adiposity and glycemic control in rhesus monkeys. Monkeys randomized 1y earl...

The adrenal steroid, dehydroepiandrosterone sulfate (DHEAS), is generally regarded as being a reliable endocrine marker of aging, because in humans and nonhuman primates its circulating concentrations are very high during young adulthood, and the concentrations then decline markedly during aging. Despite promising results from early studies, we wer...

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reporte...

Calorie restriction (CR) remains the most robust metabolic intervention to extend lifespan and improve healthspan in several species. Using global and targeted mass spectrometry-based metabolomics approaches, here we show that chronic CR prevents age-related changes in specific metabolic signatures. Global metabolomic analysis using ultra-performan...

Macronutrient balance is a critical contributor in modulating lifespan and health. Consumption of diets rich in fruits and vegetables provides numerous health benefits. The interactions among macronutrients and botanicals and how they influence aging and health remain elusive. Here we employed a nutritional geometry approach to investigate the inte...

HIV-associated neurocognitive disorders (HAND) remain prevalent even with widespread use of combination antiretroviral therapy (ART), suggesting a potential role for co-morbidities in neurologic decline. Indeed, it is well established that ART drugs, particularly HIV protease inhibitors, can induce hyperlipidemia, lipodystrophy, and insulin resista...

Feeding avocados to dogs is controversial due to a single report of fatal toxicity for two dogs living near a South African orchard that regularly ate whole avocados and other plant parts (Onderstepoort J Vet Res, 1994, 61:107). This 6‐month study evaluated the tolerance and safety of an avocado‐based ingredient fed to healthy adult dogs. The ingre...

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 diabe...

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...

Calorie restriction (CR) is a reliable anti-aging intervention that attenuates the onset of a number of age-related diseases, reduces oxidative damage, and maintains function during aging. In the current study, we assessed the effects of CR and other feeding regimens on wound healing in 7-month-old Fischer-344 rats from a larger cohort of rats that...

To assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS) appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeu...

The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its associatio...

Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponect...

We saw 2 patients who lost their sense of taste, which was restored by pharmacologic doses of biotin. The key objective is to describe the 2 case reports and suggest a potential treatment for unexplained loss of taste. The first patient was a 67-year-old woman who lost her sense of taste taking Juvenon, a dietary herbal supplement containing acyl-L...

Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezi...

Summary statistics for validation studies of the BMS. (XLSX)

Metrics corresponding to leaves in the dendrogram depicted in Figure 3. (XLSX)

Template for validation of BMC system for Mexfly. (XLSX)

Characterization of lifetime behavioral changes is essential for understanding aging and aging-related diseases. However, such studies are scarce partly due to the lack of efficient tools. Here we describe and provide proof of concept for a stereo vision system that classifies and sequentially records at an extremely fine scale six different behavi...

Botanicals rich with phytochemicals have numerous health benefits. Dietary restriction (DR) extends lifespan in diverse species. We previously demonstrated that an oregano-cranberry (OC) mixture can promote longevity in the Mexican Fruit fly (Mexfly, Anastrepha ludens Loew). However, little is known about the interaction between botanicals and DR,...

Caloric restriction (CR) is the most robust and reproducible intervention for slowing aging, and maintaining health and vitality in animals. Previous studies found that CR is associated with changes in specific biomarkers in monkeys that were also associated with reduced risk of mortality in healthy men. In this study we examine the association bet...

Calorie restriction (CR) remains the most robust environmental intervention for altering aging processes and increasing healthspan and lifespan. Emerging from progress made in many nonhuman models, current research has expanded to formal, controlled human studies of CR. Since long-term CR requires a major commitment of will power and long-term nega...

Although insect behavior is a core discipline in entomology, detailed lifetime behavior has never been recorded for any species. Using a high resolution Behavioral Monitoring System (BMS), behavior of the Mexican Fruit Fly (Anastrepha ludens) was recorded for their entire lifetime. Thirty-two females were maintained on two different diet treatments...

Quantitative microanalysis of brains from patients with Alzheimer's disease (AD) find neuronal loss and neuroinflammation in structures that control cognitive function. Though historically difficult to recapitulate in experimental models, several groups have recently reported that by middle-age, transgenic mice that co-express high levels of two AD...

Parkinson's disease (PD), an age-related movement disorder, is characterized by severe catecholaminergic neuron loss in the substantia nigra pars compacta (SN(PC))-ventral tegmental area (VTA) and locus coeruleus (LC). To assess the stability of these central catecholaminergic neurons following an acute episode of severe inflammation, 6 to 22 month...

We have previously reported a modest influence of moderate calorie restriction (CR) on testicular gene expression in young adult rhesus macaques (Macaca mulatta); however, it is unclear if these modifications correspond to subsequent changes in testicular function or sperm physiology. This study extends our earlier findings to examine potential phy...

It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies...

Increased susceptibility to energy imbalance and anorexia in old age are risk factors for malnutrition during aging, but the underlying mechanisms are not well understood. Here, we explored changes in taste-guided hedonic value ("liking") and motivation to obtain ("wanting") palatable foods as potential mediators of age-associated anorexia and weig...

J. Neurochem. (2010) 114 , 1581–1589. Abstract Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20‐month old male C57Bl/6 mice were fed either ‘western diet’ (41% fat), very high fat lard diet (60%...

Controlled ovarian stimulation (COS) is an alternative to natural breeding in nonhuman primates; however, these protocols are costly with no guarantee of success. Toward the objective of predicting COS outcome in rhesus monkeys, this study evaluated three clinically used ovarian reserve tests (ORTs): day 3 (d3) follicle-stimulating hormone (FSH) wi...

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Mannoheptulose (MH) is a 7‐carbon sugar found in avocados and other natural sources that acts to reduce glycolysis via hexokinase inhibition. It has been proposed as a calorie restriction (CR) mimetic that delivers anti‐aging and health‐promoting benefits of CR without reducing food intake. Three studies were conducted to evaluate MH bioavailabilit...

Mannoheptulose (MH) is a 7‐carbon sugar found in avocados and other natural sources. It is proposed as a calorie restriction (CR) mimetic that delivers anti‐aging and health‐promoting benefits of CR without reducing food intake. Two studies were conducted to evaluate effects of MH on fasting insulin when fed as an avocado extract (AvX) to Labrador...

Calorie restriction (CR) has been known for more than 70 years to extend life span and delay disease in rodent models. Metformin administration in rodent disease models has been shown to delay cancer incidence and progression, reduce cardiovascular disease and extend life span. To more directly test the potential of metformin supplementation (300 m...

This study describes how age and high fat diet affect the profile of NADPH oxidase (NOX). Specifically, NOX activity and subunit expression were evaluated in the frontal cerebral cortex of 7-, 16-, and 24-month old mice following a 4-month exposure to either Western diet (WD, 41% calories from fat) or very high fat lard diet (VHFD, 60% calories fro...

Calorie restriction (CR), defined as the consumption of fewer calories in the absence of malnutrition, has been shown to decelerate the rate of aging and result in several health benefits in many short-lived species. Beginning about 20 years ago, well-controlled long-term studies initiated at both the National Institute on Aging and the Wisconsin N...

Based on the hexahydropyrroloindole backbone of the natural product and alkaloid, (-)-physostigmine (eserine) - a short-acting non-selective reversible cholinesterase inhibitor, three series of compounds were designed and developed to overcome its pharmacokinetic and pharmacodynamic shortfalls to provide experimental therapeutics for Alzheimer's di...

Mice provide a highly valuable resource for investigating learning and memory processes; however, many of the established tasks for evaluating learning and memory were developed for rats. Behaviors of mice in these tasks appear to be driven by different motivational factors, and as a result, they often do not perform reliably on tasks involving rew...

Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has be...

C57Bl/6 mice were administered a high fat, Western diet (WD, 41% fat) or a very high fat lard diet (HFL, 60% fat), and evaluated for cognitive ability using the Stone T-maze and for biochemical markers of brain inflammation. WD consumption resulted in significantly increased body weight and astrocyte reactivity, but not impaired cognition, microgli...

Apyrimidinic/apurinic endonuclease (APE) is a key protein involved in the base-excision DNA repair (BER) pathway of oxidative DNA lesions. Using a novel oligonucleotide substrate, we demonstrate that APE activity in the frontal/parietal cortex (F/PCTX), cerebellum, brainstem, midbrain and hypothalamus declined with age in rats on an ad libitum (AL)...

Despite remarkable progress in treatment of chronic heart failure (CHF) over the last two decades, mortality, personal suffering and cost remain staggering, and effective interventions are still a challenge. Previously we reported that a blueberry-enriched diet (BD) attenuated necroapoptosis and inflammation in periinfarct area in a rat model of my...

The impact of moderate calorie restriction on reproductive neuroendocrine function was investigated in young adult male rhesus macaques (Macaca mulatta). The animals were subjected to either 30% calorie restriction (CR; n=5), or were fed a standard control diet (CON; n=5), starting during their peripubertal period. Plasma LH and testosterone concen...

Botanicals have numerous health benefits. Here, we used the Mexican fruit fly to screen 14 compounds and botanicals for their prolongevity effects and found an oregano and cranberry mixture (OC) improved survival. We then evaluated prolongevity effects of OC within the context of diet composition. Individual flies were fed 0%, 1%, or 2% OC in one o...

Caloric restriction (CR) mitigates neurological damage arising from aging and a variety of other sources, including neuropathology in young adult mice that express single and double transgenic (tg) mutations associated with Alzheimer disease (AD). To evaluate the potential of CR to protect against relatively heavy AD-type pathology, middle-aged (13...

The onset of age-related neurodegenerative diseases superimposed on a declining nervous system could enhance the motor and cognitive behavioral deficits that normally occur in senescence. It is likely that, in cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unles...

This study was undertaken to investigate the effects of prenatal and postnatal exposure to high fat diet on the brain. Female rats were divided into high fat diet (HFD) and control diet (CD) groups 4 weeks prior to breeding and throughout gestation and lactation. After weaning, male progeny were placed on a chow diet until 8 weeks old, and then seg...

to assess the cardioprotective properties of a blueberry enriched diet (BD). Reactive oxygen species (ROS) play a major role in ischemia-related myocardial injury. The attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results precipitating the interest in natural products. Blueberries are...

Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30...