David G. Le Couteur

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4′-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Aging Biology and Geriatric Clinical Pharmacology

Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, “start low and go slow” is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.

Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes

OBJECTIVE This study aimed to determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in community-dwelling older men. STUDY DESIGN AND SETTING Older men aged ≥ 70 years (n=1,705), enrolled in the Concord Health and Aging in Men Project were studied. Receiver operating characteristic curve analysis using the Youden Index and the area under the curve was performed to determine discriminating number of medications in relation to each outcome. RESULTS The highest value of the Youden Index for frailty was obtained for a cutoff point of 6.5 medications compared with a cutoff of 5.5 for disability and 3.5 for cognitive impairment. For mortality and incident falls, the highest value of Youden Index was obtained for a cutoff of 4.5 medications. For every one increase in number of medications, the adjusted odds ratios were 1.13 (95% confidence interval [CI]=1.06-1.21) for frailty, 1.08 (95% CI=1.00-1.15) for disability, 1.09 (95% CI=1.04-1.15) for mortality, and 1.07 (95% CI=1.03-1.12) for incident falls. There was no association between increasing number of medications and cognitive impairment. CONCLUSION The study supports the use of five or more medications in the current definition of polypharmacy to estimate the medication-related adverse effects for frailty, disability, mortality, and falls.

The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice

The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.

Reducing Inappropriate Polypharmacy: The Process of Deprescribing

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

Parkinson's disease, pesticides, and glutathione transferase polymorphisms

BACKGROUND Parkinsons disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinsons disease. METHODS We genotyped by PCR polymorphisms in four GST classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinsons disease patients and 95 controls. We asked all patients for information about pesticide exposure. FINDINGS The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients: AA 14 [54%] of 26 vs seven [18%] of 39; AB 11 [42%] of 26 vs 22 [56%] of 39; BB 1 [4%] of 26 vs six [15%] of 39; AC 0 vs four [10%] of 39, p=0.009). No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinsons disease. INTERPRETATION GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.

The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis.

A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations.Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the ‘oxygen diffusion barrier’ hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion.Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.

Are sirtuins viable targets for improving healthspan and lifespan

Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1–SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.

Loss of muscle strength, mass (sarcopenia), and quality (specific force) and its relationship with functional limitation and physical disability: the Concord Health and Ageing in Men Project.

OBJECTIVES: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men.