Title: Cross-sectional associations between nutrient intake and tooth decay in older Australian men: The Concord Health and Ageing in Men Project.

Poor nutrition is a risk factor for dental decay in younger people. However, except for sugar it is unclear if this is true in older age groups. The aim of this study was to analyze the possible associations between overall dietary intake of nutrients and diet quality and presence of dental decay in community dwelling older men. A cross-sectional analysis of a longitudinal study with a standardized validated diet history assessment and comprehensive oral health examination in 520 community dwelling men (mean age: 84 years) participating in the Concord Health and Ageing in Men Project. Nutrient Reference Values (NRVs) were used to determine if individual micronutrients and macronutrients were meeting recommendations. Acceptable Macronutrient Distribution Ranges (AMDR) were attained for fat and carbohydrate intakes and were incorporated into a dichotomous variable to determine if the participants were consuming a high fat and low carbohydrate diet. Diagnosis of coronal caries was based on visual criteria and inspection and was completed on each of the five coronal surfaces. Root surface caries was textual changes across four root surfaces. This diagnosis was used to categorize participants by presence and severity of coronal and root caries. Adjusted logistic regression showed not meeting the recommended intakes for thiamin (odds ratio (OR): 2.32 95% confidence interval (CI) 1.15 - 4.67), and zinc (OR: 3.33, 95% CI 1.71 - 6.48) were associated with presence of severe root decay. Adjusted analysis also showed that participants who were outside the recommended AMDR for fat (OR: 0.61, 95% CI 0.38 - 0.98), and those who consumed a high fat and low carbohydrate diet (OR: 0.56, 95% CI 0.35 - 0.91) were less likely to have coronal tooth decay. Our study shows associations between micronutrients and macronutrients and coronal and root surface decay. Although this study cannot prescribe causality or be generalized to all older adults, diet has a possible association with dental decay in older men.

Addressing the gaps in evaluation of new drugs for older adults: Strategies from the International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee.

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally.

Empirically derived dietary patterns are associated with major adverse cardiovascular events, all-cause mortality, and congestive cardiac failure in older men: The Concord Health and Ageing in Men Project.

BACKGROUND: Diet is associated with major adverse cardiovascular events (MACE). OBJECTIVE: We evaluated the associations between empirically derived dietary patterns and MACE. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 539 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Cox regression analyses were conducted between MACE and the three dietary patterns identified from factor analysis. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality. RESULTS: At a median of 5.3 (IQR 4.6-6.3) years of follow-up, the incidences were: five-point MACE 31.2% (n = 168); four-point MACE excluding all-cause mortality 17.8% (n = 96); all-cause mortality 20.1% (n = 111); CCF 11.3% (n = 61); MI 3.7% (n = 20); stroke 3.2% (n = 17); and coronary revascularisation 3.1% (n = 15). In fully adjusted analyses, compared to the bottom tertile, the middle tertile of 'vegetables-legumes-seafood' dietary pattern was associated with reduced five-point MACE (HR 0.67 [95% CI: 0.45, 0.99, P = .047]), and CCF (HR 0.31 [95% CI: 0.15, 0.65, P = .002]), whilst the middle tertile of 'wholegrains-milk-other fruits' dietary pattern was associated with increased five-point MACE (HR 1.78 [95% CI: 1.17, 2.70, P = .007]), four-point MACE (HR 1.92 [95% CI: 1.12, 3.30, P = .018]), and CCF (HR 2.33 [95% CI: 1.17, 4.65, P = .016]). For the 'discretionary-starchy vegetables-processed meats' dietary pattern, a higher score was associated with increased five-point MACE (HR 1.33 [95% CI: 1.09, 1.62, P = .004]), and all-cause mortality (HR 1.63 [95% CI: 1.26, 2.12, P < .001]), and compared to the bottom tertile, the top tertile was associated with increased all-cause mortality (HR 2.26 [95% CI: 1.27, 4.00, P = .005]). CONCLUSION: Older men may benefit from consuming a 'vegetables-legumes-seafood' dietary pattern rather than 'discretionary-starchy vegetables-processed meats' and 'wholegrains-milk-other fruits' dietary patterns for the prevention of MACE.

Cross-sectional and longitudinal associations between empirically derived dietary patterns and frailty among older men: The Concord Health and Ageing in Men Project.

BACKGROUND: Diet may be associated with frailty. OBJECTIVE: We aimed to evaluate the associations between empirically derived dietary patterns and frailty in older men. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 785 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Factor analysis identified three dietary patterns. Multinomial logistic regression was conducted between frailty and dietary patterns for cross-sectional analyses and longitudinal analyses over a 3-year follow-up. Frailty was defined by the Fried frailty phenotype. RESULTS: Of the 785 men, pre-frailty was prevalent in 47.1% (n = 370), and frailty in 8.3% (n = 65). In fully adjusted cross-sectional analyses, the top tertile and a higher 'vegetables-legumes-seafood' dietary pattern score were associated with reduced prevalence of frailty (OR 0.34 [95% CI: 0.12, 0.93, P = .036]) and OR 0.50 [95% CI: 0.30, 0.83, P = .007] respectively). The top tertile of the 'discretionary-starchy vegetables-processed meats' dietary pattern was also associated cross-sectionally with increased prevalence of pre-frailty (OR 1.75 [95% CI: 1.08, 2.83, P = .022]). Of the 296 robust men in fully adjusted longitudinal analyses, the incidence of pre-frailty was 52.4% (n = 155), and frailty was 5.4% (n = 16) over a 3-year follow-up. The middle tertile of the 'vegetables-legumes-seafood' dietary pattern had a non-significant trend towards reduced incident pre-frailty (OR 0.52 [95% CI: 0.27, 1.00, P = .050]). CONCLUSION: Consumption of a 'vegetables-legumes-seafood' dietary pattern appears to be less favoured by frail older men.

The association of dietary antioxidants and the inflammatory potential of the diet with poor physical function and disability in older Australian men: the Concord Health and Ageing in Men Project.

Our objective was to evaluate the association of antioxidant intake and the inflammatory potential of the diet with functional decline in older men. A diet history questionnaire was used to collect dietary intake data from men aged ≥ 75 years (n 794) participating in the Concord Health and Aging in Men Project cohort study. Intake of vitamins A, C, E and Zn were compared with the Australian Nutrient Reference Values to determine adequacy. The Energy-adjusted Dietary Inflammatory Index (E-DIITM) was used to assess the inflammatory potential of the diet. Physical performance data were collected via handgrip strength and walking speed tests, and activities of daily living (ADL) and instrumental activities of daily living (IADL) questionnaires, at baseline and 3-year follow-up (n 616). Logistic regression analysis was used to identify associations between diet and incident poor physical function and disability. Both poor antioxidant intake and high E-DII scores at baseline were significantly associated with poor grip strength and ADL disability at 3-year follow-up. No significant associations with walking speed or IADL disability were observed. Individual micronutrient analysis revealed a significant association between the lowest two quartiles of vitamin C intake and poor grip strength. The lowest quartiles of intake for vitamins A, C, E and Zn were significantly associated with incident ADL disability. The study observed that poor antioxidant and anti-inflammatory food intake were associated with odds of developing disability and declining muscle strength in older men. Further interventional research is necessary to clarify the causality of these associations.

Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia.

Injectable insulin is an extensively used medication with potential life-threatening hypoglycaemic events. Here we report on insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer to produce a responsive oral insulin nanoformulation. This formulation is pH responsive, is insoluble in acidic environments and shows increased absorption in human duodenum explants and Caenorhabditis elegans at neutral pH. The formulation is sensitive to glucosidase enzymes to trigger insulin release. It is found that the formulation distributes to the liver in mice and rats after oral administration and promotes a dose-dependent reduction in blood glucose without promoting hypoglycaemia or weight gain in diabetic rodents. Non-diabetic baboons also show a dose-dependent reduction in blood glucose. No biochemical or haematological toxicity or adverse events were observed in mice, rats and non-human primates. The formulation demonstrates the potential to orally control blood glucose without hypoglycaemic episodes.

Intra-generational social mobility and mortality among older men in the Concord Health and Ageing in Men Project: A cohort study.

Objectives: We examined associations between intra-generational social mobility (reflected in life-course socioeconomic trajectories) and mortality, among older men. Methods: Data came from a prospective Australian community-based cohort of older men. Social mobility was defined by socioeconomic indicators from three points in the life-course: educational attainment (late adolescence-early adulthood), occupation (mid-life), and current sources of income (older age). We defined indicators of social mobility trajectory (6 categories; reflecting the direction of social mobility) and social mobility status (2 categories; mobile or non-mobile). We used Cox regression to examine associations with mortality, adjusting for age, country of birth, and living arrangement. Results: We followed 1568 men (mean age 76.8, SD 5.4) for a mean duration of 9.1 years, with 797 deaths recorded. Moving upward was the predominant social mobility trajectory (36.0%), followed by mixed trajectories (25.1%), downward (15.1%), stable low (12.2%), stable high (7.6%), and stable middle (4.0%). Men with downward (Hazard ratio 1.58, 95% CI 1.13 to 2.19) and stable low socioeconomic trajectories (1.77, 1.25 to 2.50) had higher mortality risks than men with stable high socioeconomic trajectories, while men with upward trajectories had similar risks to those with stable high trajectories. 76.2% of the participants were classified as having mobile status; no associations were evident between binary social mobility status and mortality. Discussions: These findings suggest cumulative and persistent exposure to disadvantaged socioeconomic conditions across the life-course, rather than social mobility, is associated with increased mortality. For each stage of the life-course, addressing socioeconomic disadvantage may reduce inequities in mortality.

Toward reconciling the roles of FGF21 in protein appetite, sweet preference, and energy expenditure.

Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction independently of an animal's energy status, exerts profound effects on feeding behavior and metabolism. Here, we demonstrate that considering the nutritional contexts within which FGF21 is elevated can help reconcile current controversies over its roles in mediating macronutrient preference, food intake, and energy expenditure. We show that FGF21 is primarily a driver of increased protein intake in mice and that the effect of FGF21 on sweet preference depends on the carbohydrate balance of the animal. Under no-choice feeding, FGF21 infusion either increased or decreased energy expenditure depending on whether the animal was fed a high- or low-energy diet, respectively. We show that while the role of FGF21 in mediating feeding behavior is complex, its role in promoting protein appetite is robust and that the effects on sweet preference and energy expenditure are macronutrient-state-dependent effects of FGF21.

SIRT2 transgenic over-expression does not impact lifespan in mice.

The NAD+ -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity.

Associations between protein to non-protein ratio and intakes of other dietary components in a cohort aged 65-75 years: the Nutrition for Healthy Living Study.

OBJECTIVE: Diets with a low proportion of energy from protein have shown to cause overconsumption of non-protein energy, known as Protein Leverage. Older adults are susceptible to nutritional inadequacy. The aim was to investigate associations between protein to non-protein ratio (P:NP) and intakes of dietary components and assess the nutritional adequacy of individuals aged 65-75 years from the Nutrition for Healthy Living (NHL) Study. DESIGN: Cross-sectional. Nutritional intakes from seven-day weighed food records were compared with the Nutrient Reference Values for Australia and New Zealand, Australian Guide to Healthy Eating, Australian Dietary Guidelines and World Health Organisation Free Sugar Guidelines. Associations between P:NP and intakes of dietary components were assessed through linear regression analyses. SETTING: NHL Study. PARTICIPANTS: 113 participants. RESULTS: Eighty-eight (59 female and 29 male) with plausible dietary data had a median (interquartile range) age of 69 years (67-71), high education level (86 %) and sources of income apart from the age pension (81 %). Substantial proportions had intakes below recommendations for dairy and alternatives (89 %), wholegrain (89 %) and simultaneously exceeded recommendations for discretionary foods (100 %) and saturated fat (92 %). In adjusted analyses, P:NP (per 1 % increment) was associated with lower intakes of energy, saturated fat, free sugar and discretionary foods and higher intakes of vitamin B12, Zn, meat and alternatives, red meat, poultry and wholegrain % (all P < 0·05). CONCLUSIONS: Higher P:NP was associated with lower intakes of energy, saturated fat, free sugar and discretionary. Our study revealed substantial nutritional inadequacy in this group of higher socio-economic individuals aged 65-75 years.

Sarcopenia prevalence and functional outcomes in older men with obesity: Comparing the use of the EWGSOP2 sarcopenia versus ESPEN-EASO sarcopenic obesity consensus definitions.

BACKGROUND & AIMS: The potential for older adults with obesity to also have sarcopenia, and the health consequences of 'sarcopenic obesity', may be underappreciated by health professionals. The primary aim of this secondary analysis of a prospective cohort study of older men was to explore the prevalence and functional outcomes of sarcopenic obesity based on different consensus definitions. METHODS: 1416 community-dwelling men aged ≥70 years were classified into sarcopenia categories according to the European Working Group on Sarcopenia in Older People (EWGSOP2) definition, and sarcopenic obesity categories according to the European Society for Clinical Nutrition and Metabolism and the European Association for the Study of Obesity (ESPEN-EASO) definition. Descriptive analyses determined prevalence of sarcopenia in obese and non-obese older men. Multivariable analyses compared associations with functional outcomes including activity of daily living (ADL) and instrumental activity of daily living (IADL) disability and 12-month incident falls. RESULTS: According to the EWGSOP2 definition, 12.6% of men had confirmed sarcopenia but only 0.3% of men had sarcopenia and obesity (BMI ≥30 kg/m2). Conversely, 9.6% of men had sarcopenic obesity according to the ESPEN-EASO definition. Notably, no men with a BMI ≥32 kg/m2 were classified as having EWGSOP2-confirmed sarcopenia, despite the fact that 60.8% of all men with BMI ≥32 kg/m2 had low muscle strength. Due to low numbers (N = 4) of obese older men with EWGSOP2-confirmed sarcopenia, associations with functional outcomes were not assessed. Men with sarcopenic obesity according to the ESPEN-EASO definition had significantly lower hand grip strength, higher chair-stands time and slower gait speed (all P < 0.05), increased odds for ADL (odds ratio: 5.02, 95% CI: 1.85-13.58) and IADL (2.18, 1.38-3.45) disability, and higher 12-month incident falls rates (incident rate ratio: 1.59, 95% CI: 1.03-2.44) than men with neither sarcopenia nor obesity. CONCLUSION: Low muscle strength is common in older men with obesity, but the prevalence of sarcopenia is likely to be underestimated when the EWGSOP2 operational definition is applied in this population. The ESPEN-EASO operational definition of sarcopenic obesity appears to provide a valid approach for identifying older men with obesity who are at risk of poor functional outcomes related to sarcopenia.

Towards Optimizing Hospitalized Older adults' MEdications (TO HOME): Multi-centre study of medication use and outcomes in routine care.

AIMS: Comprehensively investigate prescribing in usual care of hospitalized older people with respect to polypharmacy; potentially inappropriate medications (PIMs) according to Beers criteria; and cumulative anticholinergic and sedative medication exposure calculated with Drug Burden Index (DBI). Specifically, to quantify exposure to these measures on admission, changes between admission and discharge, associations with adverse outcomes and medication costs. METHODS: Established new retrospective inpatient cohort of 2000 adults aged ≥75 years, consecutively admitted to 6 hospitals in Sydney, Australia, with detailed information on medications, clinical characteristics and outcomes. Conducted cross-sectional analyses of index admission data from cohort. RESULTS: Cohort had mean (standard deviation) age 86.0 (5.8) years, 59% female, 21% from residential aged care. On admission, prevalence of polypharmacy was 77%, PIMs 34% and DBI > 0 in 53%. From admission to discharge, mean difference (95% confidence interval) in total number of medications increased 1.05 (0.92, 1.18); while prevalence of exposure to PIMs (-3.8% [-5.4, -2.1]) and mean DBI score (-0.02 [-0.04, -0.01]) decreased. PIMs and DBI score were associated with increased risks (adjusted odds ratio [95% confidence interval]) of falls (PIMs 1.63 [1.28, 2.08]; DBI score 1.21[1.00, 1.46]) and delirium (PIMs 1.76 [1.38, 1.46]; DBI score 1.42 [1.19, 1.71]). Each measure was associated with increased risk of adverse drug reactions (polypharmacy 1.42 [1.19, 1.71]; PIMs 1.87 [1.40, 2.49]; DBI score 1.90 [1.55, 2.15]). Cost (AU$/patient/hospital day) of medications contributing to PIMs and DBI was low ($0.29 and $0.88). CONCLUSION: In this large cohort of older inpatients, usual hospital care results in an increase in number of medications and small reductions in PIMs and DBI, with variable associations with adverse outcomes.

Mixed Evidence of an Association between Self-Rated Hearing Difficulties and Falls: Prospective Analysis of Two Longitudinal Studies.

INTRODUCTION: This study aimed to assess the extent to which a single item of self-reported hearing difficulties is associated with future risk of falling among community-dwelling older adults. METHODS: We used data from two Australian population-based cohorts: three waves from the PATH Through Life study (PATH; n = 2,048, 51% men, age 66.5 ± 1.5 SD years) and three waves from the Concord Health and Ageing in Men Project (CHAMP; n = 1,448, 100% men with mean age 77.3 ± 5.3 SD years). Hearing difficulties were recorded on a four-point ordinal scale in PATH and on a dichotomous scale in CHAMP. The number of falls in the past 12 months was reported at each wave in both studies. In CHAMP, incident falls were also ascertained by triannual telephone call cycles for up to four years. Multivariable-adjusted random intercept negative binomial regression models were used to estimate the association between self-reported hearing difficulties and number of falls reported at the following wave or 4-monthly follow-ups. RESULTS: In PATH, self-reported hearing difficulties were associated with a higher rate of falls at follow-up (incidence rate ratio = 1.15, 95% CI = 1.03-1.27 per a one-level increase in self-reported hearing difficulties), after adjusting for sociodemographic characteristics, health behaviours, physical functioning, balance, mental health, medical conditions, and medications. There were no significant associations between hearing difficulties and the rate of falls based on either repeated survey or 4-monthly follow-ups in CHAMP. CONCLUSION: Though we find mixed results, findings from PATH data indicate an ordinal measure of self-reported hearing loss may be predictive of falls incidence in young-old adults. However, the null findings in the male-only CHAMP preclude firm conclusions of a link between hearing loss and falls risk.

Oral health-related quality of life of older Australian men.

OBJECTIVES: The aims of this study were to assess oral health-related quality of life (OHRQoL) in a cohort of older Australian men and explore the association between their general health conditions, socio-demographic factors and OHRQoL. METHODS: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of Australian men, initiated in 2005-2006 with an initial sample of 1705 men 70 years or over. Participants completed a self-administered health and socio-demographic questionnaire and attended an interview and clinical assessment at baseline and each of three follow-up assessments. Information on oral health and responses to the Oral Health Impact Profile (OHIP-14) were collected in the 4th follow-up in which 778 men completed the OHIP-14 questionnaire and 614 men had a dental assessment. The prevalence of oral health impact was defined as a response of fairly often or very often to one or more of the OHIP-14 questions. Mean OHIP-14 scores were calculated for the 14 questions and used as the dependent variable in the regression analyses. Zero-inflated Poisson regression was used to estimate prevalence rate ratios (PRR). RESULTS: Only 10% of men presented oral health impacts. In multivariate regression modelling, being born in Italy/Greece (PRR: 2.16, 95% CI: 1.93-2.42) or in other countries (PRR: 2.12, 95% CI: 1.89-2.38), having poor self-rated general health (PRR: 1.38, 95% CI: 1.24-1.53), having poor mental wellbeing (PRR: 1.14, 95% CI: 1.04-1.24), having ≥6 depressive symptoms (PRR: 1.18, 95% CI: 1.05-1.32), being a current smoker (PRR: 1.34, 95% CI: 1.06-1.70) and having more decayed tooth surfaces (PRR:1.01, 95% CI: 1.00-1.02) were associated with higher impact scores. CONCLUSIONS: Overall, older Australian men exhibit good oral health-related quality of life. The inter-relationship between perceptions of general health and well-being, health and oral health variables and social background supports policy objectives of closer integration of general health and oral health services for older Australian men.

Diagnostic accuracy of linked administrative data for dementia diagnosis in community-dwelling older men in Australia.

BACKGROUND: Routinely collected health administrative data can be used to estimate the prevalence or incidence of dementia at a population level but can be inaccurate. This study aimed to examine the accuracy of hospital and death data for diagnosing dementia compared with a clinical diagnosis in community dwelling older men in Australia. METHODS: We performed a retrospective analysis of the Concord Health and Ageing in Men Project (CHAMP) in Sydney, Australia. Of the 1705 men aged ≥70 years in the CHAMP study, 1400 had available linked administrative data records from 1 year prior to 1 year post the date of clinical dementia diagnosis. The primary outcome was the accuracy of dementia diagnosis using linked administrative data records compared to clinical dementia diagnosis. The linked data diagnosis was based on hospital and death records for the 1 year pre and post the clinical diagnosis. Clinical dementia diagnosis was a two-stage process with initial screening, followed by clinical assessment for those meeting a validated cut-off. A final clinical diagnosis of dementia based on the Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria was reached by a consensus panel. RESULTS: Administrative data identified 28 participants as having dementia, compared to 88 identified through clinical assessment. Administrative data had a sensitivity of 20% (95% CI: 13-30%, 18/88), specificity of 99% (95% CI: 99-100%, 1301/1312), positive predictive value (PPV) of 62% (95% CI: 44-77%), negative predictive value of 95% (95% CI: 94-95%), positive likelihood ratio of 24.4 (95% CI: 11.9-50.0) and negative likelihood ratio of 0.80 (0.72-0.89). CONCLUSIONS: Administrative hospital and death data has limited accuracy for dementia diagnosis with poor sensitivity and PPV. The prevalence of dementia is likely underestimated using hospital and deaths data.

Multidimensional associations between nutrient intake and healthy ageing in humans.

BACKGROUND: Little is known about how normal variation in dietary patterns in humans affects the ageing process. To date, most analyses of the problem have used a unidimensional paradigm, being concerned with the effects of a single nutrient on a single outcome. Perhaps then, our ability to understand the problem has been complicated by the fact that both nutrition and the physiology of ageing are highly complex and multidimensional, involving a high number of functional interactions. Here we apply the multidimensional geometric framework for nutrition to data on biological ageing from 1560 older adults followed over four years to assess on a large-scale how nutrient intake associates with the ageing process. RESULTS: Ageing and age-related loss of homeostasis (physiological dysregulation) were quantified via the integration of blood biomarkers. The effects of diet were modelled using the geometric framework for nutrition, applied to macronutrients and 19 micronutrients/nutrient subclasses. We observed four broad patterns: (1) The optimal level of nutrient intake was dependent on the ageing metric used. Elevated protein intake improved/depressed some ageing parameters, whereas elevated carbohydrate levels improved/depressed others; (2) There were non-linearities where intermediate levels of nutrients performed well for many outcomes (i.e. arguing against a simple more/less is better perspective); (3) There is broad tolerance for nutrient intake patterns that don't deviate too much from norms ('homeostatic plateaus'). (4) Optimal levels of one nutrient often depend on levels of another (e.g. vitamin E and vitamin C). Simpler linear/univariate analytical approaches are insufficient to capture such associations. We present an interactive tool to explore the results in the high-dimensional nutritional space. CONCLUSION: Using multidimensional modelling techniques to test the effects of nutrient intake on physiological dysregulation in an aged population, we identified key patterns of specific nutrients associated with minimal biological ageing. Our approach presents a roadmap for future studies to explore the full complexity of the nutrition-ageing landscape.

Targeting the liver in dementia and cognitive impairment: Dietary macronutrients and diabetic therapeutics.

Many people living with dementia and cognitive impairment have dysfunctional mitochondrial and insulin-glucose metabolism resembling type 2 diabetes mellitus and old age. Evidence from human trials shows that nutritional interventions and anti-diabetic medicines that target nutrient-sensing pathways overcome these deficits in glucose and energy metabolism and can improve cognition and/or reduce symptoms of dementia. The liver is the main organ that mediates the systemic effects of diets and many diabetic medicines; therefore, it is an intermediate target for such dementia interventions. A challenge is the efficacy of these treatments in older age. Solutions include the targeted hepatic delivery of diabetic medicines using nanotechnologies and titration of macronutrients to optimize hepatic energy metabolism.

New horizons in life extension, healthspan extension and exceptional longevity.

Many common chronic diseases and syndromes are ageing-related. This raises the prospect that therapeutic agents that target the biological changes of ageing will prevent or delay multiple diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in ageing, with the aims of reducing the burden of ageing-related diseases and increasing lifespan and healthspan. The approach to discovering gerotherapeutic drugs is similar to that used to discover drugs for diseases. This includes screening for novel compounds that act on receptors or pathways that influence ageing or repurposing of drugs currently available for other indications. A novel approach involves studying populations with exceptional longevity, in order to identify genes variants linked with longer lifespan and could be targeted by drugs. Metformin, rapamycin and precursors of nicotinamide adenine dinucleotide are amongst the frontrunners of gerotherapeutics that are moving into human clinical trials to evaluate their effects on ageing. There are also increasing numbers of potential gerotherapeutic drugs in the pipeline or being studied in animal models. A key hurdle is designing clinical trials that are both feasible and can provide sufficient clinical evidence to support licencing and marketing of gerotherapeutic drugs.