Association of Mitochondrial DNA Haplogroups with Exceptional Longevity in a Chinese Population

BACKGROUND: Longevity is a multifactorial trait with a genetic contribution, and mitochondrial DNA (mtDNA) polymorphisms were found to be involved in the phenomenon of longevity. METHODOLOGY/PRINCIPAL FINDINGS: To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population based case-control study was conducted in Rugao--a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged > or = 95 yr (EL group). Control subjects include 926 individuals aged 60-69 years (elderly group) and 463 individuals aged 40-49 years (middle-aged group) randomly recruited from Rugao. We observed significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle-aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle-aged subjects (8.6%), elderly subjects (7.2%) and longevity subjects (4.8%) (p = 0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%) and longevity subjects (21.7%) in females (p = 0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%) and longevity subjects (1.7%) in females (p = 0.045). CONCLUSIONS: Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population

Preface

In the European Union, the proportion of older people has increased in recent decades and it is predicted to increase from 25 to 40% by 2030. Together with climate changes and the increase of energy demand the aging of the population is becoming a major challenge than humanity is going to cope with. One of the major contributors to population aging is the reduced mortality among older people, which is largely due to a combination of improved lifestyles, prevention, and treatment that mainly prevent cardiovascular damages. Moreover, improved delivery of health care may have been of primary importance in decreasing old-age mortality in this century. Therefore, population aging can reasonably be described as both an outcome of, and a challenge for, European health systems. This demographic explosion emphasizes the critical importance of identifying strategies able to counteract or delay aging and the onset of age-related diseases and disabilities, and thus contribute to increasing the number of elderly European citizens in good health, and reducing age-related medical and social costs. A large part of Horizon 2020, the new work-programme of European Commission, is devoted to interventions to promote health in elderly. In 2011, the EU launched the European Innovation Partnership on Active and Healthy Aging, aimed at applying innovation to better respond to Europe's aging societies and add 2 years of good health to the average European by 2020. Evidence is increasing that the promotion of so-called healthy or active aging not only increases healthy life expectancy and postpones much health care expenditure, but also has wider economic benefits because people who live a long and healthy life are more inclined to stay in the labor force and have a strong incentive to invest in skill development. Actions will include efforts to improve living conditions and care together with primary prevention, including interventions against alcohol consumption, smoking, obesity, sedentary lifestyles and poor diets. Within this scenario epidemiological studies and intervention trials have shown that in the elderly nutrition play a major role in healthy aging, and in reducing risk of disease and improving quality of life. In particular, experimental evidence indicates that specific, key dietary constituents affect inflammation and immune function as well as single organs such as heart, bone, brain, muscle, and gastrointestinal tract. Despite its enormous complexity, one of the key mechanisms of aging is inflammation as exemplified by the fact that a typical feature of the aging process is the development of a chronic, low grade, inflammatory status named inflammaging that plays a pivotal role in the most important geriatric conditions, such as sarcopenia, frailty, and disability, as it is shared by the major age-related diseases, thus contributing to elderly morbidity and mortality. However, available data in the literature suggest that inflammaging is malleable and reversible, and can be at least in part counteracted and slowed down through changes in life-style and diet. The FP7-KBBE-NU-AGE project (G.A. n\ub0266486) coordinated by Prof. Claudio Franceschi from University of Bologna, Italy, targets nutrition as a major modulator of inflammaging and other age-related functional outcomes. The underlying hypothesis of NU-AGE is that a whole diet approach will have greater beneficial effect on overall health than single nutrient interventions. Simultaneous changes in a select range of dietary constituents, with a focus on reducing chronic low grade inflammation, will ensure that the subtle effects observed from single nutrients will act in concert to optimize healthy aging. Thus, the NU-AGE consortium will comprehensively study the effect of a Mediterranean diet newly designed according to the nutritional needs of people over 65 years of age, the so-called \u201cNU-AGE diet\u201d. A total of 1250 non-frail and pre-frail volunteers of 65\u201379 years old, equally subdivided into males and females, will be characterized before and after the dietary intervention by measuring a limited number of robust parameters capable of providing reliable data about different domains/subsystems (health and nutritional status, physical and cognitive functions, immunological, biochemical and metabolic parameters). A sub-group of subjects will be further characterized by advanced techniques (genetics, epigenetics) and high-throughput \u201comics\u201d (transcriptomics, metagenomics, metabolomics) in order to identify cellular and molecular targets and mechanisms responsible for the effects of the whole diet intervention. This approach will allow an evaluation of the whole-organism response by a systems biology approach, considering several tissues and organs/systems as a functional network instead of assessing the single tissue and organ responses separately. Here, we present a special edition of MAD dedicated to this project consisting of fifteen papers, encompassing the main topics. First of all, this special issue will focus on the conceptual framework and design of NU-AGE, with an update on inflammaging (Santoro et al.), and a critical reappraisal of the rationale of the \u201cNU-AGE diet\u201d (Berendsen et al.). Then, the special issue addresses some of the most critical aspects of nutrition in the elderly, which should illustrate the overall complexity of the dietary requirement in old age. The various contributions are devoted not only to classical topics such as protein-energy homeostasis (Boirie et al.) and micronutrients such as copper, zinc and selenium (Mocchegiani et al.), but also to neglected topics such water, hydratation and drinking dietary patterns (Hooper et al.), as well as to specific micronutrients such as iron (Fairweather-Tait et al.), owing to its clinical importance (anemia in the elderly). This special issue addresses hot topics which recent literature suggests of utmost importance to understand the systemic effects of nutrition and nutritional interventions such as that adopted by NU-AGE. Thus, there are three papers that, within an inflammaging perspective, are devoted to: (i) the interaction between diet and the gut microbiota (Candela et al.); (ii) the effect of an elderly tailored diet on cognitive decline and on the gut\u2013brain axes (Caracciolo et al.); (iii) nutritional interventions (caloric restriction, supplementation with nutrients involved in one-carbon metabolism and bioactive food components) that impact on the epigenetic profile (DNA methylation and microRNA) of cells and organs of the body (Bacalini et al.). A paper including new experimental data on the effect of resistance-type exercise training with or without protein supplementation on cognitive functioning in frail and pre-frail elderly people (van de Rest et al.) can be considered as a complement of some of the above mentioned papers within the generally recognized scenario that physical activity has been proposed as one of the most effective strategies to prevent the age-related cognitive decline. Taking into account that the major aim of the NU-AGE project is to test the hypothesis that an appropriate Mediterranean diet ad hoc modified to meet the elderly requirements will decrease the level and intensity of inflammaging, two papers are dedicated to the effect of diet on immunosenescence (Maij\uf3 et al.) and the changes occurring with age in adipose tissue(s) (Zamboni et al.), both assumed as major sources of inflammatory stimuli in old bodies. Finally, a paper by Collino and colleagues discusses the emerging perspective of a personalized and subject-tailored nutrition in the elderly, a perspective which is becoming realistic owing to the use of new \u201comics\u201d (metabolomics). This approach has several advantages, as it can help in identifying key molecular mechanisms/targets affected by diet and related to inflammaging, and in revealing basic profiles of health and functions (biomarkers) in the elderly. Two final papers try to put the problem of the best diet for attaining an active and healthy aging in a broader perspective. The first illustrates another major final aim of NU-AGE, i.e. the idea to put all the clinical, biological and omics data in an ad hoc re-designed database in order to allow an integrated analysis of all the collected data within a system biology perspective of inflammaging and nutrition (Calcada et al.). The second paper enlarges our European horizon and opens the eyes on another famous diet to attain healthy longevity in another part of the world, the so-called \u201cOkinawan diet\u201d (Willcox et al.), addressing this topic in a comprehensive and critical way. European Union and the EU-funded large projects are interested not only in the health and wellbeing of EU citizens but also in the wellbeing of EU economy, which in turn can affect the money available for welfare. Thus, the NU-AGE project was asked not only to perform basic investigations on diet and healthy aging but also to investigate the determinants of food choices in elderly, and finally to exploit the knowledge gained by NU-AGE in order to help food industries to set up new food product prototypes and to design advanced traditional foods for the old citizens in Europe. Thus, the NU-AGE consortium is constituted not only by scientists, but also by food industries and by the EU Federations of Food & Drink Industries. This part is not covered by the NU-AGE special issue in MAD, however, it is interesting to stress the link between basic food science and its economic outcomes and the social/behavioral aspects of nutrition in the elderly. To this aim the interested MAD reader is referred to the first results recently published by members of NU-AGE consortium (Irz et al., Public Health Nutrition journal, 2013). These results indicate that diet quality among the EU elderly is low on average and highly heterogeneous. Education, not living alone, and being a female are all characteristics that are positively associated with diet quality after controlling for other socio-demographic factors. The results also established that the causal relationship between diet quality and health is bi-directional: diet quality influences health and health influences diet quality. Although intuitive, this result implies that feedback mechanisms in the relationship between diet quality and health should be considered carefully when analyzing the benefits from promoting healthy eating to the elderly. To conclude, even if the NU-AGE project is represented by a core of basic and omics food science, its integrated perspective also includes research on how aging affects eating behavior as well as on the acceptability and understanding of food with nutrition/health claims. Within this scenario, NU-AGE is committed to develop guidelines for best practice in communicating to the elderly about food to improve health and wellbeing. This interdisciplinary, trans-sectoral project will integrate complementary approaches and perspectives into a unique knowledge base that will be transferred to industries to deliver products, tools and services that will support the elderly in respect of recommended diets, lifestyles and advice for healthy longevity

Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals

The regular use of medication may interfere with micronutrient metabolism on several levels, such as absorption, turnover rate, and tissue distribution, and this might be amplified during aging. This study evaluates the impact of self-reported medication intake on plasma micronutrients in the MARK-AGE Project, a cross-sectional observational study in 2217 subjects (age- and sex-stratified) aged 35-75 years from six European countries that were grouped according to age. Polypharmacy as possible determinant of micronutrient concentrations was assessed using multiple linear regression models adjusted for age-group, dietary fruit, vegetables, and juice intake, and other confounders. Younger participants reported taking fewer drugs than older participants. Inverse associations between medication intake and lutein (-3.31% difference per increase in medication group), beta-carotene (-11.44%), alpha-carotene (-8.50%) and positive associations with retinol (+2.26%), alpha-tocopherol/cholesterol (+2.89%) and gamma-tocopherol/cholesterol (+1.36%) occurred in multiple adjusted regression models. Combined usage of a higher number of medical drugs was associated with poorer status of carotenoids on the one hand and higher plasma concentrations of retinol, alpha- and gamma-tocopherol on the other hand. Our results raise concerns regarding the safety of drug combinations via the significant and surprisingly multifaceted disturbance of the concentrations of relevant micronutrients

Ageing research in Greece

Ageing research in Greece is well established. Research groups located in universities, research institutes or public hospitals are studying various and complementary aspects of ageing. These research activities include (a) functional analysis of Clusterin/Apolipoprotein J, studies in healthy centenarians and work on protein degradation and the role of proteasome during senescence at the National Hellenic Research Foundation; (b) regulation of cell proliferation and tissue formation, a nationwide study of determinants and markers of successful ageing in Greek centenarians and studies of histone gene expression and acetylation at the National Center for Scientific Research, ‘Demokritos’; (c) work on amyloid precursor protein and Presenilin I at the University of Athens; (d) oxidative stress-induced DNA damage and the role of oncogenes in senescence at the University of Ioannina; (c) studies in the connective tissue at the University of Patras; (f) protcomic studies at the Biomedical Sciences Research Center ‘Alexander Fleming’; (g) work on Caenorhabditis clegans at the Foundation for Research and Technolog;(h) the role of ultraviolet radiation in skin ageing at ‘Andreas Sygros’ Hospital; (i) follow-up studies in healthy elderly at the Athens Home for the Aged; and (j) socio-cultural aspects of ageing at the National School of Public Health. These research activities are well recognized by the international scientific community as it is evident by the group’s very good publication records as well as by their direct funding from both European Union and USA. This article summarizes these research activities and discuss future directions and efforts towards the further development of the ageing field in Greece. (C) 2002 Elsevier Science Inc. All rights reserved