Changing course in ageing research: The Healthy Ageing Phenotype☆

Article Outline

• Abstract
• 1. Introduction
• 2. The world is ageing
• 3. The malleability of the ageing process
• 4. Yin and Yang: vulnerability and resilience
• 5. Ageing and the “Healthy Ageing Phenotype”
• 6. Once ill always ill? Once frail…
• 7. Multiple tissues but common pathways: mechanisms and biomarkers of the HAP
• 8. A healthy lifestyle the key to healthy senescence
• 9. On Morpheus arms
• 10. A sound mind in a sound body: wellbeing and health
• 11. Multi-dimensional problems might need multi-dimensional solutions
• 12. Exploring the other side of the moon: a new world demands a change of course
• 13. Recommendations
• Conflicts of interest
• Acknowledgements
• References
• Copyright

Abstract 

Ageing is often associated with the aged and the diseased, nevertheless ageing is a process that starts in-uterus and is characterised by a progressive functional loss but not necessarily by the presence of disease and poor quality of life. How to meander through life without crossing the confines of major chronic disease and cognitive and physical impairment remains one of the most relevant challenges for science and humankind. Delimiting that ‘immaculate’ trajectory – that we dub as the ‘Healthy Ageing Phenotype’ – and exploring solutions to help the population to stay or return to this trajectory should constitute the core focus of scientific research. Nevertheless, current efforts on ageing research are mainly focused on developing animal models to disentangle the human ageing process, and on age-related disorders often providing merely palliative solutions. Therefore, to identify alternative perspectives in ageing research, Unilever and the Medical Research Council (MRC) UK convened a Spark workshop entitled ‘The Healthy Ageing Phenotype’. In this meeting, international specialists from complementary areas related to ageing research, gathered to find clear attributes and definitions of the ‘Healthy Ageing Phenotype’, to identify potential mechanisms and interventions to improve healthy life expectancy of the population; and to highlight areas within ageing research that should be prioritised in the future. General agreement was reached in recognising ageing research as a disaggregated field with little communication between basic, epidemiological and clinical areas of research and limited translation to society. A more holistic, multi-disciplinary approach emanating from a better understanding of healthy ageing trajectories and centred along human biological resilience, its maintenance and the reversibility from early deviations into pathological trajectories, is urgently required. Future research should concentrate on understanding the mechanisms that permit individuals to maintain optimal health when facing pathological hazards and on developing and assessing potential interventions that could aid to re-establish resilience when lost or guarantee its integrity if present. Furthermore it is fundamental that scientific findings are translated incessantly into clear messages delivered to governmental institutions, the industry and society in general.

Keywords: Ageing research, Healthy Ageing Phenotype

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1. Introduction 

“Prevention is better than cure”

Desiderius Erasmus (1466–1536)

The age distribution of the world's population is dramatically shifting; longevity continues to rise and there are steady improvements in healthcare, but there is not an accompanying increase in fertility rates [1], [2]. In total, the global proportion of people aged above 60 years is expected to increase from 10% to 21% in the next 5 decades [3]. However, research into how to achieve healthy ageing and which life-time trajectories are associated with positive health and wellbeing in older age, is still relatively under-researched. Hence, to identify alternative perspectives in ageing research, Unilever and the Medical Research Council (MRC) of UK convened a Spark workshop entitled ‘The Healthy Ageing Phenotype’ [4]. Spark workshops are strategic meetings in which scientists from different disciplines and perspectives, share knowledge, build novel concepts, and assess options for future research activities. In this particular meeting, international specialists from complementary areas related to ageing research gathered to:

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2. The world is ageing 

Global life expectancy in the last two centuries has been increasing linearly and does not appear to be approaching a plateau [2]. Longevity in best in class countries has risen by approximately 3 months per year for the past 170 years and average mean life expectancy is forecasted to be 96.4 years in 2050 [2]. Incessant progress in the prevention of mortality as a result of advances in income, hygiene, sanitation and infection control, nutrition, education, and medicine, is generally believed to account for the increases in longevity [2]. Concomitantly, fertility rates are falling, leading to an unprecedented shift in demographics [1], [2], [3]. Nevertheless, increases in life expectancy and in the proportion of individuals living longer do not necessarily translate into improvements of health and wellbeing [5], [6]. Indeed, many countries, although experiencing steady increases in longevity, are suffering from stagnation of healthy life expectancy and a greater burden caused by chronic conditions and disability [5], [6]. For example, in the UK between 1991 and 2001, life expectancy increased by 2.2 years but only 0.6 years were healthy years [5], [7]. Disparities in life expectancy between the best and worst (electoral) wards in the U.K. exceed twenty years [8] and increasing healthy life expectancy across the world has been identified as a key objective for research [5], [7].

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3. The malleability of the ageing process 

The recent history of human longevity demonstrates that the ageing process is malleable to a significant degree, but the extent of this has not yet been fully explored in humans as the majority of research on this area has been conducted in lower animal models (e.g., nematodes, flies) with a limited degree of extrapolation [4], [9]. Ageing is a multi-factorial process and it is vital to understand the mechanisms associated with ageing and those that determine healthy life trajectories [10], [11]. Aberrant gene expression, for example, is strongly involved in processes leading to the development of diseases that restrict lifespan and some have suggested that genetic factors may also underlie the ageing process itself [12], [13]. However, the ageing process seems to occur at different rates in different tissues and appears to have a considerable stochastic element [11], [14]. Although twin studies suggest that genotype explains roughly 25% of differences in life expectancy, the role of environmental and lifestyle factors (such as pollution, infections, stress, physical inactivity, psychological wellbeing, health infra-structure and financial security), combined with an element of chance, are also important and could account for the remaining variance [12], [15], [16]. It has been claimed that the influence of the environment is permanent and starts immediately after fecundation [17]. For example, several studies, have reported that the intrauterine environment has short-term influences on health outcomes as well as long-term influences on the development of diseases during adulthood [17], [18], [19]. Low birth weight and being born small for gestational age have also repeatedly been associated with development of diabetes, hypertension and cardiovascular disease (CVD) at middle age [17], [18], [19].

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4. Yin and Yang: vulnerability and resilience 

It is important to note that ageing over the lifecourse is not necessarily a steady decline from optimal physiological performance in early adulthood to poor functioning in late adulthood. To a large extent, remarkable physiological resilience in early stages of the ageing process reduces the negative effects of external stressors such as smoking, infections, psychological stress, sedentarianism and poor dietary habits and these stressors do not visibly induce morbidities at a young age. By resilience, we mean the capacity to maintain adequate function and structure at molecular and cellular levels by adapting or changing to specific challenges [20], [21]. This process relies on the interaction of multiple mechanisms that aim to preserve physical and psychological stability and homeostasis to ensure that the individual remains outside the realms of disease. The integrity of these homeostatic mechanisms determines the deviation from normality; deviation can be generalised or tissue-specific and is not necessarily clinically manifested [20], [21]. An adequate detection and measure of the level of resilience/vulnerability is key to identify the processes that lead from health to frailty and ultimately to the appearance of disease and death [20], [21]. A further exploration of the nature of resilience and the how we can prevent permanent dysregulation would provide significant insights into the healthy ageing process.

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5. Ageing and the “Healthy Ageing Phenotype” 

Ageing is often defined as the progressive loss of function accompanied by increasing morbidity and decreasing fertility with advancing age [10], [11], [14]. However, although ageing is the most significant risk factor for the appearance of morbidities, the ageing process starts in-uterus and is not necessarily accompanied by the presence of disease and poor quality of life. Life and ageing are practically synonymous and one cannot occur without the other. Unlike ageing, poor health is not a sine qua non-condition of life. As life starts so does the chance of departing from health. This chance increases with ageing and is determined by an intricate network of mechanisms that aim to maintain or recover corporal and mental homeostasis [10], [11], [14]. The ‘Healthy Ageing Phenotype’ (HAP) can be defined as the condition of being alive, while having highly preserved functioning metabolic, hormonal and neuro-endocrine control systems at the organ, tissue and molecular levels. It is further characterised by having a higher degree of physiological complexity in aspects of functioning such as heart rate variability, neuronal structure and bone architecture, which is associated with a biologically younger body. The HAP represents optimal reserve and biological resilience to respond to and accommodate daily environmental stressors, which translates into the absence of debilitating conditions (e.g., CVD, dementia, cancer) and the presence or maintenance of other important aspects of human functioning (e.g., cognitive and physical function). The HAP is multi-dimensional, age and gender-dependent and determined by the interaction between our genes, acquired epi-genetic imprinting and environmental factors.

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6. Once ill always ill? Once frail… 

To some extent frailty is the inverse of the Healthy Ageing Phenotype, but the precise extent to which they are two sides of the same coin is as yet unclear. There is no universal definition of frailty, but it is thought to be a multi-factorial dynamic state which occurs as a result of deleterious changes in the homeostatic network [20], [21], [22], [23], [24]. Cumulative defects alter the homeostatic network and lead to multi-system dysregulation and a decline in the adaptive capability to respond appropriately to stressors (the effect of stressors is likely exacerbated by poor lifestyle choices). Thus, frailty presents as a complex set of conditions including sarcopaenia, osteoporosis, poor motor function, impaired energy metabolism, extreme values of BMI, poor nutritional status, blood pressure instability and vulnerability to infection [20], [21], [22], [23], [24]. Although frailty is not a disease and it can occur independently, its presence increases the risk of development of disease, disability and death, and can occur subsequent to disease [22], [24]. For example, the occurrence of frailty (as measured by a 1 category increment in the Clinical Frailty Scale) has been independently associated with a 20% increase in the risk of death and with increased risk of developing CVD [25], [26]. Furthermore, different pre-disease states such as insulin resistance and atherosclerosis have been associated with the development of frailty [20], [21], [22], [24]. Nonetheless, frailty is to a large extent a reversible state that could be adverted or ceased by restoring resilience and homeostasis [20], [21], [22], [24]. One way to tackle frailty is through the use of pharmacological interventions. An alternative approach is to focus on lifestyle changes such as increased physical activity, smoking cessation and adequate dietary and sleep patterns as they may hold the key to improvement and/or reversal of frailty. It is also worthwhile to explore interventions and preventive strategies that combine pharmacology and lifestyle interventions as this may be the most fruitful way to achieve absence of frailty and disease.

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7. Multiple tissues but common pathways: mechanisms and biomarkers of the HAP 

Many chronic conditions share common underlying pathways and are lifestyle and age dependent (Fig. 1). For example, high-energy intake (diet) with low energy expenditure (physical activity) results in increased visceral obesity, insulin resistance and vascular inflammation. These conditions are associated with loss of metabolic flexibility (i.e., dysregulation of lipid and glucose fluxes), which may lead to CVD, diabetes and neuro-degenerative disease. This metabolic dysregulation is also associated with age-related cognitive decline and several mechanisms have been suggested to underlie this relation including microvascular and macrovascular disease, inflammation, adiposity, and insulin resistance [27]. Age-related hormonal changes, such as menopause, may contribute to this situation as a decline in circulating estrogen levels affects adiposity, lipid metabolism, and prothrombotic states which are associated with an increased risk of CVD [28], [29].

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• Fig. 1. 

  Mechanisms and phases of deviations from the Healthy Ageing Phenotype.

To prevent the accumulation of damage to the homeostatic balance, early identification of incipient dysregulation, before levels of vulnerability progress to a pathological level, is essential [20], [21]. This will allow the development of interventions to target specific pathways associated with multiple chronic conditions and morbidities and deliver effective prevention strategies. Due to the complexity of conditions such as frailty and metabolic dysregulation, an ‘integrated physiology’ (systems) approach is appropriate. This will allow a comprehensive understanding of these conditions and it will enable the identification of common pathways associated with dysregulation and how to preserve or reverse them.

In addition it is crucial to shift from a strategy of solving complex multi-morbidities in old age to strategies that target the population earlier in life and aim to prevent complex dysregulation. Rather than approaching this from an ‘individual high risk’ strategy, it should be a ‘population based’ risk reduction strategy where people are encouraged early in the ageing process to be proactive and maintain homeostatic balance through methods such as adopting a healthy lifestyle.

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8. A healthy lifestyle the key to healthy senescence 

The activities of daily living and lifestyle are very important factors in the maintenance of the homeostatic network. Several studies have demonstrated the health benefits of physical activity and adequate cardio-respiratory fitness [30], [31]. Physical activity has its effect through a variety of mechanisms (e.g., lowering the inflammatory response and positively attenuating several risk factors for CVD), and is associated with decreases in the risk of developing diabetes, CVD and mortality, as well as improvements in wellbeing [11], [30], [31]. In addition to physical activity, eating habits contribute to the delineation of our lifecourse trajectories [32], [33]. For example, experiments in rodents and lower animals have suggested caloric restriction is a potential route to healthy senescence, however, when this approach was applied to humans it was not fully suitable [34]. Nonetheless, diet and different dietary factors have been associated with positive health outcomes including reduction on mortality and of CVD and its risk factors [32], [33], [35]. Several studies have explored other aspects of a ‘healthy lifestyle’ and shown that in more than eighty thousand American nurses characteristics such as non-smoking, normal body mass index levels, moderate alcohol consumption, above moderate physical activity and a healthy diet was associated with a 83% reduction of coronary heart disease and 91% reduction on the risk of developing diabetes [36], [37]. Supporting evidence on the additive effect of several interventions targeting lifestyle factors not only comes from observational studies but also from experimental analyses. For instance, the DPS (Diabetes Prevention Study) and DPP (Diabetes Prevention Program) studies confirmed the potential benefit of multiple lifestyle changes on prevention of diabetes [38], [39].

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9. On Morpheus arms 

Another aspect of a healthy lifestyle is sleep quality and quantity. Although almost one third of human existence is spent sleeping, there is limited evidence about the impact of sleep on ageing. With age, quantity and quality of sleep deteriorates and given that there has been a reduction in the population's total average sleep time over the past 100 years the relative impact of these changes could increase [40], [41]. Among Americans, for example, the modal sleep duration has decreased 1h (from 8 to 7) in the last four decades [40]. Recent studies have demonstrated that even relatively short periods of sleep restriction lead to increased visceral adipose tissue and cardio-metabolic risk [40], [41]. Researchers have also started to explore the converse effects of sleep and shown that good sleep is related to positive psychological states [42], although the directionality (i.e., does good sleep lead to higher wellbeing or vice versa) and underlying mechanisms of this relationship remain unclear. The role of sleep in maintaining the healthy phenotype throughout the lifecourse has been under-researched and further efforts are required to clarify the mechanisms that lead from sleep disturbances to metabolic abnormalities and deterioration of health, as well as research on potential interventions that could improve the characteristics of populations’ sleep patterns.

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10. A sound mind in a sound body: wellbeing and health 

In addition to studying the physiological homeostasis of the body it is important to understand the psychological determinants that enable people to flourish (i.e., wellbeing) and how this relates to optimal mental and physical functioning. Wellbeing is a complex multi-dimensional concept and there are two main approaches to its study: the eudaimonic approach (also known as psychological wellbeing) centres on the fulfilment of personal potential and living a meaningful life and is concerned with having purpose in life, self-acceptance, personal growth and positive inter-personal relations. The hedonic approach (also known as subjective wellbeing or happiness) refers to personal satisfaction, happiness and contentment [43]. Researchers have shown that wellbeing has an important bearing on the trajectories of ageing [44], [45], [46]. Findings from the Whitehall II study, for example, have shown that high levels of wellbeing are associated with reduced neuro-endocrine, inflammatory, and cardiovascular activity [47]. In relation to lifestyle factors, high levels of wellbeing have been associated with a healthier lifestyle. Wellbeing can also be discussed in terms of psychological resilience (preservation of wellbeing in the face of adversity), which research has demonstrated to have a positive effect on health. For example, adequate management of stress has been associated with a 24% decrease risk of stroke [48]. This suggests that interventions should sustain both physiological and psychological homeostasis to maintain resilience and subsequently the absence of frailty and disease [49].

Although the integrated study of the biology and psychology of optimal functioning and its relation to health is a relatively new area of research, and further research is required to understand these relations, it holds considerable promise and will contribute to our understanding of healthy mental and physical functioning across the lifecourse.

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11. Multi-dimensional problems might need multi-dimensional solutions 

The current paper has provided a brief overview of a variety of lifestyle, environmental, psychological and physiological factors that play a role in healthy ageing. What this highlights is that there is not necessarily a single mechanism that underlies healthy ageing, and although there may be common pathways it is important to approach the preservation of the ‘Healthy Ageing Phenotype’ through the implementation of multi-factorial strategies. It may be that the best approach is a combination of single interventions with multiple and multi-systemic effects. However, current medical care and scientific research tend to be compartmentalised and performed in secluded silos, which means it is unlikely that integrated ‘solutions’ can be developed to improve healthy longevity. For example, the lack of success in preventing and halting current global epidemics of obesity, diabetes and CVD can be attributed in part to the lack of synergism of numerous isolated efforts dealing with these conditions. Wald and Law [50] commented on the inadequacy of this strategy in the BMJ: “current treatment to prevent heart disease… has generally been limited to single risk factors… a large preventive effect would require intervention in everyone at increased risk irrespective of the risk factor levels; intervention on several reversible causal risk factors together; and reducing these risk factors by as much as possible”. Consequently, to stop the current epidemic of CVD, Wald and Law proposed the Polypill—a theoretical combination of six pharmacological compounds (a statin, three antihypertensives, aspirin and folic acid) that could reduce CVD by over 80% [50]. However, the Polypill is a pharmacological solution to inherent consequences of our lifestyle and thus, cannot and should not constitute the long-term solution to our current ailments. Alternative approaches such as dietary modifications could play an essential role in the treatment and prevention of chronic disease. We argue that while the polypill approach is appropriate for high risk individuals, others would benefit from multi-dimensional interventions that aim to make overall lifestyle modifications including dietary improvements, increases in physical activity, smoking cessation and improvement of wellbeing and sleep habits. This multi-dimensional approach should not be the exception in prevention and healthcare but the rule, and in the footsteps of the Diabetes Prevention Study [39], it is vital that intervention studies address the potential of multi-dimensional interventions for extending healthy longevity.

Although both pharmacological and lifestyle interventions contribute to the prevention of major lifestyle chronic conditions (e.g., hypertension and diabetes), there has been a historical lack of resources into research on prevention. Now is the time to address this and invest in research on effective strategies for behaviour modification (whether it be through pharmacological and/or lifestyle means) to optimise lifestyle at different stages of the lifecourse. A more holistic, multi-disciplinary approach that is centred on biological resilience, its maintenance and how to reverse early deviations in the homeostatic balance before they become pathological trajectories is urgently required.

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12. Exploring the other side of the moon: a new world demands a change of course 

In conclusion, human life expectancy has been increasing linearly and is not expected to stop in the near future [2]. With increases in life expectancy the distribution of the population has changed dramatically and the chances of living to an old age are increasing, but so is the probability of time spent with disease and disability. A new society, with novel characteristics and new needs is emerging and research into healthy longevity requires an innovative approach: multi-factorial prevention and treatment of frailty, disability and disease seems the most appropriate way to steer the population to a healthier phenotype. This new strategy should be the focal point of scientific research and health care in the years to come. Although significant efforts may be required to implement the strategy, the potential rewards are tangible and of vast size, and the health expectations of the new generations demand it.

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13. Recommendations 

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Conflicts of interest 

The authors report no conflicts of interest to declare.

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Acknowledgements 

The authors would like to thank Min-Min Teh, Lucy Boniface and Diana Parry for their collaboration in organising the Spark workshop and Dr. Jonathan Powell, Dr. Joe McNamara, Dr. Mark Pitman and Prof. Stephen Holgate for their valuable comments. The Spark meeting was jointly funded (50/50) by the MRC UK and Unilever Corporate Research.

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References 

1. The Population Division Department of Economic and Social Affairs United Nations Secretariat. The Ageing of the World's Population. www un org 2005 January [cited 2006 May 10]; Available from: URL: http://www.un.org/esa/socdev/ageing/agewpop.htm.
   • View In Article
2. Oeppen J, Vaupel JW. Demography. Broken limits to life expectancy. Science. 2002;296(May (5570)):1029–1031
   • View In Article
   • CrossRef
3. The Population Division DoEaSAUNS. World Population Prospects: the 2006 revision. www un org 2007 [cited 2007 May 4]; Available from: URL: http://www.un.org/esa/population/publications/wpp2006/wpp2006_ageing.pdf.
   • View In Article
4. Franco OH, Kirkwood TB, Powell JR, et al. Ten commandments for the future of ageing research in the UK: a vision for action. BMC Geriatr. 2007;7:10
   • View In Article
   • MEDLINE
   • CrossRef
5. Office for National Statistics . Census 2001: CD supplement to the National report for England and Wales and key statistics for local authorities in England and Wales. London: Office for National Statistics; 2001;
   • View In Article
6. WHO . The World Health Report: 2003: shaping the future. Geneve: World Health Organization; 2003;
   • View In Article
7. House of Lords Select Committee on Science and Technology. Ageing: Scientific Aspects Volume I: Report. Report No.: HL 20-I; 2005 July 21.
   • View In Article
8. Woods LM, Rachet B, Riga M, Stone N, Shah A, Coleman MP. Geographical variation in life expectancy at birth in England and Wales is largely explained by deprivation. J Epidemiol Commun Health. 2005;59(February (2)):115–120
   • View In Article
9. Vijg J, Campisi J. Puzzles, promises and a cure for ageing. Nature. 2008;454(August (7208)):1065–1071
   • View In Article
   • CrossRef
10. Kirkwood TB, Austad SN. Why do we age?. Nature. 2000;408(November (6809)):233–238
    • View In Article
    • MEDLINE
    • CrossRef
11. Partridge L, Gems D. Mechanisms of ageing: public or private?. Nat Rev Genet. 2002;3(March (3)):165–175
    • View In Article
    • MEDLINE
    • CrossRef
12. Schoenmaker M, de Craen AJ, de Meijer PH, et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet. 2006;14(January (1)):79–84
    • View In Article
    • MEDLINE
13. Zwaan BJ. The evolutionary genetics of ageing and longevity. Heredity. 1999;82(June (Pt 6)):589–597
    • View In Article
    • CrossRef
14. Partridge L, Gems D. The evolution of longevity. Curr Biol. 2002;12(August (16)):R544–R546
    • View In Article
    • MEDLINE
    • CrossRef
15. Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum Genet. 1996;97(March (3)):319–323
    • View In Article
    • MEDLINE
    • CrossRef
16. Iachine IA, Holm NV, Harris JR, et al. How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins. Twin Res. 1998;1(December (4)):196–205
    • View In Article
    • MEDLINE
    • CrossRef
17. Hales CN, Barker DJ, Clark PM, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991;303(October (6809)):1019–1022
    • View In Article
    • MEDLINE
    • CrossRef
18. Poulsen P, Vaag A. The intrauterine environment as reflected by birth size and twin and zygosity status influences insulin action and intracellular glucose metabolism in an age- or time-dependent manner. Diabetes. 2006;55(June (6)):1819–1825
    • View In Article
    • MEDLINE
    • CrossRef
19. Vaag A, Jensen CB, Poulsen P, et al. Metabolic aspects of insulin resistance in individuals born small for gestational age. Horm Res. 2006;65(Suppl. 3):137–143
    • View In Article
    • CrossRef
20. Fried LP, Hadley EC, Walston JD, et al. From bedside to bench: research agenda for frailty. Sci Aging Knowledge Environ. 2005;2005(August (31)):e24
    • View In Article
21. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: towards a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006;54(June (6)):991–1001
    • View In Article
    • MEDLINE
    • CrossRef
22. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of frailty: characterization in the women's health and aging studies. J Gerontol A Biol Sci Med Sci. 2006;61(March (3)):262–266
    • View In Article
    • MEDLINE
    • CrossRef
23. Ferrucci L, Mahallati A, Simonsick EM. Frailty and the foolishness of Eos. J Gerontol A Biol Sci Med Sci. 2006;61(March (3)):260–261
    • View In Article
    • MEDLINE
    • CrossRef
24. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59(March (3)):255–263
    • View In Article
    • MEDLINE
25. Klein BE, Klein R, Knudtson MD, Lee KE. Frailty, morbidity and survival. Arch Gerontol Geriatr. 2005;41(September (2)):141–149
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (126 KB)
    • CrossRef
26. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173(August (5)):489–495
    • View In Article
    • CrossRef
27. Yaffe K. Metabolic syndrome and cognitive disorders: is the sum greater than its parts?. Alzheimer Dis Assoc Disord. 2007;21(April (2)):167–171
    • View In Article
    • CrossRef
28. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003;88(June (6)):2404–2411
    • View In Article
    • MEDLINE
    • CrossRef
29. Schneider JG, Tompkins C, Blumenthal RS, Mora S. The metabolic syndrome in women. Cardiol Rev. 2006;14(November (6)):286–291
    • View In Article
    • CrossRef
30. Church TS, Earnest CP, Skinner JS, Blair SN. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. JAMA. 2007;297(May (19)):2081–2091
    • View In Article
    • CrossRef
31. Franco OH, de LC, Peeters A, Jonker J, Mackenbach J, Nusselder W. Effects of physical activity on life expectancy with cardiovascular disease. Arch Intern Med. 2005;165(November (20)):2355–2360
    • View In Article
    • MEDLINE
    • CrossRef
32. Franco OH, Bonneux L, de LC, Peeters A, Steyerberg EW, Mackenbach JP. The polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ. 2004;329(December (7480)):1447–1450
    • View In Article
    • CrossRef
33. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004;292(September (12)):1433–1439
    • View In Article
    • CrossRef
34. Redman LM, Ravussin E. Could calorie restriction increase longevity in humans?. Aging Health. 2007;3(1):1–4
    • View In Article
35. Jenkins DJ, Kendall CW, Faulkner DA, et al. Assessment of the longer-term effects of a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. Am J Clin Nutr. 2006;83(March (3)):582–591
    • View In Article
    • MEDLINE
36. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345(September (11)):790–797
    • View In Article
    • MEDLINE
    • CrossRef
37. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343(July (1)):16–22
    • View In Article
    • MEDLINE
    • CrossRef
38. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(February (6)):393–403
    • View In Article
    • CrossRef
39. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(May (18)):1343–1350
    • View In Article
    • MEDLINE
    • CrossRef
40. Knutson KL, Spiegel K, Penev P, Van CE. The metabolic consequences of sleep deprivation. Sleep Med Rev. 2007;11(June (3)):163–178
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (259 KB)
    • CrossRef
41. Van CE, Holmback U, Knutson K, et al. Impact of sleep and sleep loss on neuroendocrine and metabolic function. Horm Res. 2007;67(Suppl. 1):2–9
    • View In Article
    • CrossRef
42. Steptoe A, O’Donnell K, Marmot M, Wardle J. Positive affect, psychological well-being, and good sleep. J Psychosom Res. 2008;64(April (4)):409–415
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (183 KB)
    • CrossRef
43. Ryan RM, Deci EL. On happiness and human potentials: a review of research on hedonic and eudaimonic well-being. Annu Rev Psychol. 2001;52:141–166
    • View In Article
    • MEDLINE
    • CrossRef
44. Friedman EM, Hayney M, Love GD, Singer BH, Ryff CD. Plasma interleukin-6 and soluble IL-6 receptors are associated with psychological well-being in aging women. Health Psychol. 2007;26(May (3)):305–313
    • View In Article
    • MEDLINE
    • CrossRef
45. Ryff CD, Singer BH, Dienberg LG. Positive health: connecting well-being with biology. Philos Trans R Soc Lond B Biol Sci. 2004;359(September (1449)):1383–1394
    • View In Article
    • MEDLINE
    • CrossRef
46. Ryff CD, Singer BH. Social environments and the genetics of aging: advancing knowledge of protective health mechanisms. J Gerontol B Psychol Sci Soc Sci. 2005;60 Spec No 1(March):12–23
    • View In Article
    • MEDLINE
47. Steptoe A, Wardle J, Marmot M. Positive affect and health-related neuroendocrine, cardiovascular, and inflammatory processes. Proc Natl Acad Sci USA. 2005;102(May (18)):6508–6512
    • View In Article
48. Surtees PG, Wainwright NW, Luben RL, Wareham NJ, Bingham SA, Khaw KT. Adaptation to social adversity is associated with stroke incidence: evidence from the EPIC-Norfolk prospective cohort study. Stroke. 2007;38(May (5)):1447–1453
    • View In Article
    • CrossRef
49. Peel NM, McClure RJ, Bartlett HP. Behavioral determinants of healthy aging. Am J Prev Med. 2005;28(April (3)):298–304
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (116 KB)
    • CrossRef
50. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326(June (7404)):1419
    • View In Article
    • CrossRef