Assessment of Dietary Intake in Three Cohorts of Advanced Age in Two Countries: Methodology Challenges.

OBJECTIVES: Dietary intake information is key to understanding nutrition-related outcomes. Intake changes with age and some older people are at increased risk of malnutrition. Application, difficulties, and advantages of the 24-hour multiple pass recall (24hr-MPR) dietary assessment method in three cohorts of advanced age in the United Kingdom (UK) and New Zealand (NZ) is described. PARTICIPANTS: The Newcastle 85+ study (UK) recruited a single year birth cohort of people aged 85 years during 2006-7. LiLACS NZ recruited a 10-year birth cohort of Maori (indigenous New Zealanders) aged 80-90 years and a single year birth cohort of non-Maori aged 85 years in 2010. MEASUREMENTS: Two 24hr-MPR were conducted on non-consecutive days by trained assessors. Pictorial resources and language were adapted for the New Zealand and Maori contexts. Detailed methods are described. RESULTS: In the Newcastle 85+ study, 805 (93%) participants consented to the 24-MPR, 95% of whom completed two 24hr-MPR; in LiLACS NZ, 218 (82%) consented and 203 (76%) Maori and 353 (90%) non-Maori completed two 24hr-MPR. Mean time to complete each 24hr-MPR was 22 minutes in the Newcastle 85+ study, and 45 minutes for Maori and 39 minutes for non-Maori in LiLACS NZ. Dietary assessment of participants residing in residential care and those requiring proxy respondents were successfully included in both studies. Most participants (83-94%) felt that data captured by the 24hr-MPR reflected their usual dietary intake. CONCLUSIONS: Dietary assessment using 24hr-MPR was successful in capturing detailed dietary data including information on portion size and time of eating for over 1300 octogenarians in the UK and New Zealand (Maori and non- Maori). The 24hr-MPR is an acceptable method of dietary assessment in this age group.

A gerophysiology perspective on healthy ageing.

Improvements in public health and health care have resulted in significant increases in lifespan globally, but also in a significant increase in chronic disease prevalence. This has led to a focus on healthy ageing bringing a shift from a pathology-centered to an intrinsic capacity and function-centered view. In parallel, the emerging field of geroscience has promoted the exploration of the biomolecular drivers of ageing towards a transverse vision by proposing an integrated set of molecular hallmarks. In this review, we propose to take a step further in this direction, highlighting a gerophysiological perspective that considers the notion of homeostasis/allostasis relating to robustness/fragility respectively. While robustness is associated with homeostasis achieved by an optimal structure/function relationship in all organs, successive repair processes occurring after daily injuries and infections result in accumulation of scar healing leading to progressive tissue degeneration, allostasis and frailty. Considering biological ageing as the accumulation of scarring at the level of the whole organism emphasizes three transverse and shared elements in the body - mesenchymal stroma cells/immunity/metabolism (SIM). This SIM tryptich drives tissue and organ fate to regulate the age-related evolution of body functions. It provides the basis of a gerophysiology perspective, possibly representing a better way to decipher healthy ageing, not only by defining a composite biomarker(s) but also by developing new preventive/curative strategies.

Fluoroquinolone use in a rural practice.

INTRODUCTION: Fluoroquinolones (FQs) are a commonly prescribed class of antibiotics in Canada. Evidence of a constellation of possible adverse events is developing. Central and peripheral nervous system abnormalities and collagen-related events (including aortic aneurysm/dissection, tendinopathy/rupture and retinal detachment) are associated with FQ exposure in large population-based aftermarket studies. In 2017, Health Canada warned about rare FQ-related persistent or disabling side effects. This study explores FQ use in a rural community. METHODS: Antibiotic prescriptions (including FQs) in the over 18 adult population (5416) were measured in the town of Sioux Lookout for 5 years, January 2013 to 31 December 2017. RESULTS: FQ prescriptions accounted for 16.0% of adult antibiotics, superseded by penicillins (21.1%) and macrolides (18.2%). Ciprofloxacin accounted for one half of FQ use (51.2%), followed by levofloxacin (36.7%) and norfloxacin (13.3%). FQs were commonly used for respiratory (33%) and urinary tract infections (18%). CONCLUSION: Aftermarket evidence reports increased risk of 'disabling and persistent serious adverse events'(Health Canada) in patients using FQs. Appropriate clinical caution should be exercised in the prescribing of FQs. Common overuse seems to occur in the treatment of uncomplicated community-acquired pneumonia and cystitis, despite recommendations to use other antimicrobial agents as first-line treatments.

Résumé Introduction: Les fluoroquinolones sont une classe d'antibiotiques souvent prescrite au Canada. Mais les données étayant une gamme d'événements indésirables possibles s'accumulent. Des anomalies du système nerveux central et périphérique, et des événements liés au collagène (dont anévrisme ou dissection de l'aorte, tendinopathie/rupture et décollement de la rétine) sont associés à l'exposition aux fluoroquinolones dans des études de pharmacovigilance d'envergure basées sur la population. En 2017, Santé Canada a émis une mise en garde au sujet des effets indésirables rares, persistants ou incapacitants liés aux fluoroquinolones. Cette étude se penche sur l'emploi de fluoroquinolones dans une communauté rurale. Méthodologie: La prescription d'antibiotiques (y compris de fluoroquinolones) a été mesurée dans la ville de Sioux Lookout pendant 5 ans, soit de janvier 2013 au 31 décembre 2017 auprès de la population de 18 ans et plus (5416 personnes). Résultats: Les fluoroquinolones comptaient pour 16,0 % des antibiotiques prescrits aux adultes, elles étaient précédées des pénicillines (21,1 %) et des macrolides (18,2 %). La ciprofloxacine représentait la moitié de l'emploi de fluoroquinolones (51,2 %), suivie de la lévofloxacine (36,7 %) et de la norfloxacine (13,3 %). Les fluoroquinolones étaient fréquemment utilisées contre les infections respiratoires (33 %) et urinaires (18 %). Conclusion: Les données de pharmacovigilance rapportent un risque accru "d'événements indésirables graves persistants et incapacitants" (Santé Canada) chez les patients sous fluoroquinolones. La prudence clinique appropriée est de mise lors de la prescription de fluoroquinolones. La pneumonie extra-hospitalière non compliquée et la cystite semblent être à l'origine de la surutilisation, malgré les recommandations d'utiliser d'autres antimicrobiens en première intention. Mots-clés: Fluoroquinolones; antibiotiques; effets indésirables; rural.

Serum 25-hydroxyvitamin D concentration and its determinants in the very old: the Newcastle 85+ Study.

SUMMARY: Data on vitamin D status in very old adults are lacking. The aim of this study was to assess 25-hydroxyvitamin D [25(OH)D] concentrations and its predictors in 775 adults aged 85 years old living in North-East England. Low 25(OH)D was alarmingly high during winter/spring months, but its biological significance is unknown. INTRODUCTION: Despite recent concerns about the high prevalence of vitamin D deficiency in much of the British adult and paediatric population, there is a dearth of data on vitamin D status and its predictors in very old adults. The objective of the present study was to describe vitamin D status and its associated factors in a broadly representative sample of very old men and women aged 85 years living in the North East of England (55° N). METHODS: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were analysed in 775 participants in the baseline phase of the Newcastle 85+ cohort study. Season of blood sampling, dietary, health, lifestyle and anthropometric data were collected and included as potential predictors of vitamin D status in ordinal regression models. RESULTS: Median serum 25(OH)D concentrations were 27, 45, 43 and 33 nmol/L during spring, summer, autumn and winter, respectively. The prevalence of vitamin D deficiency according to North American Institute of Medicine guidelines [serum 25(OH)D <30 nmol/L] varied significantly with season with the highest prevalence observed in spring (51%) and the lowest prevalence observed in autumn (23%; P < 0.001). Reported median (inter-quartile range) dietary intakes of vitamin D were very low at 2.9 (1.2-3.3) µg/day. In multivariate ordinal regression models, non-users of either prescribed or non-prescribed vitamin D preparations and winter and spring blood sampling were associated with lower 25(OH)D concentrations. Dietary vitamin D intake, disability score and disease count were not independently associated with vitamin D status in the cohort. CONCLUSION: There is an alarming high prevalence of vitamin D deficiency (<30 nmol/L) in 85-year-olds living in North East England at all times of the year but particularly during winter and spring. Use of vitamin D containing preparations (both supplements and medications) appeared to be the strongest predictor of 25(OH)D concentrations in these very old adults.

A dynamic framework for the study of optimal birth intervals reveals the importance of sibling competition and mortality risks.

Human reproductive patterns have been well studied, but the mechanisms by which physiology, ecology and existing kin interact to affect the life history need quantification. Here, we create a model to investigate how age-specific interbirth intervals adapt to environmental and intrinsic mortality, and how birth patterns can be shaped by competition and help between siblings. The model provides a flexible framework for studying the processes underlying human reproductive scheduling. We developed a state-based optimality model to determine age-dependent and family-dependent sets of reproductive strategies, including the state of the mother and her offspring. We parameterized the model with realistic mortality curves derived from five human populations. Overall, optimal birth intervals increase until the age of 30 after which they remain relatively constant until the end of the reproductive lifespan. Offspring helping each other does not have much effect on birth intervals. Increasing infant and senescent mortality in different populations decreases interbirth intervals. We show that sibling competition and infant mortality interact to lengthen interbirth intervals. In lower-mortality populations, intense sibling competition pushes births further apart. Varying the adult risk of mortality alone has no effect on birth intervals between populations; competition between offspring drives the differences in birth intervals only when infant mortality is low. These results are relevant to understanding the demographic transition, because our model predicts that sibling competition becomes an important determinant of optimal interbirth intervals only when mortality is low, as in post-transition societies. We do not predict that these effects alone can select for menopause.

Magnitude of fragility fracture risk in the very old--are we meeting their needs? The Newcastle 85+ Study.

UNLABELLED: Fractures due to osteoporosis are common in older people. This study assessed the management of osteoporosis in a group of 85-year-olds and found both assessment and current treatment to be suboptimal. INTRODUCTION: Fragility fractures are a major cause of excess mortality, substantial morbidity, and health and social service expenditure in older people. However, much less is known about fracture risk and its management in the very old, despite this being the fastest growing age group of our population. METHODS: Cross-sectional analysis of people who reached the age of 85 during the year of 2006 was carried out. Data were gathered by general practice record review (GPRR) and a multidimensional health assessment (MDHA). RESULTS: Seven hundred thirty-nine individuals were recruited. Mean age was 85.55 years (SD 0.44), and 60.2% were female; 33.7% (n = 249) had experienced one or more fragility fractures (F 45.2% vs M 16.3% p < 0.001); in total, 332 fractures occurred in these 249 individuals. A formal documented diagnosis of osteoporosis occurred in 12.4%, and 38% of individuals had experienced a fall in the last 12 months. When the fracture risk assessment tool (FRAX) and National Osteoporosis Guideline Group (NOGG) guidelines were applied, osteoporosis treatment would be recommended in 35.0%, with a further 26.1% identified as needing bone mineral density (BMD) measurement and 38.9% not requiring treatment or BMD assessment. Women were more likely than men to need treatment (47.4 vs 16.3%, p < 0.001, odds ratio (OR) 4.62 (3.22-5.63)) and measurement of BMD (40.0 vs 5.1%, p < 0.001, OR 12.4 (7.13-21.6)). Of the 259 individuals identified as requiring treatment, only 74 (28.6%) were on adequate osteoporosis treatment. CONCLUSION: The prevalence of high fracture risk in the very old is much higher than the documented diagnosis of osteoporosis or the use of adequate treatments.

Serum 25-hydroxyvitamin D and cognitive decline in the very old: the Newcastle 85+ Study.

BACKGROUND AND PURPOSE: Studies investigating the association between 25-hydroxyvitamin D [25(OH)D] and cognition in the very old (85+) are lacking. METHODS: Cross-sectional (baseline) and prospective data (up to 3 years follow-up) from 775 participants in the Newcastle 85+ Study were analysed for global (measured by the Standardized Mini-Mental State Examination) and attention-specific (measured by the attention battery of the Cognitive Drug Research test) cognitive performance in relation to season-specific 25(OH)D quartiles. RESULTS: Those in the lowest and highest season-specific 25(OH)D quartiles had an increased risk of impaired prevalent (1.66, 95% confidence interval 1.06-2.60, P = 0.03; 1.62, 95% confidence interval 1.02-2.59, P = 0.04, respectively) but not incident global cognitive functioning or decline in functioning compared with those in the middle quartiles adjusted for sociodemographic, health and lifestyle confounders. Random effects models showed that participants belonging to the lowest and highest 25(OH)D quartiles, compared with those in the middle quartiles, had overall slower (log-transformed) attention reaction times for Choice Reaction Time (lowest, ß = 0.023, P = 0.01; highest, ß = 0.021, P = 0.02), Digit Vigilance Task (lowest, ß = 0.009, P = 0.05; highest, ß = 0.01, P = 0.02) and Power of Attention (lowest, ß = 0.017, P = 0.02; highest, ß = 0.022, P = 0.002) and greater Reaction Time Variability (lowest, ß = 0.021, P = 0.02; highest, ß = 0.02, P = 0.03). The increased risk of worse global cognition and attention amongst those in the highest quartile was not observed in non-users of vitamin D supplements/medication. CONCLUSION: Low and high season-specific 25(OH)D quartiles were associated with prevalent cognitive impairment and poorer overall performance in attention-specific tasks over 3 years in the very old, but not with global cognitive decline or incident impairment.

25-hydroxyvitamin D and increased all-cause mortality in very old women: the Newcastle 85+ study.

OBJECTIVE: To investigate the associations between low and high concentrations of baseline serum 25-hydroxyvitamin D [25(OH)D] and all-cause mortality in very old (≥85 years) men and women over 6 years. DESIGN, SETTING AND SUBJECTS: Prospective mortality data from 775 participants in the Newcastle 85+ Study were analysed for survival in relation to 25(OH)D (season-specific quartiles and predefined cut-off values) and sex using Cox proportional hazards models. The models were fitted to the entire and restricted (nonusers of vitamin D-containing supplements and medication) cohorts. RESULTS: For the entire cohort, mortality was higher in both the lowest and highest 25(OH)D season-specific quartiles [SQ1: hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.01-1.69, P = 0.04; SQ4: HR 1.44, 95% CI 1.12-1.85, P = 0.004] compared with the combined middle quartiles (SQ2 + SQ3), after adjustment for sociodemographic factors. The increased risk for the highest quartile remained significant after further adjustment for lifestyle variables (SQ4: HR 1.37, 95% CI 1.06-1.77, P = 0.02) and was seen only in women in sex-specific analyses. Similarly, in sensitivity analyses with predefined 25(OH)D cut-off values, the highest 25(OH)D concentration (≥75 nmol L(-1) ) was associated with a 2.4-fold increased risk of mortality in women (restricted cohort) after adjusting for all covariates. CONCLUSION: Low and high season-specific 25(OH)D quartiles were associated with increased risks of mortality over 6 years in the very old; this effect was particularly noticeable in women, including those who reported taking vitamin D-containing supplements/medication.

The plastic fly: the effect of sustained fluctuations in adult food supply on life-history traits.

Many adult traits in Drosophila melanogaster show phenotypic plasticity, and the effects of diet on traits such as lifespan and reproduction are well explored. Although plasticity in response to food is still present in older flies, it is unknown how sustained environmental variation affects life-history traits. Here, we explore how such life-long fluctuations of food supply affect weight and survival in groups of flies and affect weight, survival and reproduction in individual flies. In both experiments, we kept adults on constant high or low food and compared these to flies that experienced fluctuations of food either once or twice a week. For these 'yoyo' groups, the initial food level and the duration of the dietary variation differed during adulthood, creating four 'yoyo' fly groups. In groups of flies, survival and weight were affected by adult food. However, for individuals, survival and reproduction, but not weight, were affected by adult food, indicating that single and group housing of female flies affects life-history trajectories. Remarkably, both the manner and extent to which life-history traits varied in relation to food depended on whether flies initially experienced high or low food after eclosion. We therefore conclude that the expression of life-history traits in adult life is affected not only by adult plasticity, but also by early adult life experiences. This is an important but often overlooked factor in studies of life-history evolution and may explain variation in life-history experiments.

Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Quality-quantity trade-off of human offspring under adverse environmental conditions.

A central paradigm in life-history theory is the trade-off between offspring number and quality. Several studies have investigated this trade-off in humans, but data are inconclusive, perhaps because prosperous socio-cultural factors mask the trade-off. Therefore, we studied 2461 offspring groups in an area under adverse conditions in northern Ghana with high fertility and mortality rates. In a linear mixed model controlling for differences in age and tribe of the mother and socioeconomic status, each additional child in the offspring group resulted in a 2.3% (95% CI 1.9-2.6%, P < 0.001) lower proportional survival of the offspring. Furthermore, we made use of the polygamous population structure and compared offspring of co-wives in 388 households, thus controlling for variation in resources between compounds. Here, offspring survival decreased 2.8% (95% CI 2.3-4.0%, P < 0.001) for each increase in offspring number. We interpret these data as an apparent quality-quantity trade-off in human offspring.

Nutrition in advanced age: dietary assessment in the Newcastle 85+ study.

BACKGROUND/OBJECTIVES: Assessing food choice and/or nutrient intake in older people, particularly the oldest old (85 years and over), presents particular challenges. In some cases the respondent may have little or no involvement in food acquisition or preparation, in others, cognitive/memory impairment may restrict the ability to recall intake, or physical limitations may affect the ability to record intake. The assessment may therefore need to involve whoever provides care for the older person, of whom there may be more than one. For these reasons, there is a need for validated methods for dietary assessment in large populations within this age range. The need is particularly acute in view of the secular increase in the numbers of older people and the interest in the role of nutrition in maintaining health and ameliorating age-related decline. This paper describes a comparison of two different methods of dietary assessment within the Newcastle 85+ Study; a UK cohort study of health and ageing in the oldest old. METHODS: Two methods, the food frequency questionnaire (FFQ) (based on broad recall of the previous 12 months intake) and the repeated multiple pass recall (MPR) tool (based on detailed recall of the previous day's intake on two separate occasions), were applied in two different groups of approximately 85 individuals aged 85 years. FFQ data were collected during a pilot study conducted between 2003 and 2004, MPR data were collected in the main Newcastle study in 2006. Relative validity was measured by calculation of the ratio of reported energy intake to estimated basal metabolic rate (EI/BMR) and by comparison with dietary intakes reported for subjects of similar age in the UK National Diet and Nutrition Survey. RESULTS: EI/BMR ratios for MPR were 1.56 and 1.39 for men and women, respectively, and for FFQ were 2.18 and 2.14. The FFQ was found to overestimate energy and nutrient intake considerably. The MPR gave more realistic estimates of energy and nutrient intakes, and was found to be acceptable for use in this population group. However, use of this tool required greater investigator (nurse) time, extra resources for training and quality assurance and additional time and expertise in data processing. CONCLUSIONS: In the Newcastle 85+ Study, where the overall aims include detailed investigation of diet in relation to many variables describing biological, clinical and psychosocial status, we concluded that MPR was the preferable method, although there remains a need for non-subjective methods for assessing dietary intake, that is, biomarker approaches, which can give a comprehensive and objective assessment of dietary exposure.

Understanding ageing from an evolutionary perspective.

There is clear heritability of human longevity. However, the genetics of ageing is likely to be complex. Evolution theory tells us not to expect genes that have been selected to promote ageing. Ageing is not programmed but results from accumulation of somatic damage, owing to limited investments in maintenance and repair. Genes controlling the levels of activities, such as DNA repair and antioxidant defence, thus regulate longevity. In addition, there may be contributions either from late-acting deleterious genes that escape the force of natural selection or that trade benefit at an early age against harm at older ages. In some species, there is evidence that genes have evolved to detect and respond to changes in the environment, e.g. food supply. Evolutionary understanding can also help to understand important features of the human life history such as menopause.

Modelling the checkpoint response to telomere uncapping in budding yeast.

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

Muscarinic stimulation of the mouse isolated whole bladder: physiological responses in young and ageing mice.

1 Peripheral autonomous bladder activity is an incompletely understood property that may be important both in normal bladder function and in functional problems of the lower urinary tract. We describe how a muscarinic agonist, arecaidine, influences intravesical pressure and intramural bladder contractions in the isolated mouse and how response varies in ageing mice. 2 A group of 12 mice aged 3-4 months was compared with an 'ageing' group of 12 mice age 28-34 months. Bladders were microsurgically removed and mounted in whole organ tissue baths. The effects of the muscarinic agonist arecaidine on intravesical pressure and intramural contractions were performed at different bladder volumes. 3 In normal mice, arecaidine elicited tonic and phasic contractions, the latter showing a more substantial increase in amplitude with bladder distension. Localized 'micromotion' contractions were seen in the bladder wall, with regional differences arising after exposure to arecaidine. A background release of acetylcholine was inferred from the pressure increase induced by the cholinesterase inhibitor physostigmine. 4 Both micromotion activity and the phasic component of the arecaidine response were substantially reduced in ageing mice; the tonic component was preserved in the same specimens. 5 We conclude that the enhanced pressure fluctuations seen at high bladder volumes may act as a peripheral determinant of bladder capacity, and that changes in such activity may contribute to altered functional capacity and lower urinary tract symptoms in ageing individuals.

The Institute for Ageing and Health, University of Newcastle, UK.

The Institute For Ageing And Health (IAH) is the largest cross-disciplinary research grouping within Newcastle University's Faculty of Medicine, which recently obtained the highest 5 or 5* ratings in all fields evaluated in the UK Research Assessment Exercise 2001. The IAH was set up in 1994 to bring together clinical, basic and social scientists in partnership with colleagues in the National Health Service. It builds upon a long tradition of outstanding clinical research on age-related disorders, particularly in the field of dementia where the pioneering studies of Tomlinson and Roth in the 1960s first showed Alzheimer's disease to be the commonest cause of cognitive decline in later life. The clinical research of the IAH now extends to both neurodegenerative and vascular dementia in a joint Medical Research Council-University Development for Clinical Brain Ageing, and to studies in many other areas including depression in later life, falls and neurovascular instability, stroke and ischaemic brain disease, and health services research on the medical and social care of older people. These diverse areas of clinical investigation are now complemented by strong research on the basic biology of ageing within the new Department of Gerontology with its programmes on the genetics of ageing and longevity; molecular mechanisms of cellular ageing, including oxidative stress, DNA damage and genomic instability, telomere reduction and regulation, mitochondrial DNA mutations, and accumulation of aberrant proteins; and theoretical models of the ageing process. An ambitious strategy for future research on ageing and age-related disorders is based on the synergy between these complementary approaches.

Molecular gerontology.

Evolutionary theory and empirical evidence from many lines of research suggest that ageing is a process of gradual accumulation of damage in cells and tissues of the body, leading eventually to frailty and increased risk from a spectrum of age-associated diseases. There are multiple kinds of damage that affect cells, ranging from mutations in DNA to oxidative attack on proteins by chemical by-products of normal cellular metabolism. In some ways the surprising thing is not that we age, but that we live as long as we do. The key to understanding longevity lies in the network of cell maintenance systems that cooperate to slow the accumulation of damage. Research has shown that long-lived species carry out cellular maintenance better than short-lived species, suggesting that enhancement of the body's natural maintenance systems may postpone aspects of ageing. Recognition that ageing results from accumulation of damage also points to a role for lifestyle interventions (e.g. nutrition and exercise) to help prevent damage or promote repair.