Aging as a consequence of selection to reduce the environmental risk of dying.

Each animal in the Darwinian theater is exposed to a number of abiotic and biotic risk factors causing mortality. Several of these risk factors are intimately associated with the act of energy acquisition as such and with the amount of reserve the organism has available from this acquisition for overcoming temporary distress. Because a considerable fraction of an individual's lifetime energy acquisition is spent on somatic maintenance, there is a close link between energy expenditure on somatic maintenance and mortality risk. Here, we show, by simple life-history theory reasoning backed up by empirical cohort survivorship data, how reduction of mortality risk might be achieved by restraining allocation to somatic maintenance, which enhances lifetime fitness but results in aging. Our results predict the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations, which may display constant, increasing, or decreasing mortality with age. This suggests that allocation to somatic maintenance is primarily tuned to expected life span by stabilizing selection and is not necessarily traded against reproductive effort or other traits. Due to this ubiquitous strategy of modulating the somatic maintenance budget so as to increase fitness under natural conditions, it follows that individuals kept in protected environments with very low environmental mortality risk will have their expected life span primarily defined by somatic damage accumulation mechanisms laid down by natural selection in the wild.

Feeding rumen-protected lysine altered immune and metabolic biomarkers in dairy cows during the transition period.

This experiment was conducted to determine the effects of feeding rumen-protected lysine (RPL; AjiPro-L Generation 3, Ajinomoto Health and Nutrition North America Inc.) from -26 ± 4.6 d prepartum (0.54% RPL of dietary dry matter intake) to 28 d postpartum (0.39% RPL of dietary dry matter intake) on immunometabolic status and liver composition in dairy cows. Seventy-five multiparous Holstein cows, blocked by parity, previous 305-d mature-equivalent milk production, expected calving date, and body condition score during the far-off dry period were assigned to 1 of 4 dietary treatments in a randomized, complete block design with a 2 × 2 factorial arrangement of treatments. Treatments prepartum consisted of total mixed ration top dressed with RPL (PRE-L) or without RPL (PRE-C), and postpartum treatments consisted of total mixed ration top dressed PRE-L prepartum and postpartum, PRE-L prepartum and PRE-C postpartum, PRE-C prepartum and PRE-L postpartum, and PRE-C prepartum and postpartum in 300 g of molasses. Blood samples were taken on -7 ± 0.5, 0 ± 0.5, 7 ± 0.9, 14 ± 0.9, and 28 ± 0.5 d relative to calving. Whole blood samples were taken on -14 ± 0.5, -7 ± 0.5, 7 ± 0.9, and 14 ± 0.9 d relative to calving for oxidative burst and phagocytic capacity of monocytes and neutrophils. Liver samples were collected via a biopsy on -12 ± 4.95 and 13 ± 2.62 d relative to calving and analyzed for liver composition (triacylglyceride and carnitine concentrations), mRNA expression of hepatic genes, and protein abundance. Protein abundance was calculated by normalizing intensity bands for a specific protein with glyceraldehyde-3-phosphate dehydrogenase. Concentrations of haptoglobin and glutathione peroxidase activity in plasma were lower at d 0 for cows in PRE-L (102 µg/mL and 339 nmol/min per mL, respectively) compared with cows in PRE-C (165 µg/mL and 405 nmol/min per mL, respectively). Oxidative burst capacity in monocytes tended to be greater on d 7 postpartum for cows in PRE-L (65.6%) than cows in PRE-C (57.5%). Additionally, feeding RPL altered the mRNA expression in liver tissue prepartum [decreased INSR (insulin receptor), CPT1A (carnitine palmitoyltransferase 1A), and IL1B (interleukin 1 ß)] and postpartum [increased IL8 (interleukin 8), EHMT2 (euchromatic histone lysine methyltransferase 2), TSPO (translocator protein), and SLC3A2 (solute carrier family 3 member 2); and decreased SLC7A1 (solute carrier family 7 member 1), SOD1 (superoxide dismutase 1), and SAA3 (serum amyloid A 3)] compared with cows not consuming RPL]. Additionally, cows in the PRE-C prepartum and PRE-L postpartum treatment tended to have greater protein abundance of mTOR postpartum compared with the PRE-C prepartum and postpartum treatment. Protein abundance of SLC7A7 (solute carrier family 7 member 7) pre- and postpartum tended to be greater and BBOX1 (gamma-butyrobetaine dioxygenase 1) tended to be less when RPL was consumed prepartum. In conclusion, cows that consumed RPL during the transition period had molecular changes related to liver composition, enhanced liver function indicated by greater total protein and albumin concentrations in plasma, and improved immune status indicated by decreased haptoglobin, glutathione peroxidase activity, and immune related mRNA expression.

Feeding rumen-protected lysine to dairy cows prepartum improves performance and health of their calves.

Providing adequate concentrations of AA in the prepartum diet is pivotal for the cow's health and performance. However, less is known about the potential in utero effects of particular AA on early-life performance of calves. This experiment was conducted to determine the effects on dairy calves when their dams were fed rumen-protected lysine (RPL; AjiPro-L Generation 3, Ajinomoto Heartland Inc.; 0.54% dry matter of total mixed ration as top dress) from 26 ± 4.6 d (mean ± standard deviation) before calving until calving. Seventy-eight male (M) and female (F) Holstein calves were assigned to 2 treatments based on their dams' prepartum treatment, RPL supplementation (PRE-L) or without RPL (CON). At the time of birth (0.5-2 h after calving), before colostrum was fed, blood samples were collected. An initial body weight was obtained at 1 to 3 h after birth. Calves were fed 470 g of colostrum replacer (Land O'Lakes Bovine IgG Colostrum Replacer, Land O'Lakes, Inc.) diluted in 3.8 L of water. Calves were provided water ad libitum and fed milk replacer (Advance Excelerate, Milk Specialties Global Animal Nutrition; 28.5% crude protein, 15% fat) at 0600 h and 1700 h until 42 d of age. Calves were measured weekly, at weaning (d 42), and at the end of the experimental period (d 56). Plasma concentrations of AA were measured on d 0, 7, and 14 d using ultra-performance liquid chromatography-mass spectrometry (Waters) with a derivatization method (AccQ-Tag Derivatization). Final body weight was greater for M (87 ± 11 kg) than F (79 ± 7 kg). Calves in PRE-L tended to have greater dry matter (814 ± 3 g/d) and crude protein (234 ± 6 g/d) intakes than those in CON (793 ± 9 g/d and 228 ± 11 g/d, respectively). Calves in PRE-L had greater average daily gain (0.96 ± 0.04 kg/d) than calves in CON (0.85 ± 0.03 kg/d) during wk 6 to 8. Calves in PRE-L tended to be medicated fewer days than CON (4.7 ± 1.2 d vs. 6.2 ± 3.4 d, respectively). Calves in PRE-L-M and CON-F (2,916 ± 112 µM and 2,848 ± 112 µM, respectively) had greater total AA concentration in plasma than calves in PRE-L-F and CON-M (2,684 ± 112 µM and 2,582 ± 112 µM, respectively). Calves in PRE-L-F and CON-M (4.09 ± 0.11% and 4.16 ± 0.11%, respectively) had greater concentration of Lys as a percentage of total AA compared with calves in CON-F and PRE-L-M (3.91 ± 0.11% and 3.90 ± 0.11%, respectively). Calves in PRE-L tended to have greater percentage of phagocytic neutrophils (39.6 ± 1.59%) than calves in CON (35.9 ± 1.59%). In conclusion, increasing the metabolizable lysine provided to prepartum dairy cows had modest effect over offspring performance, with the major result being a greater average daily gain for calves in PRE-L during the preweaning phase (wk 6-8).

Should patients with low-risk renal cell carcinoma be followed differently after nephron-sparing surgery vs radical nephrectomy?

OBJECTIVE: To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR). SUBJECTS: A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear-cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence-free survival (RFS) and cancer-specific mortality (CSM). RESULTS: From the database 1995 patients were identified as low-risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14-1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73-3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03-2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3-4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3-8.5; P < 0.001). Kaplan-Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above-mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study. CONCLUSION: Our results showed that follow-up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow-up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow-up strategy is proposed.

Feeding rumen-protected lysine prepartum increases energy-corrected milk and milk component yields in Holstein cows during early lactation.

Feeding rumen-protected Lys (RPL) may be used to increase lactation performance in dairy cows; however, the effect of feeding RPL during the prepartum period and subsequent effect on postpartum performance is not well explored. Therefore, this experiment was conducted to determine the effects of feeding RPL (AjiPro-L Generation 3, Ajinomoto Heartland Inc., Chicago, IL) prepartum, postpartum, or both on performance, health, and blood metabolites. Seventy-five multiparous Holstein cows, blocked by parity, previous 305-d mature-equivalent milk production, expected calving date, and body condition score during the far-off dry period were assigned to 1 of 2 dietary treatments: total mixed ration with or without RPL in a randomized, complete block design. A 2 × 2 factorial arrangement of treatments was used. Prepartum (-28 d to calving), animals were fed a diet (forage, 68% of dietary DM) with RPL [PRE-L; 0.54% RPL of dietary dry matter intake (DMI)] or without RPL (control; PRE-C). After calving, half of the cows from each prepartum treatment group were assigned to a diet (forage, 55.5% of dietary DM) with RPL (PRE-L POST-L; PRE-C POST-L; 0.40% RPL of dietary DMI) or without RPL (PRE-C POST-C; PRE-L POST-C) until d 28 postpartum. Cows were milked twice a day and milk samples were taken on 7 ± 1.3, 14 ± 1.4, and 28 ± 1.1 d relative to calving (DRC). Milk yield and DMI were recorded daily. Blood samples were taken for plasma AA analysis on -7 ± 0.5, 0 ± 0.5, 7 ± 0.9, and 14 ± 0.9 DRC. Cows in PRE-L had greater body weight at -2 and -1 wk before calving compared with those in PRE-C, though body weight change from wk -4 to -1 was not different. Body weight (717 ± 6 kg) was greater and DMI (18.1 ± 0.7 kg) tended to be greater for cows in PRE-L POST-L and PRE-L POST-C compared with those that were in PRE-C POST-L and PRE-C POST-C (707 ± 6 and 16.8 ± 0.7 kg, respectively). Energy-corrected milk (48.8 ± 1.9 kg/d), milk fat (1.9 ± 0.1 kg/d), milk true protein (1.4 ± 0.1 kg/d), milk casein (0.6 ± 0.04 kg/d), and milk lactose yields (2.1 ± 0.1 kg/d) were greater for cows in PRE-L POST-L and PRE-L POST-C compared with those that were in PRE-C POST-L and PRE-C POST-C (44.2 ± 1.9, 1.7 ± 0.1, 1.3 ± 0.1, 0.5 ± 0.04, 1.9 ± 0.1 kg/d, respectively). Plasma concentrations of Lys prepartum (69.8 ± 1.8 µM) increased for cows in PRE-L compared with those in PRE-C (62.5 ± 1.3 µM). In conclusion, RPL consumed prepartum tended to increase postpartum DMI and increased energy-corrected milk and milk component yields. This indicates that prepartum supply of intestinally available Lys is pertinent to postpartum performance. However, postpartum supply of intestinally available Lys had no effect on cows' performance.

The place of genetics in ageing research.

Rapidly increasing numbers of older people present many countries with growing social and economic challenges. Yet despite the far-reaching implications of ageing, its biological basis remains a topic of much debate. Recent advances in genomics have spurred research on ageing and lifespan in human populations, adding to extensive genetic studies being carried out in model organisms. But how far is ageing controlled by our genes? In this Viewpoint, six experts present their opinions and comment on future directions in ageing research.

Longitudinal changes in global and domain specific cognitive function in the very-old: findings from the Newcastle 85+ Study.

OBJECTIVE: Ageing is associated with changes in cognition in some, but not all domains. In young-old adults, defined as persons aged 65-84 years, baseline cognitive function has been shown to impact on cognitive trajectories. Whether similar patterns occur in the very-old, defined as persons aged 85 years and over, is not known. METHODS: Longitudinal changes (5 years' follow-up) in global and domain specific cognitive function including memory, attention and speed were investigated in participants from the Newcastle 85+ Study (n = 845). At baseline, participants were grouped using Mini-Mental State Examination cut-off scores and dementia status into the following: not impaired, mildly impaired or severely impaired/dementia groups. RESULTS: Only a limited number of cognitive measures showed significant decline in performance over time. Where observed, change generally occurred only in the severely impaired group. In the severely impaired group, small differences in baseline age were associated with poorer performance over time on most measures. Education was not protective against cognitive decline in any group. CONCLUSIONS: There are individuals who maintain a high level of cognitive function or only show mild impairments even into their ninth decade of life. This group of successful cognitive agers may provide insight for identifying predictors of cognitive integrity in later life. In individuals with severe impairment, cognitive performance shows significant decline over time, especially in measures of attention and speed. Further work to identify those individuals at highest risk of cognitive decline is necessary to implement early support and intervention strategies in this rapidly expanding age group. © 2017 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

New horizons in the compression of functional decline.

Population ageing, which has come about through the combination of increases in life expectancy, larger post-war cohorts reaching older age and reductions in fertility, is challenging societies and particularly health and care providers, worldwide. In Europe, the USA and Japan, there have been increases in years spent with disability and dependency. The majority of such research, as well as professional health and social care practice, measures loss of functional capability or need for social care, by aggregate disability scores, based around activities of daily living and instrumental activities of daily living. Although useful for defining whether an individual has passed a threshold, aggregate scores obscure how functional decline unfolds, and therefore where early intervention might improve intrinsic capacity and reverse or slow down decline, or maintain function. We propose a framework, the compression of functional decline (CFD), based on the latest understanding of the hierarchy of age-related functional decline, which has the potential to (i) help people understand how to live better for longer, (ii) allow the various stakeholders to be able to measure, at a population level, whether that is happening and (iii) identify which interventions are most effective at which stages. CFD is coherent with the World Health Organisation's Healthy Ageing model and is more easily understood by stakeholders and older people themselves, than current indicators such as frailty. CFD thus provides a realistic view of age-related functional decline in the context of modifiable behaviour to counter widespread public misconceptions about ageing and inform improvements.

Why and how are we living longer?

NEW FINDINGS: What is the topic of this review? The reasons for the continuing increase in human life expectancy are examined in the light of progress in understanding the physiological basis of ageing. Prospects for further extending the health span - the period free of age-related disability and disease - are critically assessed. What advances does it highlight? No active programming directly causes ageing, which instead results as a side effect of how evolution optimises the physiological allocation of resources between growth, reproduction and maintenance. Under pressure of natural selection, there was insufficient priority in maintaining the body well enough that it could endure without progressive accumulation of multiple kinds of molecular and cellular damage. Understanding human ageing is a major challenge for the physiological sciences. It is made all the more urgent by the survival of inreasing numbers of people to advanced old age and by a shift in the underlying causes of the continuing increase in life expectancy. The previous increase was caused almost entirely by the prevention of deaths in the early and middle years of life; a process that has seen such success that in developed countries there remains little scope for significant further increase from this cause. The more recent increase is driven by something new. We are reaching old age in generally better health, and it is the death rates at advanced ages that are now falling fast. At the same time, biology has established that there is almost certainly no fixed programme for ageing, which is caused instead by the lifelong accumulation of damage. It is becoming evident that the ageing process is much more malleable than we used to think. We need urgently to establish the factors that govern this malleability and to identify the interactions between, on the one hand, intrinsic biological processes that drive the many chronic diseases and disabilities for which age is by far the largest risk factor and, on the other hand, the social and lifestyle factors that influence our individual trajectories of health in old age. Ageing is no longer as mysterious and intractable a process as used to be thought, offering new opportunities for contributions from other branches of the physiological sciences.

Systematic review of the oncological and functional outcomes of pelvic organ-preserving radical cystectomy (RC) compared with standard RC in women who undergo curative surgery and orthotopic neobladder substitution for bladder cancer.

CONTEXT: Pelvic organ-preserving radical cystectomy (POPRC) for women may improve postoperative sexual and urinary functions without compromising the oncological outcome compared with standard radical cystectomy (RC). OBJECTIVE: To determine the effect of POPRC on sexual, oncological and urinary outcomes compared with RC in women who undergo standard curative surgery and orthotopic neobladder substitution for bladder cancer. EVIDENCE ACQUISITION: Medline, Embase, Cochrane controlled trials databases and clinicaltrial.gov were systematically searched for all relevant publications. Women with bladder cancer who underwent POPRC or standard RC and orthotopic neobladder substitution with curative intent were included. Prospective and retrospective comparative studies and single-arm case series were included. The primary outcomes were sexual function at 6-12 months after surgery and oncological outcomes including disease recurrence and overall survival (OS) at >2 years. Secondary outcomes included urinary continence at 6-12 months. Risk of bias (RoB) assessment was performed using standard Cochrane review methodology including additional domains based on confounder assessment. EVIDENCE SYNTHESIS: The searches yielded 11 941 discrete articles, of which 15 articles reporting on 15 studies recruiting a total of 874 patients were eligible for inclusion. Three papers had a matched-pair study design and the rest of the studies were mainly small, retrospective case series. Sexual outcomes were reported in seven studies with 167/194 patients (86%) having resumed sexual activity within 6 months postoperatively, with median (range) patients' sexual satisfaction score of 88.5 (80-100)%. Survival outcomes were reported in seven studies on 197 patients, with a mean follow-up of between 12 and 132 months. At 3 and 5 years, cancer-specific survival was 70-100% and OS was 65-100%. In all, 11 studies reported continence outcomes. Overall, the daytime and night-time continence rates were 58-100% and 42-100%, respectively. Overall, the self-catheterisation rate was 9.5-78%. Due to poor reporting and large heterogeneity between studies, instead of subgroup-analysis, a narrative synthesis approach was used. The overall RoB was high across all studies. CONCLUSION: For well-selected patients, POPRC with orthotopic neobladder may potentially be comparable to standard RC for oncological outcomes, whilst improving sexual and urinary function outcomes. However, in women undergoing RC, oncological and functional data regarding POPRC remain immature and require further evaluation in a prospective comparative setting.

Grip strength and inflammatory biomarker profiles in very old adults.

Background: weak grip strength (GS) and chronic inflammation have been implicated in the aetiology of sarcopenia in older adults. Given the interrelationships between inflammatory biomarkers, a summary variable may provide better insight into the relationship between inflammation and muscle strength. This approach has not been investigated in very old adults (aged ≥85) who are at highest risk of muscle weakness. Methods: we used mixed models to explore the prospective association between GS over 5 years in 845 participants in the Newcastle 85+ Study, and inflammatory components identified by principal component analysis (PCA). Cut-offs of ≤27 kg (men) and ≤16 (women) were used to define sub-cohorts with weak and normal GS at each assessment. Results: PCA identified three components, which explained 70% of the total variance in seven baseline biomarkers. Basal interleukin-6 (IL-6) and tumour necrosis factor (TNF-α) had the highest loadings on Component 1; stimulated IL-6 and TNF-α and homocysteine the highest on Component 2; high-sensitivity C-reactive protein (hsCRP) loaded positively and albumin negatively to Component 3. In adjusted mixed models, only Component 3 was associated with GS. One SD increase of Component 3 was associated with a 0.41 kg lower GS initially (P = 0.03) in all participants, but not with GS decline over time. Similar conclusions held for those in the weak and normal GS sub-cohorts. Conclusion: an inflammatory profile including hsCRP and albumin was independently associated with baseline GS. Future studies linking inflammatory profiles and muscle strength are needed to corroborate these findings in older adults.

Initial level and rate of change in grip strength predict all-cause mortality in very old adults.

Objective: to investigate the associations between initial level and rate of change in grip strength (GS) and all-cause mortality in very old adults (≥85 years) over a 9.6-year follow-up. Methods: prospective mortality data from 845 participants in the Newcastle 85+ Study were analysed for survival in relation to GS (kg, baseline and 5-year mean change) using Cox proportional hazards models. Results: during the follow-up, 636 (75.3%) participants died. Higher baseline GS was associated with a decreased risk of mortality in all participants [hazard ratio (HR) = 0.95, 95% confidence interval (CI): 0.93-0.98, P < 0.001], men (HR = 0.97, 95% CI: 0.95-0.99, P = 0.009) and women (HR = 0.96, 95% CI: 0.94-0.99, P = 0.007) after adjustment for health, lifestyle and anthropometric factors. Overall GS slope had a downward trajectory and was determined in 602 participants: 451 experienced constant decline (negative slope) and 151 had increasing GS (positive slope) over time. Men and women with a negative slope had a 16 and 33% increased risk of mortality, respectively, with every kg/year decline in GS (P ≤ 0.005), and participants with a positive slope had a 31% decreased risk of mortality (P = 0.03) irrespective of baseline GS and key covariates. Conclusion: higher baseline GS and 5-year increase in GS were protective of mortality, whilst GS decline was associated with an increased risk of mortality in the very old over 9.6 years, especially in women. These results add to the biological and clinical importance of GS as a powerful predictor of long-term survival in late life.

Transcription could be the key to the selection advantage of mitochondrial deletion mutants in aging.

The mitochondrial theory of aging is widely popular but confronted by several apparent inconsistencies. On the one hand, mitochondrial energy production is of central importance to the health and proper functioning of cells, and single-cell studies have shown that mtDNA deletion mutants accumulate in a clonal fashion in various mammalian species, displacing the wild-type mtDNAs. On the other hand, no explanation exists yet for the clonal expansion of mtDNA mutants that is compatible with experimental observations. We present here a new idea based on the distinctive connection between transcription and replication of metazoan mtDNA. Bioinformatic analysis of mtDNA deletion spectra strongly supports the predictions of this hypothesis and identifies specific candidates for proteins involved in transcriptional control of mtDNA replication. Computer simulations show the mechanism to be compatible with the available data from short- and long-lived mammalian species.

Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.

Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques (Random Mutation Capture, Next Generation Sequencing and mitochondrial enzyme histochemistry), and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (<20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

Respiratory health and disease in a U.K. population-based cohort of 85†year olds: The Newcastle 85+ Study.

BACKGROUND: People aged 85 years and older are the fastest growing age group worldwide. This study assessed respiratory health, prevalence of respiratory disease and use of spirometry in respiratory diagnosis in a population-based cohort of 85 year olds to better understand respiratory health and disease in this sector of society. METHODS: A single year birth-cohort of 85 year olds participated in a respiratory assessment at their home or residential institution including self-reporting of symptoms and measurement of spirometry. General practice medical records were reviewed for respiratory diagnoses and treatments. FINDINGS: In the 845 participants, a substantial burden of respiratory disease was seen with a prevalence of COPD in medical records of 16.6% (n=140). A large proportion of the cohort had environmental exposures through past or current smoking (64.2%, n=539) and occupational risk factors (33.6%, n=269). Spirometry meeting reliability criteria was performed in 87% (n=737) of participants. In the subgroup with a diagnosis of COPD (n=123), only 75.6% (n=93) satisfied Global Initiative in Obstructive Lung Disease (GOLD) criteria for airflow obstruction, and in a healthy subgroup without respiratory symptoms or diagnoses (n=151), 44.4% (n=67) reached GOLD criteria for airflow obstruction and 43.3% (n=29) National Institute of Health and Care Excellence criteria for at least moderate COPD. INTERPRETATION: Spirometry can be successfully performed in the very old, aged 85 years, and may help identify respiratory diseases such as COPD. However interpretation in this age group using current definitions of COPD based on spirometry indices may be difficult and lead to overdiagnosis in a healthy group with transient symptoms.

Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling.

Unrepaired or inaccurately repaired DNA damage can lead to a range of cell fates, such as apoptosis, cellular senescence or cancer, depending on the efficiency and accuracy of DNA damage repair and on the downstream DNA damage signalling. DNA damage repair and signalling have been studied and modelled in detail separately, but it is not yet clear how they integrate with one another to control cell fate. In this study, we have created an integrated stochastic model of DNA damage repair by non-homologous end joining and of gamma irradiation-induced cellular senescence in human cells that are not apoptosis-prone. The integrated model successfully explains the changes that occur in the dynamics of DNA damage repair after irradiation. Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model. Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence. The integrated model is valuable for studying the processes of DNA damage induced cell fate and predicting the effectiveness of DNA damage related medical interventions at the cellular level.

Micronutrient intake and food sources in the very old: analysis of the Newcastle 85+ Study.

A number of socio-economic, biological and lifestyle characteristics change with advancing age and place very old adults at increased risk of micronutrient deficiencies. The aim of this study was to assess vitamin and mineral intakes and respective food sources in 793 75-year-olds (302 men and 491 women) in the North-East of England, participating in the Newcastle 85+ Study. Micronutrient intakes were estimated using a multiple-pass recall tool (2×24 h recalls). Determinants of micronutrient intake were assessed with multinomial logistic regression. Median vitamin D, Ca and Mg intakes were 2·0 (interquartile range (IQR) 1·2-6·5) µg/d, 731 (IQR 554-916) mg/d and 215 (IQR 166-266) mg/d, respectively. Fe intake was 8·7 (IQR 6·7-11·6) mg/d, and Se intake was 39·0 (IQR 27·3-55·5) µg/d. Cereals and cereal products were the top contributors to intakes of folate (31·5 %), Fe (49·2 %) and Se (46·7 %) and the second highest contributors to intakes of vitamin D (23·8 %), Ca (27·5 %) and K (15·8 %). More than 95 % (n 756) of the participants had vitamin D intakes below the UK's Reference Nutrient Intake (10 µg/d). In all, >20 % of the participants were below the Lower Reference Nutrient Intake for Mg (n 175), K (n 238) and Se (n 418) (comparisons with dietary reference values (DRV) do not include supplements). As most DRV are not age specific and have been extrapolated from younger populations, results should be interpreted with caution. Participants with higher education, from higher social class and who were more physically active had more nutrient-dense diets. More studies are needed to inform the development of age-specific DRV for micronutrients for the very old.

Macronutrient intake and food sources in the very old: analysis of the Newcastle 85+ Study.

Food and nutrient intake data are scarce in very old adults (85 years and older) - one of the fastest growing age segments of Western societies, including the UK. Our primary objective was to assess energy and macronutrient intakes and respective food sources in 793 85-year-olds (302 men and 491 women) living in North-East England and participating in the Newcastle 85+ cohort Study. Dietary information was collected using a repeated multiple-pass recall (2×24 h recalls). Energy, macronutrient and NSP intakes were estimated, and the contribution (%) of food groups to nutrient intake was calculated. The median energy intake was 6·65 (interquartile ranges (IQR) 5·49-8·16) MJ/d - 46·8 % was from carbohydrates, 36·8 % from fats and 15·7 % from proteins. NSP intake was 10·2 g/d (IQR 7·3-13·7). NSP intake was higher in non-institutionalised, more educated, from higher social class and more physically active 85-year-olds. Cereals and cereal products were the top contributors to intakes of energy and most macronutrients (carbohydrates, non-milk extrinsic sugars, NSP and fat), followed by meat and meat products. The median intakes of energy and NSP were much lower than the estimated average requirement for energy (9·6 MJ/d for men and 7·7 MJ/d for women) and the dietary reference value (DRV) for NSP (≥18 g/d). The median SFA intake was higher than the DRV (≤11 % of dietary energy). This study highlights the paucity of data on dietary intake and the uncertainties about DRV for this age group.

Age-related frailty and its association with biological markers of ageing.

BACKGROUND: The relationship between age-related frailty and the underlying processes that drive changes in health is currently unclear. Considered individually, most blood biomarkers show only weak relationships with frailty and ageing. Here, we examined whether a biomarker-based frailty index (FI-B) allowed examination of their collective effect in predicting mortality compared with individual biomarkers, a clinical deficits frailty index (FI-CD), and the Fried frailty phenotype. METHODS: We analyzed baseline data and up to 7-year mortality in the Newcastle 85+ Study (n = 845; mean age 85.5). The FI-B combined 40 biomarkers of cellular ageing, inflammation, haematology, and immunosenescence. The Kaplan-Meier estimator was used to stratify participants into FI-B risk strata. Stability of the risk estimates for the FI-B was assessed using iterative, random subsampling of the 40 FI-B items. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves. RESULTS: The mean FI-B was 0.35 (SD, 0.08), higher than the mean FI-CD (0.22; SD, 0.12); no participant had an FI-B score <0.12. Higher values of each FI were associated with higher mortality risk. In a sex-adjusted model, each one percent increase in the FI-B increased the hazard ratio by 5.4 % (HR, 1.05; CI, 1.04-1.06). The FI-B was more powerful for mortality prediction than any individual biomarker and was robust to biomarker substitution. The ROC analysis showed moderate discriminative ability for 7-year mortality (AUC for FI-CD = 0.71 and AUC for FI-B = 0.66). No individual biomarker's AUC exceeded 0.61. The AUC for combined FI-CD/FI-B was 0.75. CONCLUSIONS: Many biological processes are implicated in ageing. The systemic effects of these processes can be elucidated using the frailty index approach, which showed here that subclinical deficits increased the risk of death. In the future, blood biomarkers may indicate the nature of the underlying causal deficits leading to age-related frailty, thereby helping to expose targets for early preventative interventions.