Immunosenescence profiles of lymphocyte compartments and multiple long-term conditions (multimorbidity) in very old adults: The Newcastle 85+ Study.

Immunosenescence, a decline in immune system function, has been linked to several age-related diseases and ageing syndromes. Very old adults (aged ≥ 85 years) live with multiple long-term conditions (MLTC, also known as multimorbidity)-a complex phenomenon of poor health defined by either counts, indices, or patterns, but little is known about the relationship between an ageing immune system and MLTC in this age group. We utilised baseline data from the Newcastle 85+ Study to investigate the associations between previously defined immunosenescence profiles of lymphocyte compartments and MLTC counts and patterns (from 16 chronic diseases/ageing syndromes). Seven hundred and three participants had MLTC and complete data for all 16 conditions, a median and mean of 5 (range 2-11) and 62.2% had ≥ 5 conditions. Three distinct MLTC patterns emerged by clustering: Cluster 1 ('Low frequency cardiometabolic-cerebrovascular diseases', n = 209), Cluster 2 ('High ageing syndromes-arthritis', n = 240), and Cluster 3 ('Hypertensive-renal impairment', n = 254). Although having a more senescent phenotype, characterised by higher frequency of CD4 and CD8 senescence-like effector memory cells and lower CD4/CD8 ratio, was not associated with MLTC compared with less senescent phenotype, the results warrant further investigation, including whether immunosenescence drives change in MLTC and influences MLTC severity in late adulthood.

Senolytics and the compression of late-life mortality.

Senescent cells play an important role in mammalian ageing and in the etiology of age-related diseases. Treatment of mice with senolytics - drugs that selectively remove senescent cells - causes an extension of median lifespan but has little effect on maximum lifespan. Postponement of some mortality to later ages, without a corresponding increase in maximum mortality, can be termed 'compression of mortality'. When we fit the standard Gompertz mortality model to the survival data following senolytic treatment, we find an increase in the slope parameter, commonly described as the 'actuarial ageing rate'. These observations raise important questions about the actions of senolytic treatments and their effects on health and survival, which are not yet sufficiently understood. To explore how the survival data from senolytics experiments might be explained, we combine a recent exploration of the evolutionary basis of cellular senescence with theoretical consideration of the molecular processes that might be involved. We perform numerical simulations of senescent cell accumulation and senolytic treatment in an ageing population. The simulations suggest that while senolytics diminish the burden of senescent cells, they may also impair the general repair capacity of the organism, leading to a faster accumulation post-treatment of new senescent cells. Our results suggest a framework to address the benefits and possible side effects of senolytic therapies, with the potential to aid in the design of optimal treatment regimens.

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.

On the evolution of cellular senescence.

The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age-related diseases and extends the life span of mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti-cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Mitochondria in the signaling pathways that control longevity and health span.

Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis, nutrient-sensing, and genome damage response signaling pathways, as prominent regulators of longevity and health span in various species. Mitochondria are the primary sites of ATP production and are key players in several other important cellular processes. Mitochondrial dysfunction diminishes tissue and organ functional performance and is a commonly considered feature of the aging process. Here we review the evidence that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process. An important characteristic of these pathways is their extensive crosstalk and apparent malleability to modification by non-invasive pharmacological, dietary, and lifestyle interventions, with promising effects on lifespan and health span in animal models and potentially also in humans.

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.

Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts.

Stem cell (SC) dynamics within the human colorectal crypt SC niche remain poorly understood, with previous studies proposing divergent hypotheses on the predominant mode of SC self-renewal and the rate of SC replacement. Here we use age-related mitochondrial oxidative phosphorylation (OXPHOS) defects to trace clonal lineages within human colorectal crypts across the adult life-course. By resolving the frequency and size distribution of OXPHOS-deficient clones, quantitative analysis shows that, in common with mouse, long-term maintenance of the colonic epithelial crypt relies on stochastic SC loss and replacement mediated by competition for limited niche access. We find that the colonic crypt is maintained by ~5 effective SCs. However, with a SC loss/replacement rate estimated to be slower than once per year, our results indicate that the vast majority of individual SC divisions result in asymmetric fate outcome. These findings provide a quantitative platform to detect and study deviations from human colorectal crypt SC niche homeostasis during the process of colorectal carcinogenesis.

Resolving the Enigma of the Clonal Expansion of mtDNA Deletions.

Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging.

Do reef corals age?

Hydra is emerging as a model organism for studies of ageing in early metazoan animals, but reef corals offer an equally ancient evolutionary perspective as well as several advantages, not least being the hard exoskeleton which provides a rich fossil record as well as a record of growth and means of ageing of individual coral polyps. Reef corals are also widely regarded as potentially immortal at the level of the asexual lineage and are assumed not to undergo an intrinsic ageing process. However, putative molecular indicators of ageing have recently been detected in reef corals. While many of the large massive coral species attain considerable ages (>600 years) there are other much shorter-lived species where older members of some populations show catastrophic mortality, compared to juveniles, under environmental stress. Other studies suggestive of ageing include those demonstrating decreased reproduction, increased susceptibility to oxidative stress and disease, reduced regeneration potential and declining growth rate in mature colonies. This review aims to promote interest and research in reef coral ageing, both as a useful model for the early evolution of ageing and as a factor in studies of ecological impacts on reef systems in light of the enhanced effects of environmental stress on ageing in other organisms.

Is There a Link Between Cognitive Reserve and Cognitive Function in the Oldest-Old?

Background: The oldest-old (aged ≥85 years) are the fastest growing age group, with the highest risk of cognitive impairment and dementia. This study investigated whether cognitive reserve applies to the oldest-old. This has implications for cognitive interventions in this age group. Methods: Baseline and 5-year follow-up data from the Newcastle 85+ Study were used (N = 845, mean age = 85.5, 38% male). A Cognitive Reserve Index (CRI) was created, including: education, social class, marital status, engagement in mental activities, social participation, and physical activity. Global (Mini-Mental State Examination) and domain specific (Cognitive Drug Research Battery subtests assessing memory, attention, and speed) cognitive functions were assessed. Dementia diagnosis was determined by health records. Logistic regression analysis examined the association between CRI scores and incident dementia. Mixed effects models investigated baseline and longitudinal associations between the CRI scores and cognitive function. Analyses controlled for sex, age, depression, and cardiovascular disease history. Results: Higher reserve associated with better cognitive performance on all baseline measures, but not 5-year rate of change. The CRI associated with prevalent, but not incident dementia. Conclusions: In the oldest-old, higher reserve associated with better baseline global and domain-specific cognitive function and reduced risk of prevalent dementia; but not cognitive decline or incident dementia. Increasing reserve could promote cognitive function in the oldest-old. The results suggest there would be little impact on trajectories, but replication is needed. Development of preventative strategies would benefit from identifying the role of each factor in building reserve and why rate of change is not affected.

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.

Pervasive gene expression responses to a fluctuating diet in Drosophila melanogaster: The importance of measuring multiple traits to decouple potential mediators of life span and reproduction.

Phenotypic plasticity is an important concept in life-history evolution, and most organisms, including Drosophila melanogaster, show a plastic life-history response to diet. However, little is known about how these life-history responses are mediated. In this study, we compared adult female flies fed an alternating diet (yoyo flies) with flies fed a constant low (CL) or high (CH) diet and tested how whole genome expression was affected by these diet regimes and how the transcriptional responses related to different life-history traits. We showed that flies were able to respond quickly to diet fluctuations throughout life span by drastically changing their transcription. Importantly, by measuring the response of multiple life-history traits we were able to decouple groups of genes associated with life span or reproduction, life-history traits that often covary with a diet change. A coexpression network analysis uncovered which genes underpin the separate and shared regulation of these life-history traits. Our study provides essential insights to help unravel the genetic architecture mediating life-history responses to diet, and it shows that the flies' whole genome transcription response is highly plastic.

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.

Explaining sex differences in lifespan in terms of optimal energy allocation in the baboon.

We provide a quantitative test of the hypothesis that sex role specialization may account for sex differences in lifespan in baboons if such specialization causes the dependency of fitness upon longevity, and consequently the optimal resolution to an energetic trade-off between somatic maintenance and other physiological functions, to differ between males and females. We present a model in which females provide all offspring care and males compete for access to reproductive females and in which the partitioning of available energy between the competing fitness-enhancing functions of growth, maintenance, and reproduction is modeled as a dynamic behavioral game, with the optimal decision for each individual depending upon his/her state and the behavior of other members of the population. Our model replicates the sexual dimorphism in body size and sex differences in longevity and reproductive scheduling seen in natural populations of baboons. We show that this outcome is generally robust to perturbations in model parameters, an important finding given that the same behavior is seen across multiple populations and species in the wild. This supports the idea that sex differences in longevity result from differences in the value of somatic maintenance relative to other fitness-enhancing functions in keeping with the disposable soma theory.

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.

Vitamin D Status, Muscle Strength and Physical Performance Decline in Very Old Adults: A Prospective Study.

Mixed reports exist about the role of 25-hydroxyvitamin D (25(OH)D) in muscle ageing and there are few prospective studies involving the very old (aged ≥ 85) who are at highest risk of low 25(OH)D, loss of muscle mass and strength, and physical performance decline. In the Newcastle 85+ Study (n = 845), we aimed to determine the association between 25(OH)D season-specific quartiles (hereafter SQ1-SQ4), grip strength (GS) and physical performance decline (Timed Up-and-Go Test, TUG) over 5 years using mixed models. In the time-only models with linear and quadratic slopes, SQ1 and SQ4 of 25(OH)D were associated with weaker GS initially in men (SQ1: ß (SE) = -2.56 (0.96); SQ4: -2.16 (1.06)) and women (SQ1: -1.10 (0.52); SQ4: -1.28 (0.50)) (all p ≤ 0.04). In the fully adjusted models, only men in SQ1 had a significant annual decline in GS of 1.41 kg which accelerated over time (-0.40 (0.1)), (both p ≤ 0.003) compared with those in combined middle quartiles. Only women in SQ1 and SQ4 of 25(OH)D had worse TUG times initially, but the rate of TUG decline was not affected. Low baseline 25(OH)D may contribute to muscle strength decline in the very old and particularly in men.