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Centenarians: An excellent example of resilience for successful ageing
Abstract
Centenarians are remarkable not only because of their prolonged life, but also because they compress morbidity until the very last moments of their lives, thus being proposed as a model of successful, extraordinary ageing. From the medical viewpoint, centenarians do not escape the physiological decline or the age-related diseases or syndromes (i.e. frailty), but the rate of such processes is slow enough to be counterbalanced by their increased intrinsic capacity to respond to minor stresses of daily life (i.e. resilience). These new concepts are reviewed in this paper. Allostatic stresses lead to a chronic low-grade inflammation that has led to the proposal of the "inflammaging" theory of ageing and frailty. The biology of centenarians, described in this review, provides us with clues for intervention to promote healthy ageing in the general population. One of the major reasons for this healthy ageing has to do with the genetic signature that is specific for centenarians and certainly different from octogenarians who do not enjoy the extraordinary qualities of centenarians.
... Of note, lifespan and healthspan are closely related and some individuals can present exceptional longevity in good health compared to others [4][5][6]. From a holistic point of view, two paradigms have been proposed for human longevity and successful aging [7], either relying on models developed from the "compression of morbidity" hypothesis that was first stated by Fries in 1980 [8,9], or the "deceleration aging" hypothesis [10,11]. ...
... Concerning genetics, the long-known existence of centenarian families had always suggested a genetic and heritable component of longevity [13,14]. The heritability of human longevity, first measured in a Danish twin study [15], was estimated at between 20 and 30% [7,16]. Moreover, the parents, siblings and offspring of long-lived individuals have a higher average lifespan than individuals without long-lived relatives [12,16,17]. ...
... In this context, centenarians are considered as an exceptional model for healthy aging and longevity studies, due to their remarkable ability to achieve successful aging. Thus, they escaped death or strongly debilitating diseases for most of their life and resisted well in the face of the frailties and diseases of the great age [7,12,16,18,19]. This is particularly true for genetic studies as the heritably of longevity was shown to increase with old age, notably in centenarians and (semi-)supercentenarians [20,21]. ...
The increasing aging of the human population is currently and for the coming decades a major public health issue in many countries, requiring the implementation of global public health policies promoting healthy and successful aging. Individuals are not equal in the face of aging and some can present exceptional healthspan and/or lifespan, which are notably influenced by both genetic and environmental factors. Research and studies on human aging, healthy aging and longevity should rely in particular on cohorts of long-lived individuals, also including biological samples allowing studies on the biology of aging and longevity. In this manuscript, we provide for the first time a complete description of the CEPH (Centre d’Etude du Polymophisme Humain) Aging cohort, an exceptional cohort recruited during the 90s to 2000s, including more than 1700 French long-lived individuals (≥ 90 years old) born between 1875 and 1916 as well as for some of them their siblings and offspring. Among the participants, 1265 were centenarians, including 255 semi-supercentenarians ([105–110] years old) and 25 supercentenarians (≥ 110 years old). The available anthropometric, epidemiologic and clinical data for the cohort participants are described and especially the collection of blood-derived biological samples associated with the cohort which includes DNA, cryopreserved cells and cell lines, plasma, and serum. This biological collection from the first cohort of centenarians in the world is an inestimable resource for ongoing and future molecular, cellular, and functional studies aimed at deciphering the mechanisms of human (successful) aging and longevity.
... Several hypotheses have been described to explain it, including early recognition and treatment of osteoporosis, preventive measures for falls, healthier habits, and an active lifestyle [25,26]. The last point is especially relevant among centenarians, who maintain their daily activity for a longer time and have better functional status [27]. This results in early functional recovery at discharge and a reduction in the risk of new fractures due to frailty [28]. ...
... Finally, centenarians are characterized by a concentration of morbidity in the last years of life and the onset of the most severe diseases when death is near [27], such as PHF (with an incidence of mortality four times higher in centenarians than in younger individuals) [41]. Therefore, despite observing a progressive decrease in surgical delay and LOS, mortality figures have remained stable [28]. ...
Background
Proximal hip fractures (PHFs) increased worldwide due to population ageing and represent the third cause of admission in Spanish centenarians. Recognizing trends in their evolution could improve their healthcare.
Aim
To describe changes in trends in clinical characteristics, surgical decisions and in-hospital outcomes in PHF among centenarians in Spain, 2004 and 2020.
Methods
This retrospective observational study included centenarians hospitalized with a principal diagnosis of PHF using data from the Hospital Discharge Records-Minimum Basic Data Set of the Spanish National Health System. Trends were analyzed using joinpoint regression analysis and descriptive and univariate statistics.
Results
4,261 PHF admissions among centenarians were recorded. The number of PHF admissions increased from 147 in 2004 to 339 in 2020 (Average Percentage Change (APC)= 3.8%), with a higher increase in women. However, there was a reduction in the incidence of admissions in the last five years. Despite a significant increase in multimorbidity (from 44.4 to 64.1%) and in-hospital complications, there was a decreased in surgical delay (with more surgeries performed within 48 h: from 27.6 to 43.3%) and length of hospital stay (from 12.2 ± 8.6 to 9.7 ± 8.0 days), with a notable shift towards arthroplasty (from 28.7 to 52.7%), and stable mortality rates (APC=-1.5).
Conclusion
This study indicates an increased complexity in patient profiles, with higher rates of multimorbidity and complications, but improvements in surgical care have led to reduced surgical delays and shorter hospital stays. Future studies are necessary to understand the factors associated with these trends and to design specific strategies in this vulnerable population.
... Internal factors are involved in approaching the different types of resilience, like the intrinsic capacity, biological reserve, and people's psychological resources, as well as external factors like the support network, economic support and cultural context. The balance between these factors is key in responding to the allostatic load and maintaining the body's homeostasis [2][3][4][5][6][7] . ...
... In a second model, both the onset of morbidity as well as years of life accumulated move toward the right, with no gains or losses in morbidity, and in the third model, the onset of morbidity is delayed and accompanied by accumulated years of life, leading to morbidity compression. This theory was tested in a study in Massachusetts which indicated that the centenarian cohort lived 96% or more of their lives functionally independent and in good health 2,8 . ...
... When considering the prevalence of escapers, we observed that this prevalence was lower in lifespans around life expectancy (in most diseases, between lifespans of 70 and 90 years) depending on the system and that individuals with the longest lifespans had a similar prevalence of escapers than those with the shortest ones. These results could be explained by a higher severity of specific diseases in individuals with shorter lifespans, which may prevent the onset of other diseases before death [29], in contrast with a higher protection against developing diseases in longer-lived individuals, as suggested by other authors [30,31]. We also observed how globally, the number of systems free of disease decreased until the ages of death 87-88 and started increasing thereafter, indicating that up to these ages (87-88) individuals die with more systems affected as their lifespan increases whereas after these ages, individuals progressively die with less systems affected as their lifespan increases. ...
... Individuals that die after 87-88 years of age may have greater protection against suffering age-related diseases, which may be the result of optimized homeostatic protective mechanisms. Until now, there has been a consensus that considers centenarians as chronological age-based models of successful aging [30], together with other individual-centered models such as the one proposed by Rowe and Kahn [33]. However, based on our data, we propose that centenarians are the most extreme case of successful aging, and individuals with lifespans over 87-88 years are also relevant for the study of extreme lifespan. ...
Background
Slower paces of aging are related to lower risk of developing diseases and premature death. Therefore, the greatest challenge of modern societies is to ensure that the increase in lifespan is accompanied by an increase in health span. To better understand the differences in human lifespan, new insight concerning the relationship between lifespan and the age of onset of diseases, and the ability to avoid them is needed. We aimed to comprehensively study, at a population-wide level, the sex-specific disease patterns associated with human lifespan.
Methods
Observational data from the SIDIAP database of a cohort of 482,058 individuals that died in Catalonia (Spain) at ages over 50 years old between the 1st of January 2006 and the 30th of June 2022 were included. The time to the onset of the first disease in multiple organ systems, the prevalence of escapers, the percentage of life free of disease, and their relationship with lifespan were evaluated considering sex-specific traits.
Results
In the study cohort, 50.4% of the participants were women and the mean lifespan was 83 years. The results show novel relationships between the age of onset of disease, health span, and lifespan. The key findings include: Firstly, the onset of both single and multisystem diseases is progressively delayed as lifespan increases. Secondly, the prevalence of escapers is lower in lifespans around life expectancy. Thirdly, the number of disease-free systems decreases until individuals reach lifespans around 87–88 years old, at which point it starts to increase. Furthermore, long-lived women are less susceptible to multisystem diseases. The associations between health span and lifespan are system-dependent, and disease onset and the percentage of life spent free of disease at the time of death contribute to explaining lifespan variability. Lastly, the study highlights significant system-specific disparities between women and men.
Conclusions
Health interventions focused on delaying aging and age-related diseases should be the most effective in increasing not only lifespan but also health span. The findings of this research highlight the relevance of Electronic Health Records in studying the aging process and open up new possibilities in age-related disease prevention that should assist primary care professionals in devising individualized care and treatment plans.
... Traditionally, studies on centenarians supported the idea that they were exceptionally healthy individuals, although these studies have evident selection biases due to methodological problems that call their results into question (Rasmussen & Andersen-Ranberg, 2016). It seems more reasonable to speak of autonomous centenarians (Andersen- Ranberg et al., 2001), who have a unique capacity to delay the severe diseases and disability of the last years of life and, therefore, delaying hospitalization (Borras et al., 2020;Pignolo, 2019). When hospitalization does occur, complications arise and admissions can occur repeatedly until death (Engberg et al., 2009). ...
... In Spain, the older populations, including centenarians (Fuentes et al., 2021;Pérez-Díaz & Abellán-García, 2018), have been mostly concentrated in the northern regions (especially in the northwest) and in those in the interior contiguous to the north, which have been characterized by more rural areas (based on the fact that Spain is a highly urbanized country, and understanding rural areas as those with great geographical dispersion, primary activities based on agriculture and less access to resources) (Jiménez, 2008;Prieto-Lara & Ocaña-Riola, 2010), as shown in this study. This suggests that the progressive and unequal increase of the centenarian population in Spain is due more to ecological factors (healthier lifestyle and living habits, with a higher quality of life and disability-free life expectancy) and social factors (more social support related to the rural community lifestyle), than to factors related to advances in health (Brandão et al., 2019;Borras et al., 2020). Second, it shows that the population increase has had a significant repercussion on the increase in admissions among centenarians. ...
ABSTRACT
Background
This study aims to describe the distribution and temporal trends of the centenarian population and their hospital admissions in Spain over the past two decades, focusing on regional and sex-based differences.
Methods
A retrospective study was conducted using data from the Spanish National Health System's Hospital Discharge Records-Minimum Basic Data Set. The analysis included all hospitalized patients ≥100 years between January 2004 and December 2020. The crude annual centenarian population and admission rates were calculated. Joinpoint regression analysis and cross-correlation analysis were used to identify trends and associations.
Results
From 2004 to 2020, the centenarian population in Spain increased by 89.0%, with a larger increase observed in women (86.6%) than men (32.9%). Significant geographic variability was found, with rates from 1.1 to 5.2 × 10,000 inhabitants per year across different regions. Joinpoint analysis identified three trends: a decline from 2004–2008, an increase from 2008–2015, and a slower increase from 2015–2020. Hospital admissions of centenarians increased by 121.5%, with a larger increase in women than men (212.1% vs 90.7%); women represented 75.4% of admissions. The proportion of centenarian admissions to total hospitalizations showed an upward trend until 2015 and then stabilized; it also varied among regions.
Conclusion
There was a significant increase in the centenarian population and hospital admissions of centenarians in Spain. There are regional disparities in their distribution, with women representing a larger proportion of centenarians and hospital admissions. Understanding these trends and differences is crucial for implementing interventions that ensure adequate healthcare for centenarians.
... The biology of centenarians, described in this review, provides us with clues for intervention to promote healthy ageing in the general population. One of the major reasons for this healthy ageing has to do with the genetic signature that is specific to centenarians and certainly different from octogenarians who do not enjoy the extraordinary qualities of centenarians [27]. ...
... In an ageing population, with increasing numbers of centenarians and a growing prevalence of non-communicable chronic diseases, health promotion will need to rely on encouraging individuals to adopt healthy habits such as exercise and meditation, a balanced diet, and social interaction [61,62]. From a medical viewpoint, centenarians do not escape physiological decline or age-related diseases or syndromes (e.g., frailty), but the rate of such processes is slow enough to be counterbalanced by their increased intrinsic capacity to respond to the minor stresses of daily life (i.e., resilience) [27]. ...
Life expectancy at birth (hereafter, life expectancy) and longevity are established indicators of population health [...]
... In recent decades, lifespan has considerably increased and, at the same time, the worldwide population of centenarians has also enlarged. These days, centenarians' prevalence rate in Europe is around 1 per 5000 and, nowadays, centenarians pose as an established model of successful aging [1]. It is justified by the fact that they can compress morbidity and comply with the group of individuals less prone to age-related diseases, including type 2 diabetes mellitus, neurodegenerative diseases (Alzheimer's and Parkinson's), cardiovascular disease, and cancers [2]. ...
... In another study, results suggest that centenarians could be less prone to oxidative stress owing to better-developed antioxidant mechanisms [5]. Identical observations were made for inflammaging and immune changes [1,[6][7][8][9][10][11][12][13][14][15][16][17]. What is more, the endocrine system of centenarians is possibly capable of efficient glucose handling and shows higher insulin sensitivity compared to the young cohort [18]. ...
We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people—nonagenarians to (semi)supercentenarians—maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity. We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the “young” level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance. We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.
... Another study based on Baltimore Longitudinal Study of Aging indicated that being edentulous or having fewer than 20 teeth was independently associated with the mortality of older adults [11]. Centenarians comprise those who successfully age and have good resilience, and the number of centenarians is increasing worldwide [12][13][14]. Centenarians and their offspring demonstrated better oral health, suggesting the potential relationship between natural teeth retention and longevity [8]. Moreover, possessing ≤20 natural teeth was an independent risk factor for frailty among centenarians [3]. ...
Background
In recent decades, the global life expectancy has risen notably to approximately 73.5 years worldwide, coinciding with a rapid growth in the older adult population, which presents a significant public health challenge in promoting healthy aging and longevity.
Objective
This study aimed to prospectively investigate the link between edentulousness and the likelihood of reaching centenarian status among individuals aged 80 years and older.
Methods
Data from the Chinese Longitudinal Healthy Longevity Survey were analyzed. Logistic regression models were used to assess the relationship between edentulousness and the likelihood of becoming a centenarian. Demographic characteristics, lifestyle habits, and disease histories were adjusted as confounding factors. Several sensitivity analyses, including propensity score matching and 2-year lag analyses, were conducted to further assess the association between edentulousness and the likelihood of becoming a centenarian. The correlation between the number of natural teeth as a continuous variable and the likelihood of becoming a centenarian was evaluated as well.
Results
The study included 4239 participants aged 80-100 years. After adjusting for all covariates, the likelihood for becoming a centenarian increased in the nonedentulous group compared to the edentulous group (odds ratio [OR] 1.384, 95% CI 1.093‐1.751). The relationship persisted after propensity score matching analysis (OR 1.272, 95% CI 1.037‐1.561). The association remained statistically significant after excluding participants with a follow-up duration of less than 2 years (OR 1.522, 95% CI 1.083‐2.140; P =.02). Furthermore, a significant positive association between the number of natural teeth and the likelihood of becoming a centenarian was found after adjusting for all covariates (OR 1.022, 95% CI 1.002‐1.042; P =.03), which aligned with the main results of the study.
Conclusions
The findings revealed that the presence of natural teeth was linked to an increased probability of becoming a centenarian, underscoring the importance of maintaining oral health even in advanced age.
... Studies focused on cancer in centenarians are still scarce [5][6][7]15]. The use of Electronic Health Records for analyzing cancer incidence, types, and survival allowed us to characterize centenarians in the context of this disease. ...
Cancer is one of the leading causes of death and its prevalence increases with age. While centenarians exhibit extreme longevity and potential to avoid or delay aging-related diseases, their response to cancer is still barely explored. Our study took advantage of the Electronic Health Records to retrospectively compare the severity of cancer in centenarians ( n = 649) and non-centenarians ( n = 62,753) in the Basque Country (province of Gipuzkoa), Spain, through analyzing all the recorded diagnoses throughout their lifetime. Descriptive statistics were applied to discern differences between the two population groups in terms of prevalence of tumor types, number of diagnoses, and treatments. Survival analysis was performed through Kaplan–Meier estimator. We found that centenarians had fewer cancer diagnoses (17.1%, n = 111) than non-centenarians (40.5%, n = 25,405), and notably avoided the most aggressive cancer types and did not develop metastasis. Furthermore, they barely had records of treatments or drugs and had extended survival both since the first and last diagnosis of cancer. These results suggest resilience of the centenarians against malignant cancers explaining, in part, their extended longevity.
... Hence, extending the human lifespan while achieving healthy aging to longevity simultaneously are the major goals of global aging and anti-aging research. The healthy elderly over 90 years old, who are the representatives of extreme longevity, have reached the limit of human longevity while largely avoiding and postponing major age-related diseases, thereby making them the most successful examples of healthy Ivyspring International Publisher aging [3,4]. As individuals who are deemed most likely to achieve extreme longevity, the offspring of healthy longevity have the unique interests of researchers [5,6]. ...
... Besides medical issues, ethical dilemmas about the proper way of treating centenarians are also discussed [11]. On the other hand, centenarians are described as the lowest complexity patients with the lowest Charlson Co-morbidity Index (CCI) compared to younger hip fracture patients [12] and their comparatively healthy aging process is based on their genetic signature [13]. It is widely known that orthogeriatric care has led to a decrease in in-house mortality [14]. ...
Background/Objectives: Outcomes for hip fracture patients have improved over the years, yet the population of older patients (≥80 years) continues to grow. By 2100, the global centenarian population is projected to exceed 25 million, but data on hip fracture outcomes in this group are rare and often derived from small samples. This study aimed to analyze outcomes for centenarian hip fracture patients in specialized geriatric trauma centers and compare them with those of patients under 80. Methods: We conducted a retrospective analysis of the AltersTraumaRegister DGU® from 2016 to 2022, including all proximal femur fracture data. Patients were categorized into two groups: under 80 years and centenarians. The primary outcome was in-hospital mortality, with secondary outcomes including quality of life, walking ability on postoperative day seven, length of hospital stay, readmission rates, and changes in living situations. Results: Among 14,521 patients, 316 were over 99 years old. In-house mortality was significantly higher in centenarians (15.44% vs. 3.58%; p < 0.001), with more discharged to nursing homes. After matching by the Geriatrics at Risk (GeRi) score, mortality differences diminished. Conclusions: While age is a risk factor for mortality, centenarian hip fracture patients’ outcomes do not significantly differ from those aged ≤80 when considering other risk factors.
... This understanding could also focus on other factors contributing to longer, healthier lives. 30 This study area has sparked significant interest in uncovering these individuals' developmental and evolutionary origins to develop targeted therapies for aging. ...
We explore aging as a global phenomenon, questioning whether it constitutes a treatable condition or follows a natural course. Acknowledging its multifactorial nature, we delve into the challenges and opportunities inherent in this intricate biological process. The inclusion of old age in the 11th International Classification of Diseases sparks debate, categorizing it as a disease based on mechanistic explanations, blood-based biomarkers, and anti-aging products. Ethical dilemmas arise, emphasizing the difficulty of defining the transition from normal to pathological states during this process. We suggest that aging should be regarded as a treatable condition without necessarily labeling it a ‘disease.’ While anti-aging research unveils promising interventions like Metformin, Rapamycin, and cellular therapy, achieving biological immortality remains a formidable challenge. The future promises to prolong life and enhance quality by comprehensively understanding aging’s implications for human health.
... This study is the first to examine the lipid profile of centenarians compared with the elderly people in Kazakhstan and is also a continuation of the study of centenarians of the Republic of Kazakhstan. As the world's aging population is increasing, so the problem of healthy longevity and healthy aging in general is receiving a lot of [1,2]. Studies focus on all-cause mortality in general, and cardiovascular mortality in particular. ...
Introduction. The health of centenarians is a major focus in global studies. Dyslipidemia is directly linked to the risk of cardiovascular diseases, which pose a growing burden on healthcare due to the increasing elderly population. Studying the lipid profiles of centenarians is important for preventing circulatory system diseases and promoting healthy aging. This research aims to compare the prevalence of dyslipidemia in centenarians (median age 96 [95-97]) with elderly individuals (median age was 69 [64 – 74]) in the Republic of Kazakhstan and examine potential predictors of dyslipidemia in the centenarian group. Methods. The study involved 46 centenarians (study group) and 82 elderly individuals (control group). Statistical analysis was used to process the data, including blood markers and demographic variables, to identify factors contributing to dyslipidemia. Results and conclusion. The prevalence of hypercholesterolemia in centenarians was 32.6% (15 people - 3 men; 12 women), with elevated LDL levels in 4.3% (2 women). In the control group, hypercholesterolemia prevalence was 29.3% (24 people - 6 men; 18 women) and elevated triglycerides in 6.1% (3 women; 2 men). The study and control groups were compared based on their lipid profile characteristics, which showed similarities as indicated by all p-values being above 0.05: Cholesterol (p=0.348), HDL (p=0.975), LDL (p=0.161), and Triglycerides (p=0.159). Decreased physical activity was a predictor of dyslipidemia in centenarians. Excessive cholesterol levels were significantly higher among women than men in both groups. The primary factor for dyslipidemia was low physical activity, with other predictors having no significant impact on the lipid profiles of centenarians. This factor should be considered when assessing cardiovascular disease risks and all-cause mortality.
... The incidence of age-related chronic diseases among centenarians is lower compared to other older people (Evert et al., 2003;Pavlidis et al., 2012;Borras et al., 2020;Cruces-Salguero et al., 2023). Compared to other older people, centenarians have lower levels of circulating triglycerides, cholesterol, and glucose (Camacho-Pereira et al., 2016;Murata et al., 2024). ...
Human ageing is a normal process and does not necessarily result in the development of frailty. A mix of genetic, environmental, dietary, and lifestyle factors can have an impact on ageing, and whether an individual develops frailty. Frailty is defined as the loss of physiological reserve both at the physical and cellular levels, where systemic processes such as oxidative stress and inflammation contribute to physical decline. The newest “omics” technology and systems biology discipline, metabolomics, enables thorough characterisation of small-molecule metabolites in biological systems at a particular time and condition. In a biological system, metabolites—cellular intermediate products of metabolic reactions—reflect the system’s final response to genomic, transcriptomic, proteomic, epigenetic, or environmental alterations. As a relatively newer technique to characterise metabolites and biomarkers in ageing and illness, metabolomics has gained popularity and has a wide range of applications. We will give a comprehensive summary of what is currently known about metabolomics in studies of ageing, with a focus on biomarkers for frailty. Metabolites related to amino acids, lipids, carbohydrates, and redox metabolism may function as biomarkers of ageing and/or frailty development, based on data obtained from human studies. However, there is a complexity that underpins biological ageing, due to both genetic and environmental factors that play a role in orchestrating the ageing process. Therefore, there is a critical need to identify pathways that contribute to functional decline in people with frailty.
... They do not escape physiological decline or agerelated diseases or syndromes (ie, frailty), but the rate of such processes is slow enough to be offset by their increased functional capacity to respond to minor stresses of daily life (ie, resilience). 4 The WHO advocated in its World Report on a comprehensive bibliometric analysis of IC older adults over the 8 years 2015-2023 and also provide scholars who have entered or are about to enter this field of study with insights on the current state, emerging trends, and future research hot spots in this field from a global viewpoint. ...
Objective
The concept of intrinsic capacity (IC) revolves around healthy aging and active aging. Since the Introduction of the concept by the World Health Organization in 2015, a series of studies have been conducted by scholars from multiple fields. However, no bibliometric analysis has systematically investigated this issue. We aim to identify the current landscape and frontier trends of scientific achievements on IC in older adults through bibliometric approaches.
Methods
Quantitative analysis of publications relating to IC in older adults from 2015 to 2023 was interpreted and graphed through the Web of Science Core Collection database on December 5, 2023. A variety of quantitative variables was analyzed, including publication and citation counts, H-index, and journal citation reports. Co-authorship, citation, co-citation, and co-occurrence analyses were performed for countries/regions, institutions, authors, and keywords using the VOSviewer and CiteSpace.
Results
A total of 952 original and review articles in English were identified. The European countries possessed an absolute advantage in this field. The most contributive institution was the University of São Paulo. The most productive author is Cesari Matteo from France, followed by Qaisar Rizwan from the United Arab Emirates. However, a relatively low level of research cooperation existed between institutions and authors. Important topics mainly include the connotations, theoretical framework models, evaluation, screening tools, and application scenarios of IC. Among the promising hotspots, “biological aging”, “ICOPE”, “Covid-19”, “prevention”, “inflammation”, “caf22”, “prevalence”, and “randomized controlled trial” displayed relatively latest average appearing year.
Conclusion
Global trends indicate a growing scientific output on IC in older adults, and developed countries are leading the way. There is still room for improvement in research team collaboration. The focus gradually shifts from theoretical research to empirical research. It is recommended to pay attention to the latest hot spots, such as “biological aging”, “ICOPE implementation”, “post-COVID-19 syndrome”, and “biomarkers”.
... However, they can adapt and recalibrate these parameters at very old ages, showing optimal levels when they are longlived. Our results support the hypothesis that individuals endowed with heightened biological plasticity or adaptive homeostasis (Pomatto and Davies 2017;Borras et al. 2020), manifesting in an increased proportion of CD4+ and CD8+ T cells expressing TNF or macrophages expressing IL-10, are more likely to achieve an extended lifespan. Nevertheless, due to the small sample size of mice that reached extreme longevity together with the batch effects and technical variability that affects intracellular staining of cytokines, the results of the present study should be validated using a larger number of long-lived mice. ...
Peritoneal immune cell function is a reliable indicator of aging and longevity in mice and inflammaging is associated with a shorter lifespan. Nevertheless, it is unknown if the content of cytokines in these immune cells is linked to individual differences in lifespan. Therefore, this work aimed to investigate different peritoneal leukocyte populations and their content in intracellular pro-inflammatory (TNF and IL-6) and anti-inflammatory (IL-10) cytokines by flow cytometry in adult (10 months-old, n = 8) and old (18 months-old, n = 20) female Swiss/ICR mice. In addition, old mice were monitored longitudinally throughout their aging process, and the same markers were analyzed at the very old (24 months-old, n = 8) and long-lived (30 months-old, n = 4) ages. The longitudinal follow-up allowed us to relate the investigated parameters to individual lifespans. The results show that long-lived female mice exhibit an adult-like profile in most parameters investigated but also display specific immune adaptations, such as increased CD4+ and CD8+ T cells containing the pro-inflammatory TNF cytokine and CD4+ T cells and macrophages containing the anti-inflammatory cytokine IL-10. These adaptations may underlie their exceptional longevity. In addition, a negative correlation was obtained between the percentage of cytotoxic T cells, KLRG-1/CD4, large peritoneal macrophages, and the percentage of CD4+ T cells containing IL-6 and macrophages containing IL-10 in old age and lifespan, whereas a positive correlation was found between the CD4/CD8 ratio and the longevity of the animals at the same age. These results highlight the crucial role of peritoneal leukocytes in inflammaging and longevity.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10522-024-10110-0.
... In fact, aging is characterized by the continuous adaptation of the organism to life-long exposure to stress that finally leads to a relevant clinical complexity 8, 9 . It is reasonable to think that centenarians do not escape the physiological decline or the age-related diseases or syndromes (i.e., frailty), but the rate of such processes is slow enough to be counterbalanced by their increased intrinsic capacity to respond to stresses of daily life (i.e., resilience) 10 . Depending on the ability of each person to respond successfully or not to stress factors, the aging process changes, thus leading to extremely heterogeneous phenotypes 11 , particularly evident among persons of exceptional longevity 12,13 . ...
People reaching old age are increasing exponentially in recent decades, and centenarians represent the fastest-growing group. Aging is characterized by the continuous adaptation of the organism to life-long exposure to stress that leads to a relevant clinical complexity. It is reasonable to think that centenarians do not escape the physiological decline or the age-related diseases and syndromes, but the rate of such processes is slow enough to be counterbalanced by their increased capacity to respond to stresses. Therefore, depending on the ability of each person to respond successfully or unsuccessfully to stressors, the aging process changes, leading to extremely heterogeneous phenotypes, particularly evident among centenarians. In a cohort of Italian centenarians, the high heterogeneity in health status was well captured by means of the Frailty Index (FI) computed utilizing clinical variables. Surprisingly, in the same cohort, a FI computed utilizing biological variables showed average lower values and a narrower distribution than the clinical one. Interestingly, these centenarians showed higher blood free T4 (FT4) and thyroid-stimulating hormone (TSH) levels, and lower blood free T3 (FT3) levels and FT3/ FT4 ratio than younger persons. Moreover, their endocrine profile was characterized by high adiponectin levels and insulin sensitivity, and low insulin growth factor-1 (IGF-1) and leptin levels. Under these premises, studies on centenarians open a window to extreme longevity. Metabolic remodelling of these persons is suggestive of benefits that play a critical and positive role in shaping healthy aging.
... Centenarians represent the most successful model of biological aging in humans [10]. These individuals, who have a chronological age equal to or greater than 100 years, have special health characteristics, mostly partially known [11,12], that contradict the previously described theoretical concept of autoimmunity in the elderly. Unfortunately, there is a lack of robust evidence describing or discussing autoimmunity in centenarians. ...
Autoimmune diseases (ADs) are one of the groups of chronic illnesses that impose a significant burden of disease and health costs worldwide. Age is a crucial risk factor for the onset of ADs. Theoretically, it is inferred that with organic and immune system aging, the loss of immune tolerance and specificity of immune activity becomes more intense, the probability of autoimmunity is increasing. However, there is a group of individuals whose prevalence of ADs is very low or non-existent, despite the biological aging. This paradox in autoimmunity raises questions. Centenarians, individuals who are over 100 years old, are possibly the most successful model of biological aging in humans. Most of these individuals exhibit a favorable health phenotype. To date, primary data evidence and potential hypotheses explaining this phenomenon are lacking globally, even though this paradox could provide valuable, original, and relevant information regarding the understanding of risk or protective factors, biological drivers, and biomarkers related to autoimmunity. Herein we discuss some hypothesis that may explain the absence of ADs in centenarians, including inflammaging, immunosenescence and immune resilience, immune system hyperstimulation, proteodynamics, and genetics.
... En un segundo modelo, tanto el inicio de la morbilidad como los años de vida acumulados se desplazan hacia la derecha, sin ganancias ni pérdidas de morbilidad, y en el tercer modelo, el inicio de la morbilidad se retrasa y se acompaña de años de vida acumulados, lo que da lugar a una compresión de la morbilidad. Esta teoría se comprueba con un estudio realizado en Massachussets que indica que la cohorte de centenarios vive el 96% o más de su vida funcionalmente independiente y con buena salud 2,8 . ...
Physiological resilience is acquired according to the individual capacity to adapt to stress. The aim of this article is to describe the factors that influence resilience in older adults. This is a narrative review based on a database research (PubMed and BVS) with MeSH and DeCS descriptors and keywords such as: resilience, physiological resilience and older adults. Of the 67 initial articles, 23 met the inclusion criteria for analysis and 10 were selected. The individual exposome influences changes in the epigenome, allowing a differential response to the allostatic load and access to active aging that can be modified through early and lasting interventions in older adults to impact on improved quality of life. Modifiable and multidomain contributors to resilience (intrinsic and extrinsic) are the key to its enrichment and contribute to a successful aging process in older adults.
... The term biological age depicts a snapshot at a certain point of chronological age. That functional state results from salutogenetic resources, capabilities, and resilience [14] but also from impairments, disabilities, and handicaps. The latter coins the term biological age with a rather negative connotation: Although biological age is an indisputable function of advancing chronological age, it is afflicted by an impenetrable maze of intervening variables which makes the life phase of aging interindividually so heterogenous [15]. ...
Background
Increasing proportions of geriatric patients pose tremendous challenges for our society. Developments in assistive technologies have the potential to support older and frail people in aging and care. To reach a sustainable adoption of these technologies, the perceptions and wishes of future users must be understood. In particular, the relationships between individual health-related factors, and the perceptions of aging and using assistive technologies in severe health situations must be empirically examined.
Methods
Addressing this research gap, our quantitative study (N = 570) investigates the impact of diverse future users’ age and health status on their a) perceptions of aging, b) perceptions and acceptance of using assistive technologies in aging and care, as well as c) end-of-life decisions regarding technology usage. For this, four groups were segmented for the comparison of younger (< 50 years) healthy, younger chronically ill, older (50 + years) healthy, and older chronically ill participants.
Results
The results revealed that health status is more decisive for age-related perceptions compared to age. The technology-related perceptions were slightly impacted by either chronological age or health status. The end-of-life decisions showed the most striking differences in the willingness to use assistive technologies, revealing older chronically ill participants to have more restrained attitudes towards technology usage than older healthy as well as all younger participants.
Conclusions
The findings suggest that the benefits of assistive technologies in private or professional care contexts should be communicated and implemented tailored to the respective user group’s needs. Moreover, the results allow us to derive practical implications within the geriatric care context.
... This study focused on neighborhood environment characteristics including housing suitability, neighborhood satisfaction, trust, and access to facilities [8] rather than on social support from families, friends, community, and social organization that is most closely related to individual health [8,21]. Besides, it is not very appropriate to take the number of chronic diseases as a proxy of IC in this study since IC declines much earlier before the emergence of age-associated diseases or symptoms and is conceptually distinct from chronic diseases [22]. Lower IC as an early signal of diseases may facilitate the more effective health management of older population [2]. ...
To examine how social support might moderate the relationship between intrinsic capacity and health-related quality of life (HRQoL) based on the buffering model of social support.
This was a cross-sectional study with a sample of 1181 Chinese community-dwelling older adults aged ≥ 60 years in 2016. Social support was assessed using the Social Support Rating Scale. Intrinsic capacity was assessed using the revised integrated care for older people screening tool. HRQoL was measured by the 12-item Short Form Health Survey. Hierarchical linear regression analysis was implemented to test the moderating effect of social support.
Support utilization attenuated the relationship between lower intrinsic capacity and poor physical HRQoL while subjective support attenuated the relationship between lower intrinsic capacity and poor mental HRQoL. However, objective support had no significant moderating effect on the relationship between intrinsic capacity and specific domains of HRQoL.
The moderating effects of social support on the association between intrinsic capacity and HRQoL vary by support types. Effective interventions should target the perception and utilization of available support among older adults with lower intrinsic capacity to maintain their physical and mental HRQoL.
... It was also observed that older patients without vitamin D deficiency presented better primary clinical outcomes regarding to death rate, disease severity, and requirement of oxygen therapy or invasive mechanical ventilation [20]. An Australian study with 21.315 older adults randomized to 60.000 IU of vitamin D or placebo monthly for 5 years showed a slight reduction in the number of episodes for antibiotic prescriptions, total prescriptions, and repeated prescriptions, suggesting a particular benefit for those with low vitamin D status [21]. ...
Changes occurring in the immune system along the ageing process increase the risk of infection, susceptibility to tumor development, and autoimmunity. Interventions such as physical exercise, supplements, and probiotics have been proposed in order to circumvent these conditions. Vitamin D supplementation could contribute to the immune system homeostasis in older adults since a large proportion of this population has low levels of circulating vitamin D. Additionally, observational studies have shown the association between vitamin D status and infections, chronic diseases such as cancer, diabetes, and cardiovascular disease. Recently it was observed that old patients with COVID-19 and vitamin D deficiency had enhanced severity of lung damage, longer stay at the hospital, and increased risk of death, suggesting that vitamin D plays an important role in the patient outcome from COVID-19. A high dose of vitamin D supplementation improved clinical recovery in a case-series report but in another study, no evident link between levels of vitamin D and risk of COVID-19 infection was found. Results also remain debatable for vitamin D supplements and improvement of immune response after vaccination, tuberculosis, pneumonia, and sepsis. It has been hypothesized that vitamin D could modulate the immune system and thus provide both efficacies in the immune response to pathogens/vaccinations and reduction of the inflammatory phenotype. This review will discuss vitamin D and homeostasis of the immune system; the literature-based clinical data on vitamin D and infections; and the possible link between vitamin D and immune response after vaccination.
... même si cette baisse pourraitêtre de moindre ampleur et contribuerait de moins en moinsà la croissance de l'espérance de vie.La longévité humaine est déterminée par des facteurs génétiques mais aussi sociétaux. Les conditions de vie aux jeunesâges, les modes de vie adoptés, les régimes alimentaires pourraient etre des déterminants potentiels(Borras et al., 2019;Carey et al., 1992;C.O., 1981).À l'heure actuelle, il n'existe aucun consensus. Le débat continueà porter sur l'existence d'unâge biologique limite de l'être humain entre différents courants de pensées. ...
La forme de la courbe de mortalité aux très grands âges reste incertaine. Le débat entre une trajectoire de décélération et une croissance exponentielle avec l’âge n’est pas tranché. Ce manque de consensus est essentiellement dû à la qualité inégale des données et à la variété des hypothèses servant à la modélisation. Cette thèse mobilise des données d’excellente qualité sur les décès survenus en France, en Belgique et au Québec pour identifier la trajectoire la plus plausible aux âges extrêmes par des modèles paramétriques. Nous étudions les différentes lois de probabilité applicables à nos données : loi de Poisson, loi binomiale négative et loi binomiale, en nous appuyant sur une palette d’outils d’évaluation de la performance des modèles (intervalles de confiance, résidus de déviance et critères d’information). L’hétérogénéité de la population, d’abord supposée inobservable, est prise en compte par les modèles de fragilité puis, supposée observable, elle est étudiée par les modèles de l’analyse de survie. Selon les données disponibles, la loi de Poisson reste appropriée pour la modélisation de la mortalité aux très grands âges. Une trajectoire de décélération de la mortalité apparaît comme la plus plausible dans la majorité des populations féminines mais une croissance exponentielle est plus convaincante pour les populations masculines. Une surmortalité masculine est présente dans toutes populations. Et il n’est pas possible d’identifier un plateau de mortalité. Ces résultats ne permettent pas de clore le débat. Pour trancher définitivement sur la forme de la trajectoire de mortalité, les efforts de collecte sur les décès aux très grands âges doivent être poursuivis.
... Understanding this conundrum continues to constitute a challenge to clients and therapists. Further research in genetics, medicine, public health, sociology, the humanities, and an interdisciplinary array of other fields will certainly help (Borras et al., 2020;Jopp et al., 2016;Perls et al., 1999). This clinical case study demonstrates that psychotherapy during older adulthood can be an important path for helping individuals achieve a good long life. ...
... A persistent immune system activation and a heightened inflammatory state are undoubtedly the most prominent and documented typical hallmarks of advanced age and a major contributor to several age-related pathologies, including frailty and sarcopenia [68,69]. This inflammatory process, identified with the term of "inflammaging" is often facilitated by physiologic and pathophysiologic alterations of the immune system occurring with aging, such as "immunosenescence", an impairment of the functionality of immune cells that contributes to an increased incidence and severity of infections in older subjects [70,71]. ...
Microgravity exposure causes several physiological and psychosocial alterations that challenge astronauts’ health during space flight. Notably, many of these changes are mostly related to physical inactivity influencing different functional systems and organ biology, in particular the musculoskeletal system, dramatically resulting in aging-like phenotypes, such as those occurring in older persons on Earth. In this sense, sarcopenia, a syndrome characterized by the loss in muscle mass and strength due to skeletal muscle unloading, is undoubtedly one of the most critical aging-like adverse effects of microgravity and a prevalent problem in the geriatric population, still awaiting effective countermeasures. Therefore, there is an urgent demand to identify clinically relevant biological markers and to underline molecular mechanisms behind these effects that are still poorly understood. From this perspective, a lesson from Geroscience may help tailor interventions to counteract the adverse effects of microgravity. For instance, decades of studies in the field have demonstrated that in the older people, the clinical picture of sarcopenia remarkably overlaps (from a clinical and biological point of view) with that of frailty, primarily when referred to the physical function domain. Based on this premise, here we provide a deeper understanding of the biological mechanisms of sarcopenia and frailty, which in aging are often considered together, and how these converge with those observed in astronauts after space flight.
As the global population ages, caring for the oldest old in our communities is becoming more difficult. Research suggests that people prefer to age in place (i.e. in their own home), however there are still occasions where older people need to access residential aged care. Models of aged care provision have changed significantly over time, as a result of societal changes, policy directives and aged care research. This chapter presents the results of a literature review investigating the models of Aged Care, and how the newer household model impacts upon the quality of life of older people living in aged care facilities.
Before human genome sequencing, a genome-wide study of sibling centenarian pairs identified a longevity-associated locus on chromosome 4. Here, we mapped the genes in this locus and identified a collagen gene, COL25A1. Introducing an SNP linked to longevity that changes a serine predicted to be phosphorylated to leucine in COL25A1 , into col-99 , the C. elegans ortholog, extended lifespan. These col-99(gk694263 [S106L] ) SNP-mutants exhibited enhanced innate immune-related transcriptional responses, and their lifespan extension was abolished by inhibiting the p38 MAPK pathway. YAP-1, a transcriptional co-activator responsive to extracellular matrix changes, was essential for this longevity. Mechanistically, we propose that this SNP modifies furin-mediated cleavage of this transmembrane collagen in vitro, and expressing the cleaved extracellular domain of COL-99 alone was sufficient to prolong lifespan. These findings reveal a potential mechanism by which a human centenarian-associated SNP in COL25A1 influences furin cleavage and shedding of the collagen ectodomain to promote healthy longevity.
The quest to decipher the determinants of human longevity has intensified with the rise in global life expectancy. Long-lived individuals (LLIs), who exceed the average life expectancy while delaying age-related diseases, serve as a unique model for studying human healthy aging and longevity. Longevity is a complex phenotype influenced by both genetic and non-genetic factors. This review paper delves into the genetic, epigenetic, metabolic, immune, and environmental factors underpinning the phenomenon of human longevity, with a particular focus on LLIs, such as centenarians. By integrating findings from human longevity studies, this review highlights a diverse array of factors influencing longevity, ranging from genetic polymorphisms and epigenetic modifications to the impacts of diet and physical activity. As life expectancy grows, understanding these factors is crucial for developing strategies that promote a healthier and longer life.
In considering “What matters for healthy ageing?” we must ask “what matters to whom?” The answers may be very different considering older people themselves, health care providers, industry, governments, or scientists.
Aging inevitably gives rise to many challenges and transitions that can greatly impact our (mental) well-being and quality of life if these are not controlled adequately. Hence, the key to successful aging may not be the absence of these stressors, but the ability to demonstrate resilience against them. The current study set out to explore how resilience and successful aging may intersect by investigating how various resilience capacity-promoting (protective) and resilience capacity-reducing (risk) factors relate to mental well-being and quality of life. Through a large-scale (N = 2000, age 55+, 30 factors) network analysis, we established the interplay between risk/protective factors from various domains, including demographics, (mental) health, (environmental) stress, lifestyle, coping/personality, and ageism. We revealed some unique pathways through which each of these factors contribute to individuals’ mental well-being and/or quality of life, and interpreted these findings in terms of a resilience-based framework of successful aging. Our findings emphasize the complexity of factors that can impact quality of life and mental well-being in later life and can steer researchers and practitioners in devising efficacious, multi-pronged interventions that target risk and protective factors simultaneously, thereby maximizing their potential in boosting beneficial outcomes among older individuals.
As the numbers of older adults continue to increase globally, the need for facilitating healthy aging has become critical. While a physically healthy lifestyle, including exercise and diet, is important, recent research has highlighted a major impact of psychosocial determinants of health, such as resilience, wisdom, positive social connections, and mental well-being, on whole health. This article focuses on keeping the mind and brain healthy with psychosocially active aging. It has six sections: Philosophy Concepts of Wisdom, Resilience, and Well-Being; Wisdom: Clinical, Neurobiological, and Evolutionary Perspectives; Resilience, Adaptation, and Augmentation; Psychological Resilience, Brain Health, and Whole Person Health; Preventing Depression and Promoting Resilience and Well-Being in Old Age; and The Centenarian as a Model of Resilience and Well-Being. We discuss the biopsychosocial mechanisms and effectiveness of healthy lifestyle strategies and propose a framework for future research and its practical implications for promoting wisdom, resilience, and well-being at the individual, societal, and policy levels.
Resumen introducción: Los centenarios (100-105 años) y casi-centenarios (95-99 años) constituyen un importante grupo poblacional con un aumento progresivo en los próximos años, especialmente en los países de bajos y medianos ingresos. Pocos estudios sobre casi-centenarios y centenarios han sido llevados a cabo en Latinoamérica y en Colombia. El objetivo de este estudio fue analizar las características de los casi-centenarios y centenarios, con datos procedentes de un estudio poblacional en ancianos SABE Colombia (Salud, Bienestar y Envejecimiento). Materiales y Métodos: SABE fue un estudio tras-versal realizado entre el 2014 y el 2015 que involucró 23694 participantes de 60 años y más que vivían en áreas urbanas y rurales de Colombia. Para este análisis se tuvieron en cuenta un total de 130 individuos con edades entre 95 y 108 (mediana 97,1). Las entrevistas cubrieron cuatro áreas principales del en-1.
Los cambios demográficos desde el siglo XIX se han asociado con un aumento progresivo en la esperanza de vida, mejor supervivencia de los mayores de 80 años y un incremento de la población centenaria, creando un desafío demográfico global con consecuencias a nivel individual, familiar y social. Igualmente, para la atención en salud son evidentes los retos y necesidades que ha traído la longevidad extrema, determinado por las enfermedades crónicas, el grado de dependencia y fragilidad, la heterogeneidad del envejecimiento y el limitado número de geriatras que puedan garantizar su abordaje integral. En este marco, presentamos una revisión de la situación actual de la atención en salud del paciente centenario y una propuesta de ruta basada en el manejo de morbilidad compleja y la detección de necesidades individuales y paliativas de este grupo poblacional.
Objective
To describe types and outcomes of elective otolaryngological surgeries undergone by patients ≥90 years of age and to assess whether very old age is an independent risk factor for postsurgical complications and death.
Methods
The National Surgical Quality Improvement Program, a validated national prospective surgical outcomes database, was used to identify all patients aged 65 years and older who underwent elective otolaryngological procedures from 2011 to 2020. Study outcomes included minor complications, major life‐threatening complications, and 30‐day mortality. Predictors of outcomes, including frailty, were identified using univariable analyses and age was added into the final logistic regression models with stepwise selection.
Results
A total of 40,723 patients met inclusion criteria; 629 (1.5%) patients were ≥90 years of age. Of the 63,389 procedures, head and neck (67.6%) and facial plastics and reconstructive (15.0%) procedures were most common. The overall incidence of major life‐threatening complications, minor complications, and death was 2.0%, 3.5%, and 0.4%, respectively. Age ≥90 was significantly associated with an increased risk for 30‐day mortality, but not with major or minor postoperative complications. A high modified frailty index was significantly associated with an increased risk for major postoperative complications and death amongst patients ≥90 years.
Conclusions
Elective otolaryngological surgery can be safe in relatively healthy nonagenarians and centenarians, though there is a small increased risk of 30‐day mortality. Although older age can predispose patients to other comorbidities, age alone should not deter surgeons and patients from considering elective otolaryngological procedures. Frailty may be a better predictor for surgical outcomes.
Level of Evidence
Level IV Laryngoscope , 2024
A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. Here, we propose a loss‐or‐gain survival model, represented by the ratio of cumulative stress span to life span, to quantify stress resilience at organismal level. As a proof of concept, this is demonstrated by reduced survival resilience in Caenorhabditis elegans exposed to exogenous oxidative stress induced by paraquat or with endogenous proteotoxic stress caused by polyglutamine or amyloid‐β aggregation. Based on this, we reveal that a hidden peptide (“cryptide”)—AbaPep#07 (SETYELRK)—derived from abalone hemocyanin not only enhances survival resilience against paraquat‐induced oxidative stress but also rescues proteotoxicity‐mediated behavioral deficits in C. elegans , indicating its capacity against stress and neurodegeneration. Interestingly, AbaPep#07 is also found to increase cost‐free longevity and age‐related physical fitness in nematodes. We then demonstrate that AbaPep#07 can promote nuclear localization of SKN‐1/Nrf, but not DAF‐16/FOXO, transcription factor. In contrast to its effects in wild‐type nematodes, AbaPep#07 cannot increase oxidative stress survival and physical motility in loss‐of‐function skn‐1 mutant, suggesting an SKN‐1/Nrf‐dependent fashion of these effects. Further investigation reveals that AbaPep#07 can induce transcriptional activation of immune defense, lipid metabolism, and metabolic detoxification pathways, including many SKN‐1/Nrf target genes. Together, our findings demonstrate that AbaPep#07 is able to boost stress resilience and reduce behavioral frailty via SKN‐1/Nrf‐governed transcriptional reprogramming, and provide an insight into the health‐promoting potential of antioxidant cryptides as geroprotectors in aging and associated conditions.
The number of centenarians is increasing year by year. Considering that happier people are likely to live longer, we asked ourselves whether healthy centenarians share psychological resources or positive personality characteristics that have enabled them to face traumatic situations and the challenges life more successfully. To our knowledge this is an issue that has not been sufficiently researched. Mixed methodology was applied. Qualitative Study 1: Nineteen centenarians participated between 100 and 107 years old of which 16 were women. Semi-structured, in-depth interviews about their life story were done. Quantitative Study 2: The purpose was to control the results of Study 1. Fifteen proxies for the centenarians participated. Results: In Study 1, 35 psychological resources were identified, of which 19 were central or identifying resources of the centenarians, and 16 peripheral or the product of individual differences. The central resources were grouped into six categories: vitality, taking pleasure in interaction, commitment, control, intellectually motivated and positivity, with resilience and intelligence added. The results in Study 2 were completely concordant. In conclusion, analysis of the lives of healthy centenarians provides us with knowledge that could help in achieving a healthy old age. Additionally, the study opens up new lines of research.
Diverse individuals age at different rates and display variable susceptibilities to tissue aging, functional decline and aging-related diseases. Centenarians, exemplifying extreme longevity, serve as models for healthy aging. The field of human aging and longevity research is rapidly advancing, garnering significant attention and accumulating substantial data in recent years. Omics technologies, encompassing phenomics, genomics, transcriptomics, proteomics, metabolomics and microbiomics, have provided multidimensional insights and revolutionized cohort-based investigations into human aging and longevity. Accumulated data, covering diverse cells, tissues and cohorts across the lifespan necessitates the establishment of an open and integrated database. Addressing this, we established the Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.
Whole health is a holistic health care delivery approach that focuses on the interconnectedness of physical, mental, spiritual, and social well-being. This chapter examines the concept of whole health in the context of centenarians. We discuss the increasing population of centenarians worldwide and the unique challenges they face in terms of health and well-being. It then explores the various components of whole health and discusses the importance of addressing the social determinants of health in this population, including access to healthcare and social support and the role of community engagement and support networks in promoting a sense of purpose and fulfillment The mental aspect of whole health is also examined, highlighting the importance of social connections, cognitive stimulation, and emotional support in promoting well-being in centenarians.. We highlight the role of age friendly environments in empowering centenarians to live an independent and functional life.
A recent call was made for autonomic nervous system (ANS) measures as digital health markers for early detection of Alzheimer's disease and related dementia (AD/ADRD). Nevertheless, contradictory or inconclusive findings exist. To help advance understanding of ANS' role in dementia, we draw upon aging and dementia-related literature, and propose a framework that centers on the role of ANS flexibility to guide future work on application of ANS function to differentiating the degree and type of dementia-related brain pathologies. We first provide a brief review of literature within the past 10 years on ANS and dementia-related brain pathologies. Next, we present an ANS flexibility model, describing how the model can be applied to understand these brain pathologies, as well as differentiate or even be leveraged to modify typical brain aging and dementia. Lastly, we briefly discuss the implication of the model for understanding resilience and vulnerability to dementia-related outcomes.
Somatic mutations accumulate with age and are associated closely with human health, their characterization in longevity cohorts remains largely unknown. Here, by analyzing whole genome somatic mutation profiles in 73 centenarians and 51 younger controls in China, we found that centenarian genomes are characterized by a markedly skewed distribution of somatic mutations, with many genomic regions being specifically conserved but displaying a high function potential. This, together with the observed more efficient DNA repair ability in the long-lived individuals, supports the existence of key genomic regions for human survival during aging, with their integrity being of essential to human longevity.
Providing care for the elderly has been considered a significant challenge for modern medicine. As age progresses, diseases become more frequent and severe than those observed at a younger age. This is particularly relevant for infectious diseases, typical in the elderly and usually associated with poor outcomes. Moreover, when persisting and diffusing into the bloodstream (i.e. bacteremia), these infections keep up with the demand for immune cells’ response and consequently increase the concentration of inflammatory markers systemically. This phenomenon is known as “inflammaging”, which potentially triggers or facilitates the development and progression of several age-related disorders, such as cancer, cardiovascular and neurodegenerative diseases. Periodontal disease is one of the most prominent among the disparate number of causal factors responsible for bacteremia and low-grade systemic inflammation in the aging population. This inflammatory disorder is triggered by a dysbiosis of certain bacterial species that activates a massive local toxic deleterious immune response leading to non-reversible damage of supportive tissues surrounding the teeth. In chronic, oral pathogens and their toxic factors can penetrate the bloodstream contributing to systemic inflammation. Based on this premise, it seems evident that maintaining oral health in the elderly is vital not just for owning healthy mouth but also because it contributes to a healthy aging. This review provides an updated account of molecular insights into the bidirectional association between oral health and “successful” aging.
Objectives
The increase in the number of people living beyond age 90 pose challenges to mental health professionals, many of whom still harbor ageist notions concerning the efficacy of psychotherapy for the oldest old. This paper demonstrates how integrated psychotherapy with an oldest old woman can provide opportunities for integration and personal growth.
Clinical intervention
Integrated psychotherapy based on self-psychology psychodynamic approach, was provided to a woman from age 90 to 100 concerning age-related changes and losses and unresolved traumatic experiences in life. which troubled her notwithstanding previous efforts to resolve them.
Outcomes
Over the course of almost ten years, the client came to terms with her aging losses, experiences, worked through the therapeutic process, and learned how to express and accept her deepest feelings, thereby achieving psychological well-being and internal peace.
Clinical Implications
Psychotherapy for the oldest old may contribute to their well-being by offering significant opportunities to process and understand major events and unresolved issues along the life cycle. This study demonstrates that the older self is flexible and capable of growth, even as physical health wanes. Transference and countertransference reactions between therapists and clients can be instrumental in understanding and improving the well-being of the oldest old.
Background:
It is unclear to what degree centenarians are successful agers. We assess successful aging (SA) and its subtypes in a large Chinese sample.
Methods:
Based on a large national sample of 18,311 Chinese centenarians, we first estimated the prevalence of SA among centenarians, and then used the Latent Class Analysis to classify centenarians into different types based on the five dimensions of SA. Multinomial regression analysis was used to examine how demographic, socioeconomic, and lifestyle covariates are associated with these identified types.
Results:
5.7% of centenarians fulfilled all five criteria of SA, and 1.3% failed all five criteria. The remainder could be classified into six types of SA. The regression analysis further revealed that these SA types were related to various social factors. For example, with timely access to medical care, centenarians were three times more likely to be successful agers.
Conclusions:
Centenarians demonstrate substantial heterogeneity in terms of achieving five SA criteria. Social factors are found to be significantly associated with centenarians' aging performances. Specific subtypes of SA among centenarians may be associated with and help explore different underlying biological-environmental mechanisms of exceptional longevity.
A lipid profile resistant to oxidative damage is an inherent trait associated with animal lifespan. However, there is a lack of lipidomic studies on human longevity. Here we use mass spectrometry based technologies to detect and quantify 137 ether lipids to define a phenotype of healthy humans with exceptional lifespan. Ether lipids were chosen because of their antioxidant properties and ability to modulate oxidative stress. Our results demonstrate that a specific ether lipid signature can be obtained to define the centenarian state. This profile comprises higher level of alkyl forms derived from phosphatidylcholine with shorter number of carbon atoms and double bonds; and decreased content in alkenyl forms from phosphatidylethanolamine with longer chain length and higher double bonds. This compositional pattern suggests that ether lipids from centenarians are more resistant to lipid peroxidation, and that ether lipid signature expresses an optimized feature associated with exceptional human longevity. These results are in keeping with the free radical theory of aging.
Background
Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally.
Methods
The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950.
Findings
Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development.
Interpretation
This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing.
Geroprotectors, a class of drugs targeting multiple deficits occurring with age, necessitate the development of new animal models to test their efficacy. The COST Action MouseAGE is a European network whose aim is to reach consensus on the translational path required for geroprotectors, interventions targeting the biology of ageing. In our previous work we identified frailty and loss of resilience as a potential target for geroprotectors. Frailty is the result of an accumulation of deficits, which occurs with age and reduces the ability to respond to adverse events (physical resilience). Modelling frailty and physical resilience in mice is challenging for many reasons. There is no consensus on the precise definition of frailty and resilience in patients or on how best to measure it. This makes it difficult to evaluate available mouse models. In addition, the characterization of those models is poor. Here we review potential models of physical resilience, focusing on those where there is some evidence that the administration of acute stressors requires integrative responses involving multiple tissues and where aged mice showed a delayed recovery or a worse outcome then young mice in response to the stressor. These models include sepsis, trauma, drug- and radiation exposure, kidney and brain ischemia, exposure to noise, heat and cold shock.
Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self). A limited number of receptors, whose degeneracy allows them to recognize many signals and to activate the innate immune responses, sense these stimuli. In this situation, metaflammation (the metabolic inflammation accompanying metabolic diseases) is thought to be the form of chronic inflammation that is driven by nutrient excess or overnutrition; metaflammation is characterized by the same mechanisms underpinning inflammaging. The gut microbiota has a central role in both metaflammation and inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms and crosstalk with other organs and systems. We argue that chronic diseases are not only the result of ageing and inflammaging; these diseases also accelerate the ageing process and can be considered a manifestation of accelerated ageing. Finally, we propose the use of new biomarkers (DNA methylation, glycomics, metabolomics and lipidomics) that are capable of assessing biological versus chronological age in metabolic diseases.
Geroscience, the new interdisciplinary field that aims to understand the relationship between aging and chronic age-related diseases (ARDs) and geriatric syndromes (GSs), is based on epidemiological evidence and experimental data that aging is the major risk factor for such pathologies and assumes that aging and ARDs/GSs share a common set of basic biological mechanisms. A consequence is that the primary target of medicine is to combat aging instead of any single ARD/GSs one by one, as favored by the fragmentation into hundreds of specialties and sub-specialties. If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, a major question emerges: which is the difference, if any, between aging and ARDs/GSs? The hypothesis that ARDs and GSs such as frailty can be conceptualized as accelerated aging will be discussed by analyzing in particular frailty, sarcopenia, chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Alzheimer and Parkinson as well as Down syndrome as an example of progeroid syndrome. According to this integrated view, aging and ARDs/GSs become part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process. Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. If ARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological and chronological age to identify subjects at higher risk of developing ARDs and GSs. To this aim, we propose the use of DNA methylation, N-glycans profiling, and gut microbiota composition to complement the available disease-specific markers.
Physical resilience is the ability of an organism to respond to stressors that acutely disrupt normal physiological homeostasis. By definition, resilience decreases with increasing age, while frailty, defined as a decline in tissue function, increases with increasing age. Assessment of resilience could therefore be an informative early paradigm to predict healthy aging compared to frailty, which measures late life dysfunction. Parameters for resilience in the laboratory mouse are not yet well defined, and no single standardized stress test exists. Since aging involves multiple genetic pathways, integrative responses involving multiple tissues, organs, and activities need to be measured to reveal the overall resilience status, suggesting a battery of stress tests, rather than a single all-encompassing one, would be most informative. Three simple, reliable, and inexpensive stressors are described in this review that could be used as a panel to determine levels of resilience. Brief cold water immersion allows a recovery time to normothermia as an indicator of resilience to hypothermia, i.e. the quicker the return to normal body temperature, the more robust the resilience. Sleep deprivation (SD) impairs remote memory in aged mice, and has detrimental effects on glucose metabolism. Cyclophosphamide (CYP) targets white blood cells, especially myeloid cells resulting in neutropenia with a rebound neutrophilia in an age-dependent manner. Thus a strong neutrophilic response indicates resilience. In conclusion, resilience promises to be an especially useful measurement of biological age, i.e. how fast a particular organ or tissue ages. The three stressors, cold, SD, and CYP, are applicable to human medicine and aging because they represent clinically relevant stress conditions that have effects in an age-dependent manner. They are thus an attractive perturbation for resilience testing in mice to measure the effectiveness of interventions that target basic aging processes.
Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014): on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049), while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05) compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01) and old control mice (p < 0.05). These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes. © 2017 Wolf, Lotan, Lifschytz, Ben-Ari, Kreisel Merzel, Tatarskyy, Valitzky, Mernick, Avidan, Koroukhov and Lerer.
Background
While compression of morbidity has now been studied in multiple cohorts, we hypothesize that centenarians might also have fewer chronic conditions as well. We assume that individuals who die as centenarians have less comorbidities and have a less steep rise of the number of comorbidities over the final years before death compared to those who died as nonagenarians (90-99 years) or octogenarians (80-89 years of age).
Methods
This German cohort study used health insurance data. The data contains complete information on diagnoses and health care transactions for the six years prior to death. The sample (N=1,398; 34,735-person calendar quarters) is comprised of three groups of individuals; those who died as centenarians were compared with random samples of individuals who died as nonagenarians or as octogenarians. Community-dwelling and institutionalized individuals were included.
Results
One quarter prior to death, individuals who died as centenarians had, on average, 3.3 comorbidities. Octogenarians had 4.6 comorbidities one quarter prior to death. Further, there was a significant time-to-death by age-at-death interaction (B=-.03, p<.001), where centenarians showed a less steep increase in the number of comorbidities than the comparison groups in their last 6 years prior to death.
Conclusions
The lower prevalence of comorbidities in individuals who died as centenarians compared with those who died at a younger age reinforces the notion of centenarians as a selective group. Avoiding the confounding and potentially synergistic effects of having multiple chronic illnesses is likely vital to being able to survive to extreme ages.
Aims:
Epidemiological studies indicate that traffic noise increases the incidence of coronary artery disease, hypertension and stroke. The underlying mechanisms remain largely unknown. Field studies with nighttime noise exposure demonstrate that aircraft noise leads to vascular dysfunction, which is markedly improved by vitamin C, suggesting a key role of oxidative stress in causing this phenomenon.
Methods and results:
We developed a novel animal model to study the vascular consequences of aircraft noise exposure. Peak sound levels of 85 and mean sound level of 72 dBA applied by loudspeakers for 4 days caused an increase in systolic blood pressure, plasma noradrenaline and angiotensin II levels and induced endothelial dysfunction. Noise increased eNOS expression but reduced vascular NO levels because of eNOS uncoupling. Noise increased circulating levels of nitrotyrosine, interleukine-6 and vascular expression of the NADPH oxidase subunit Nox2, nitrotyrosine-positive proteins and of endothelin-1. FACS analysis demonstrated an increase in infiltrated natural killer-cells and neutrophils into the vasculature. Equal mean sound pressure levels of white noise for 4 days did not induce these changes. Comparative Illumina sequencing of transcriptomes of aortic tissues from aircraft noise-treated animals displayed significant changes of genes in part responsible for the regulation of vascular function, vascular remodelling, and cell death.
Conclusion:
We established a novel and unique aircraft noise stress model with increased blood pressure and vascular dysfunction associated with oxidative stress. This animal model enables future studies of molecular mechanisms, mitigation strategies, and pharmacological interventions to protect from noise-induced vascular damage.
Systems biology approaches have been increasingly employed in clinical studies to enhance our understanding of the role of genetics, environmental factors and their interactions on nutritional, health and disease status. Amongst the new omics technologies, metabonomics has emerged as a robust platform to capture metabolic and nutritional requirements by enabling, in a minimally invasive fashion, the monitoring of a wide range of biochemical compounds. Their variations reflect comprehensively the various molecular regulatory processes, which are tightly controlled and under the influence of genetics, diet, gut microbiota and other environmental factors. They are providing key insights into complex metabolic phenomena as well as into differences and specificities at individual and population level. The aim of this review is to evaluate promising metabolic insights towards understanding metabolism of a long and healthy life from pre-clinical and clinical metabonomics studies. We will also discuss analytical approaches to enable data integration, with an emphasis on the longitudinal component. Herein, we will illustrate current examples, challenges and perspectives in the applications of metabonomics monitoring and modelling approaches in the context of healthy ageing research.
Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl - xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl- xL in cellular aging, we found thay lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of BcL-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the BcL-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that BcL- xL plays an important role in exceptional aging.
Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models.
Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10−5). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.
Although populations around the world are rapidly ageing, evidence that increasing longevity is being accompanied by an extended period of good health is scarce. A coherent and focused public health response that spans multiple sectors and stakeholders is urgently needed. To guide this global response, WHO has released the first World report on ageing and health, reviewing current knowledge and gaps and providing a public health framework for action. The report is built around a redefinition of healthy ageing that centres on the notion of functional ability: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics. This Health Policy highlights key findings and recommendations from the report.
Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodelling by environmental stimuli affects several aspects of transcription and genomic stability, with important consequences for longevity, and outline epigenetic differences between the 'mortal soma' and the 'immortal germ line'. Finally, we discuss the inheritance of characteristics of ageing and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases.
Objectives: To use primary care electronic health records (EHRs) to evaluate the health of men and women at age 100.
Design: Population-based cohort study.
Setting: Primary care database in the United Kingdom, 1990-2013.
Participants: Individuals reaching the age of 100 between 1990 and 2013 (N = 11,084, n = 8,982 women, n = 2,102 men).
Measurements: Main categories of morbidity and an index of multiple morbidities, geriatric syndromes and an index of multiple impairments, cardiovascular risk factors.
Results: The number of new female centenarians per year increased from 16 per 100,000 in 1990-94 to 25 per 100,000 in 2010-13 (P < .001) and of male centenarians from four per 100,000 to six per 100,000 (P = .06). The most prevalent morbidities at the age of 100 were musculoskeletal diseases, disorders of the senses, and digestive diseases. Women had greater multiple morbidity than men (odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.42-1.89, P < .001). Geriatric syndromes, including falls, fractures, hearing and vision impairment, and dementia, were frequent; 30% of women and 49% of men had no recorded geriatric syndromes. Women had greater likelihood of having multiple geriatric syndromes (OR = 2.14, 95% CI = 1.90-2.41, P < .001).
Conclusion: Fewer men than women reach the age of 100, but male centenarians have lower morbidity and fewer geriatric syndromes than women. Research using EHRs offers opportunities to understand the epidemiology of aging and improve care of the oldest old.
© 2015 The Authors. The Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.
Psychological resilience is comprised of an adaptive functioning standard before the current and accumulated risks of life. Furthermore, it has a comprehensive range of psychological resources which are essential to overcome adversities, such as personal competences, self-beliefs and interpersonal control which interact with the social networks support. The objectives are to show the concepts of psychological resilience in elderly, relative to dominant theoretical models and the main data about psychological resilience in aging, found in an international and Brazilian review from 2007 to 2013. The descriptors "resilience, psychological resilience and aging", "resiliência e envelhecimento, velhice e velho", were used in PubMed, PsychInfo, SciELO and Pepsic databases. Fifty three international and eleven national articles were selected. The international articles were classified in four categories: psychological and social coping resources, emotional regulation before stressing experiences, successful resilience and aging and correlates, and resilience measures. The Brazilian articles were grouped in three: psychological and social resources, resilience in carers and theory review. Articles on psychological resources and on emotional regulation prevailed as key factors associated with psychological resilience in aging.
Background: Heat stress induces many pathophysiological responses and has a profound impact on brain structure. It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans. Although the effects of heat stress have long been studied, the mechanisms by which heat stress affects brain structure and cognition not well understood.
Methods: In our longitudinal study of mice exposed to heat over 7, 14, or 42 days, we found that heat stress time dependently impaired cognitive function as determined by Y-maze, passive avoidance, and novel object recognition tests. To elucidate the histological mechanism by which thermal stress inhibited cognitive abilities, we examined heat stress-induced inflammation in the hippocampus.
Results: In mice subjected to heat exposure, we found: 1) an increased number of glial fibrillary acid protein (GFAP)- and macrophage-1 antigen (Mac-1)-positive cells, 2) up-regulated nuclear factor (NF)-κB, a master regulator of inflammation, and 3) marked increases in cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cytokine interleukin (IL)-1 and tumor necrosis factor (TNF)- in the mouse hippocampus. We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression. Moreover, in heat-exposed mice, we found that the number of cells positive for doublecortin (DCX), a marker of neurogenesis, was significantly decreased compared with control mice. Finally, anti-inflammatory agent minocycline inhibited the heat stress-induced cognitive deficits and astogliosis in mice.
Conclusions: Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis.
Objectives:
Frailty is a geriatric syndrome that identifies individuals at higher risk of disability, institutionalization, and death. We previously reported that frailty is related to oxidative stress and cognitive impairment-related biomarkers. The aim of this study was to determine whether frailty is associated with genetic variants.
Design:
Longitudinal population-based cohort of 2488 community-dwelling people from Toledo, Spain, aged 65 years or older.
Setting and participants:
We obtained blood samples from 78 individuals with frailty and 74 nonfrail individuals who were nonfrail (according to Fried criteria) from the Toledo Study of Healthy Ageing and extracted DNA using the Chemagic DNA blood kit.
Measures:
Sample genotyping was carried out by means of Axiom Exome 319 Genotyping Array (Thermo Fisher Scientific), which contains 295,988 markers [single-nucleotide polymorphisms (SNPs) and rare variants], and transferred to the GeneTitan Instrument (Affymetrix).
Results:
We found 15 SNPs (P < .001), 18 genes (P < .005), and 4 pathways (P < .05) related to cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, regulation of autophagy, and renin-angiotensin system as the most strongly associated with frailty.
Conclusions/implications:
The specific genetic features related to energy metabolism, biological processes regulation, cognition, and inflammation highlighted by this preliminary analysis offer useful insights for finding biologically meaningful biomarkers of frailty that allow early diagnosis and treatment. Further research is needed to confirm our novel findings in a larger population. Indeed, the EU-funded FRAILOMICS research effort will address this question.
Exceptional longevity represents an extreme phenotype. Current centenarians are survivors of a cohort who display delayed onset of age-related diseases and/or resistance to otherwise lethal illnesses occurring earlier in life. Characteristics of aging are heterogeneous, even among long-lived individuals. Associations between specific clinical or genetic biomarkers exist, but there is unlikely to be a single biomarker predictive of long life. Careful observations in the oldest old offer some empirical strategies that favor increased health span and life span, with implications for compression of disability, identification and implementation of lifestyle behaviors that promote independence, identification and measurement of more reliable markers associated with longevity, better guidance for appropriate health screenings, and promotion of anticipatory health discussions in the setting of more accurate prognostication. Comprehensive PubMed literature searches were performed, with an unbiased focus on mechanisms of longevity. Overall, the aggregate literature supports that the basis for exceptional longevity is multifactorial and involves disparate combinations of genes, environment, resiliency, and chance, all of which are influenced by culture and geography.
Human longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequences for biomedicine. The genetics of human longevity is still poorly understood despite several investigations that used different strategies and protocols. Here, we argue that such rather disappointing harvest is largely because of the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan seems to be the result of an intriguing mixture of gene-environment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological, and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status, and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as genome-wide association study and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as apolipoprotein E, Forkhead box O3, interleukin 6, insulin-like growth factor-1, chromosome 9p21, 5q33.3, and somatic mutations among others. The major results of this approach suggest that (1) the genetics of longevity is highly population specific; (2) small-effect alleles, pleiotropy, and the complex allele timing likely play a major role; (3) genetic risk factors are age specific and need to be integrated in the light of the geroscience perspective; (4) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the 3 genetics of human body, that is, nuclear, mitochondrial, and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.
Sarcopenia is a major component of the frailty syndrome, both being considered as strong predictors of morbidity, disability, and death in older people. In this review, we explore the definitions of sarcopenia and frailty and summarize the current knowledge on their relationship with oxidative stress and the possible therapeutic interventions to prevent or treat them, including exercise-based interventions and multimodal strategies. We highlight the relevance of the impairment of the nervous system and of the anabolic response (protein synthesis) in muscle aging leading to frailty and sarcopenia. We also discuss the importance of malnutrition and physical inactivity in these geriatric syndromes. Finally, we propose multimodal interventions, including exercise programs and nutritional supplementation, as the strategies to prevent and treat both sarcopenia and frailty.
Human mesenchymal cells can become pluripotent by the addition of Yamanaka factors OCT3/4, SOX2, c-MYC, KLF4. We have recently reported that centenarians overexpress BCL-xL, which has been shown to improve pluripotency, thus we aimed to determine the expression of pluripotency-related genes in centenarians. We recruited 22 young, 32 octogenarian and 47 centenarian individuals and determined the mRNA expression of Yamanaka factors and other stemness-related cell surface marker genes (VIM, BMP4, NCAM, BMPR2) in peripheral blood mononuclear cells by reverse transcription polymerase chain reaction. We found that centenarians overexpress OCT3/4, SOX2, c-MYC, VIM, BMP4, NCAM and BMPR2, when compared to octogenarians (p<0.05). We further tested the functional role of BCL-xL in centenarians’ ability to express pluripotency-related genes: lymphocytes from octogenarians transduced with BCL-xL overexpressed SOX2, c-MYC, and KLF4. We conclude that centenarians overexpress Yamanaka Factors and other stemness-related cell surface marker genes, which may contribute to their successful aging.
Individuals capable of reaching the extreme limit of human life such as centenarians are characterized by an exceptionally healthy phenotype—that is, a low number of diseases, low blood pressure, optimal metabolic and endocrine parameters, and increased diversity in the gut microbiota—and they are epigenetically younger than their chronological age. We present data suggesting that such a remarkable phenotype is largely similar to that found in adults following a calorie-restricted diet. Interviews with centenarians and historical data on the nutritional and lifestyle habits of Italians during the twentieth century suggest that as children and into adulthood, centenarians lived in an environment that was nonobesogenic, but at the same time the environment did not produce malnutrition. Centenarians appear to be creatures of habit, and we argue that their habit of eating meals at the same time each day favored the maintenance of circadian rhythms, including their sleep cycle. Finally, we argue that centenarians’ chronic inflammatory status, which we dubbed inflammaging, is peculiar, likely adaptive, and less detrimental than in younger people. Expected final online publication date for the Annual Review of Nutrition Volume 38 is August 21, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Healthy ageing can be defined as “the process of developing and maintaining the functional ability that enables wellbeing in older age”. Functional ability (i.e., the health-related attributes that enable people to be and to do what they have reason to value) is determined by intrinsic capacity (i.e., the composite of all the physical and mental capacities of an individual), the environment (i.e., all the factors in the extrinsic world that form the context of an individual’s life), and the interactions between the two. This innovative model recently proposed by the World Health Organization has the potential to substantially modify the way in which clinical practice is currently conducted, shifting from disease-centered towards function-centered paradigms. By overcoming the multiple limitations affecting the construct of disease, this novel framework may allow the worldwide dissemination of a more proactive and function-based approach towards achieving optimal health status.
In order to facilitate the translation of the current theoretical model into practice, it is important to identify the inner nature of its constituting constructs. In this paper, we consider intrinsic capacity. Using the International Classification of Functioning, Disability and Health (ICF) framework as background and taking into account available evidence, five domains (i.e., locomotion, vitality, cognition, psychological, sensory) are identified as pivotal for capturing the individual’s intrinsic capacity (and therefore also reserves) and, through this, pave the way for its objective measurement.
Centenarians are a model of successful ageing. The data favours the theory that, in order to live to 100, it is mandatory to inherit the right genetic variants from parents or acquire epigenetic variants through the environment. Therefore, the study of epigenetic signatures of healthy ageing is becoming an important aspect to identify the role of chromatin modification in ageing and understand how manage this fine-tuning system. So, according to the concept of developmental plasticity, establishment of a longevity phenotype requires a combination of stochastic and non-stochastic events that modulate the genetic substrate and leads to a different outcome. It can be concluded that centenarians have a more powerful "engine" shaped by evolution, and that the environment, through epigenetic system, is a component influencing outcome.
Background
Physical frailty and depression are common comorbid conditions that have important impact on older adults. Few studies however have examined their co-occurrence in centenarians. This paper explores the relationship between the two conditions and the most characteristic depressive symptoms associated with the frailty syndrome.
Methods
Data come from two Portuguese Centenarian Studies. Frailty was measured using Fried's phenotype, which includes at least three clinical signs: exhaustion, weight loss, weakness, slowness, and low physical activity level; the Geriatric Depression Scale was used to assess depression. Descriptive comparison and binary logistic regression models were used for data analysis.
Results
The final sample comprised 91 centenarians (mean age = 101.0, SD = 1.3; 85.7% female). From these, 5.5% were classified as robust, 42.9% as pre-frail, and 51.6% as frail. The prevalence of depression in the whole sample was 35.2% (51.1% in frail centenarians; 21.1% in pre-frail centenarians; 0% in robust centenarians). Frail centenarians presented higher risk of depression (OR = 3.92; 95% CI 1.48–10.4) when compared to pre-frail centenarians. Findings from the multivariable model (gender, living arrangements, education, cognition, subjective health, current illness, and functionality) revealed that only subjective health remained significant.
Conclusion
It seems that depression is a comorbid clinical independent condition that is frequent in frail and pre-frail centenarians.
Objectives:
Chronic cerebral hypoperfusion (CCH) can result in vascular dementia and small vessel white matter ischemic injury. These findings have previously been demonstrated in a murine experimental model of CCH secondary to bilateral common carotid artery stenosis (BCAS). This study sought to elucidate the effects of CCH on recognition memory as assessed by the novel object recognition (NOR) test and histological analysis of the hippocampus and perirhinal cortex.
Methods:
Studies were performed on ten-week-old male mice using bilateral 0.18 mm microcoils to narrow the carotid arteries in accordance with prior publications. Following surgery, BCAS (n = 6) and sham (n = 6) mice were evaluated using NOR and 8-arm radial maze testing paradigms. Tissue damage was assessed using H&E staining on a parallel cohort of mice (n = 6 BCAS, n = 7 sham).
Results:
In the NOR paradigm, BCAS mice demonstrated significant deficits in short-term memory. Consistent with prior studies, BCAS mice also performed significantly worse on 8-arm radial maze testing. BCAS mice exhibited significantly more neuronal injury in the perirhinal cortex when compared to sham-operated mice. However, no significant differences in neuronal damage were observed in the CA1 region of the hippocampus.
Discussion:
Experimental CCH secondary to BCAS results in recognition memory deficits on NOR testing. Damage to the perirhinal cortex, rather than to the hippocampus, may underlie this impairment.
Objectives
The group of individuals aged 80 and over is growing faster than other segments of the population, and within this group the number of centenarians has risen exponentially worldwide. This paper reports the numbers of centenarians (total, and ratio relative to total population) in 32 European countries and their key characteristics: gender distribution, level of education, and type of residence.
Study design
Population based study.
Measures
We used national census data collected in 2011 for individuals aged 100 and over living in Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the UK. Data on gender, residence and education were used.
Results
The total number of centenarians was 89156, corresponding to 17.3 centenarians per 100000 inhabitants of the total population and 98.0 centenarians per 100000 individuals aged 65 and older. Centenarian ratios were highest in France, Italy and Greece, and lowest in Bulgaria, Romania, and Croatia. The percentage of men was 16.5% on average, and ranged from around 13% (Germany, Latvia, Belgium) to 37% (Hungary). Across Europe, 62.7% of the centenarians lived in private households, with a range from 10.9% (Iceland) to 90.0% (Romania). Education levels varied across countries, with an average of 13.6% having no formal education, ranging from 0.0% (the UK, Finland, Iceland) to 61.6% (Portugal).
Conclusions
Centenarian numbers have increased substantially since last available data. The findings will inform specific health promotion policies, the strengthening of current services and the development of innovative care systems.
Centenarians but not octogenarians up regulate the expression of miRNAs, as we previously reported. We have looked into miRNA biogenesis. We show that RNA POL II, DROSHA, EXPORTIN 5 and DICER, are up-regulated in centenarians compared with octogenarians. Furthermore, factors involved in the control of these miRNAs biogenesis genes are also up-regulated in centenarians. Therefore, the up-regulation of miRNA expression in centenarians can be explained in part because miRNA biogenesis pathway is depressed in octogenarians (ordinary aging) while it is maintained in centenarians (extraordinary aging).
Background/objectives:
Resilience, the ability to resist or recover from adverse effects of a stressor, is of widespread interest in social, psychologic, biologic, and medical research and particularly salient as the capacity to respond to stressors becomes diminished with aging. To date, research on human resilience responses to and factors influencing these responses has been limited.
Methods:
The National Institute on Aging convened a workshop in August 2015 on needs for research to improve measures to predict and assess resilience in human aging. Effects of aging-related factors in impairing homeostatic responses were developed from examples illustrating multiple determinants of clinical resilience outcomes. Research directions were identified by workshop participants.
Results:
Research needs identified included expanded uses of clinical data and specimens in predicting or assessing resilience, and contributions from epidemiological studies in identifying long-term predictors. Better measures, including simulation tests, are needed to assess resilience and its determinants. Mechanistic studies should include exploration of influences of biologic aging processes on human resiliencies. Important resource and infrastructure needs include consensus phenotype definitions of specific resiliencies, capacity to link epidemiological and clinical resilience data, sensor technology to capture responses to stressors, better laboratory animal models of human resiliencies, and new analytic methods to understand the effects of multiple determinants of stress responses.
Conclusions:
Extending the focus of care and research to improving the capacity to respond to stressors could benefit older adults in promoting a healthier life span.
The global number of centenarians should strongly increase during the 21 st century. According to the Population Division of the United Nations it should reach more than 25 million people in 2100. To better understand the dynamics of the emergence and growth of the centenarian population, we focused on four European countries having long chronological series and high quality data about centenarians, Denmark, France, Sweden, and Switzerland, and Japan which has had the highest life expectancy at birth for several years. we analysed the emergence of the centenarian populations and their pace of growth in the wider context of the adult longevity revolution, as well as the trends in mortality level among these new populations. We found that out of the 5 countries studied, the decrease in mortality at age 100 for females who are leading the adult longevity revolution, seems to be interrupted in 4 countries, including in Japan. These results are in favour of the scenario of “compression of mortality”, possibly limiting the future number of centenarians. However, previous studies have shown that demographic transitions are not linear and, after periods of interruption, trends can resume towards an always greater longevity.
The aim of the present review was to summarize knowledge about thyroid hormones (THs) and longevity. Longevity is a complex multifactorial phenomenon on which specific biological pathways, including hormonal networks involved in the regulation of homeostasis and survival, exert a strong impact. THs are the key responsible for growth, metabolism rate and energy expenditure, and help in maintaining cognition, bone and cardiovascular health. THs production and metabolism are fine tuned, and may help the organism to cope with a variety of environmental challenges. Experimental evidence suggests that hypothyroid state may favor longevity by reducing metabolism rate, oxidative stress and cell senescence. Data from human studies involving healthy subjects and centenarians seem to confirm this view, but THs changes observed in older patients affected by chronic diseases cannot be always interpreted as a protective adaptive mechanism aimed at reducing catabolism and prolonging survival. Medications, selected chronic diseases and multi-morbidity can interfere with thyroid function, and their impact is still to be elucidated.
The scope and purpose of this review was to summarize the aims, methods, findings, and future of centenarian and (semi)-supercentenarian studies in Japan, particularly those from our own interdisciplinary laboratory. Medically, approximately 97% of centenarians contract chronic diseases including hypertension and gastrointestinal disease; however, they present with few cardiovascular risk factors. The low prevalence of diabetes mellitus and carotid atherosclerotic plaques are peculiarities of centenarians, which could be associated with high adiponectin levels. While conducting the Tokyo centenarian study (TCS), we found that only 20% of centenarians enjoyed physical and cognitive independence at the age of 100 years, although most remained independent in daily living until into their 90s. Those who maintained physical independence at 100 years of age were highly likely to become semi-supercentenarians (over 105 years) or even supercentenarians (beyond 110 years). We also describe parts of results of the Japan Semi-supercentenarian Study (JSS), which showed that the suppression of chronic inflammation is an important driver of successful aging at extreme old age. Telomere maintenance and an extremely low frequency of APOE-ε4 alleles are genetic peculiarities of (semi)-supercentenarians. The available data confirm our conviction that semi-supercentenarians are a more appropriate model for the study of human longevity.
The changing physiology and lifestyle of elderly people affect the gut microbiota composition, the changes of which can, in turn, affect the health maintenance of the ageing host. In a co-evolutionary vision of the relationship between gut microbiota and ageing as an adaptive process of the human superorganism, long-living individuals who get to “successfully” age might be the ones whose microbiota manages to continuously re-establish a mutualistic relationship with the host, adapting to the progressive endogenous and environmental changes. The study of the gut microbiota of long-living people might provide insights on whether and how the gut microbiota can contribute to health maintenance and survival. Here, we provide the state of the art on the study of the gut microbiota in ageing and longevity, with particular attention to the perspective and direction this peculiar field of the microbiota research should take, in order to be a starting point for future mechanistic, pharmacological and clinical studies in ageing research. In particular, longevous people having different genetic, environmental, and cultural background must be analyzed and compared in the attempt to describe “universal” longevity dynamics, useful to unravel how the gut microbial ecosystem can help in expanding human healthspan.
The endocrine system plays a major role in the regulation of several biological activity and in the ageing process. Evolutionary conservation of GH/IGF-I/insulin pathway from worms to mice and similarities in this system between mice and humans raised expectations that downregulated activity of the GH/IGF-I/insulin pathway could be beneficial for the extension of human life span.
Centenarians represent the best example of successful ageing having reached the very extremes of the human life span, escaping and delaying the occurrence of several fatal age-related diseases, such as cancer and cardiovascular diseases.
This review describes the endocrine profile of centenarians concerning the GH/IGF-I/insulin system, focusing on the relevance of this pathway on the modulation of ageing and longevity.
Introduction:
The use of forced-swim, rat-validated cognition tests in mouse models of Traumatic Brain Injury (TBI) raises methodological concerns; such models are vulnerable to a number of confounding factors including impaired motor function and stress-induced non-compliance (failure to swim). This study evaluated the ability of a Radial Water Tread (RWT) maze, designed specifically for mice, that requires no swimming to distinguish mice with controlled cortical impact (CCI) induced TBI and Sham controls.
Methods:
Ten-week-old, male C57BL6/J mice were randomly assigned to receive either Sham (n=14) or CCI surgeries (n=15). Mice were tested for sensorimotor deficits via Gridwalk test and Noldus CatWalk gait analysis at 1 and 32 days post-injury. Mice received RWT testing at either 11 days (early time point) or 35 days (late time point) post-injury.
Results:
Compared to Sham-treated animals, CCI-induced TBI resulted in significant impairment in RWT maze performance. Additionally, CCI injured mice displayed significant deficits on the Gridwalk test at both 1 day and 32 days post-injury, and impairment in the CatWalk task at 1 day, but not 32 days, compared to Shams.
Conclusions:
The Radial Water Tread maze capitalizes on the natural tendency of mice to avoid open areas in favor of hugging the edges of an apparatus (thigmotaxis), and replaces a forced-swim model with water shallow enough that the animal is not required to swim, but aversive enough to motivate escape. Our findings indicate the RWT task is a sensitive species-appropriate behavioral test for evaluating spatial memory impairment in a mouse model of TBI.
Noise exposure has been well characterized as an environmental stressor, and is known to have auditory and non-auditory effects. Phosphodiesterase 5 (PDE5) inhibitors affect memory and hippocampus plasticity through various signaling cascades which are regulated by cGMP. In this study, we investigated the effects of sildenafil on memory deficiency, neuroprotection and oxidative stress in mice caused by chronic noise exposure. Mice were exposed to noise for 4 hours every day up to 14 days at 110 dB SPL of noise level. Sildenafil (15 mg/kg) was orally administered 30 minutes before noise exposure for 14 days. Behavioral assessments were performed using novel object recognition (NOR) test and radial arm maze (RAM) test. Higher levels of memory dysfunction and oxidative stress were observed in noise alone-induced mice compared to control group. Interestingly, sildenafil administration increased memory performance, decreased oxidative stress, and increased neuroprotection in the hippocampus region of noise alone-induced mice likely through affecting memory related pathways such as cGMP/PKG/CREB and p25/CDK5, and induction of free radical scavengers such as SOD1, SOD2, SOD3, Prdx5, and catalase in the brain of stressed mice.
'Inflammaging' refers to the chronic, low-grade inflammation that characterizes aging. Inflammaging is macrophage centered, involves several tissues and organs, including the gut microbiota, and is characterized by a complex balance between pro- and anti-inflammatory responses. Based on literature data, we argue that the major source of inflammatory stimuli is represented by endogenous/self, misplaced, or altered molecules resulting from damaged and/or dead cells and organelles (cell debris), recognized by receptors of the innate immune system. While their production is physiological and increases with age, their disposal by the proteasome via autophagy and/or mitophagy progressively declines. This 'autoreactive/autoimmune' process fuels the onset or progression of chronic diseases that can accelerate and propagate the aging process locally and systemically. Consequently, inflammaging can be considered a major target for antiaging strategies.
Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance healthspan and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt.
This state-of-the-art handbook will keep researchers and practitioners in gerontology abreast of the newest theories and models of aging. With virtually all new contributors and content, this edition contains 35 chapters by the most highly respected luminaries in the field. It addresses theories and concepts built on cumulative knowledge in four disciplinary areas - biology, psychology, social sciences, and policy and practice - as well as landmark advances in trans-disciplinary science. With its explicit focus on theory, the handbook is unique in providing essential knowledge about primary explanations for aging, spanning from cells to societies.
The chapters in the third edition place a strong emphasis on the future of theory development, assessing the current state of theories and providing a roadmap for how theory can shape research, and vice versa, in years to come. Many chapters also address connections between theories and policy or practice. Each set of authors has been asked to consider how theories in their area address matters of diversity and inequalities in aging, and how theories might be revised or tested with these matters in mind. The third edition also contains a new section, "Standing on the Shoulders of Giants," which includes personal essays by senior gerontologists who share their perspectives on the history of ideas in their fields, and on their experiences with the process and prospects of developing good theory.
As the world population ages, so the prevalence increases of individuals aged 100 years or more, known as centenarians. Reaching this age has been described as exceptional longevity (EL) and is attributed to both genetic and environmental factors. Many genetic variations known to affect life expectancy exist in centenarians. This review of studies conducted on centenarians and supercentenarians (older than 110 years) updates knowledge of the impacts on longevity of the twenty most widely investigated single nucleotide polymorphisms (SNPs).
Plasma lipidomic profile is species specific and an optimized feature associated with animal longevity. In the present work,
the use of mass spectrometry technologies allowed us to determine the plasma lipidomic profile and the fatty acid pattern
of healthy humans with exceptional longevity. Here, we show that it is possible to define a lipidomic signature only using
20 lipid species to discriminate adult, aged and centenarian subjects obtaining an almost perfect accuracy (90%–100%). Furthermore,
we propose specific lipid species belonging to ceramides, widely involved in cell-stress response, as biomarkers of extreme
human longevity. In addition, we also show that extreme longevity presents a fatty acid profile resistant to lipid peroxidation.
Our findings indicate that lipidomic signature is an optimized feature associated with extreme human longevity. Further, specific
lipid molecular species and lipid unsaturation arose as potential biomarkers of longevity.
Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for
disability and survival. Natural selection has built the “engine” of mobility with great robustness, redundancy, and functional
reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments.
Analogously, age-associated impairments in mobility-related physiological systems are compensated and overt limitations of
mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple
impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical
changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline,
compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of
mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding
the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the
burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength
resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach
to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing
normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories
of the mobility-relevant physiological domains.
Aging is one of the risk factors for delayed fracture healing. Sonic hedgehog (SHH) protein, an inducer of embryonic development, has been demonstrated to be activated in osteoblasts at the dynamic remodeling site of a bone fracture. Herein, we compared and examined the distribution patterns of SHH and the functional effect of SHH signaling on osteogenesis and osteoclastogenesis between young (5-week-old) and aged (60-week-old) mice during fracture healing. We found that SHH was expressed in bone marrow cells from the fractured site of the rib of young mice on day 5, but was barely detectable in the corresponding cells from the rib of aged mice. SHH was also detected in osteoblasts and bone marrow cells at the callus remodeling stage on days 14 and 28 in both young and aged mice. The number of alkaline phosphatase (ALP)-positive osteoblasts was significantly higher in young mice on days 5 and 14, whereas the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts was significantly higher in aged mice. SHH stimulated significantly more osteoblast formation in the young compared to old mice. SHH stimulated the osteoclast formation directly in the aged mice and suppressed the formation indirectly through osteoprotegerin expression in the young mice. Results indicate that an aged-related delay of fracture healing may contribute to the unbalanced bone formation and resorption, regulated by hedgehog signaling.
Background:
Resilience has been described in the psychosocial literature as the capacity to maintain or regain well-being during or after adversity. Physical resilience is a newer concept that is highly relevant to successful aging. Our objective was to characterize the emerging construct of resilience as it pertains to physical health in older adults, and to identify gaps and opportunities to advance research in this area.
Methods:
We conducted a systematic review to identify English language papers published through January 2015 that apply the term "resilience" in relation to physical health in older adults. We applied a modified framework analysis to characterize themes in implicit or explicit definitions of physical resilience.
Results:
Of 1,078 abstracts identified, 49 articles met criteria for inclusion. Sixteen were letters or concept papers, and only one was an intervention study. Definitions of physical resilience spanned cellular to whole-person levels, incorporated many outcome measures, and represented three conceptual themes: resilience as a trait, trajectory, or characteristic/capacity.
Conclusions:
Current biomedical literature lacks consensus on how to define and measure physical resilience. We propose a working definition of physical resilience at the whole person level: a characteristic which determines one's ability to resist or recover from functional decline following health stressor(s). We present a conceptual framework that encompasses the related construct of physiologic reserve. We discuss gaps and opportunities in measurement, interactions across contributors to physical resilience, and points of intervention.
Centenarians not only have an extraordinary longevity, but also show a compression of morbidity. They preserve the capacity of maintaining homeostasis, and this is the reason for them to reach such a long life. We studied their mRNA expression profile and identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. A sub-network analysis showed six common genes: interferon, T-cell receptor, tumor necrosis factor, SP1 transcription factor, transforming growth factor and IL-32.These six centenarian-specific genes are related to Bcl-xL, Fas, and Fas ligand all of them involved in the control of apoptosis. RT-PCR analysis confirmed that centenarians up-regulate Bcl-xL. This is in keeping with the fact that they have lower plasma cytochrome C levels than septuagenarians. Bcl-xL is a mitochondrial protein involved not only in the control of apoptosis, but also in mitochondrial damage protection, control of mitochondrial respiration and immune response. We found that mitochondrial membrane potential (ΔΨm) as assessed by JC-1 cytometry was significantly higher in PBMCs obtained from centenarians versus septuagenarians as well as young people, suggesting that the functional state of mitochondria was maintained. Moreover, centenarians showed lower malondyaldhehyde and protein carbonyl levels than septuagenians. When analyzing the immune system, we found that leukocyte chemotaxis and NK cell activity were significantly impaired in septuagenarians compared with young people whereas in centenarians these indicators of immunosenescence were similar to the picture noted in young people. In conclusion, centenarians, who constitute an example of successful ageing, overexpress Bcl-xL, which confers them a protection against apoptosis, oxidative stress and immunosenescence. Supported by SAF2010-19498; SAF2013-44663-R; ISCIII2012-RED-43-029; PROMETEOII2014/056; RS2012-609; CM1001 and FRAILOMIC-HEALTH.2012.2.1.1-2. The study has been co-financed by FEDER funds from the European Union.