Health care trends for older people.

Research is showing us a radically different view of aging from the one seen by earlier generations. Attitudes, which were based on the myth that physical and mental decline are inevitable with age, are beginning to change as a result of new scientific information. What we are learning is that aging involves both intrinsic and extrinsic factors. The universal phenomena that occur in all of us as we advance in age are intrinsic characteristics of aging, while extrinsic factors are those characteristics that can be prevented or modified, such as lifestyle choices, environmental exposure, and disease.     

Intrinsic aging-related mortality in birds

Actuarial senescence in captive populations of 28 species of bird was quantified by estimating the parameters of Weibull models fitted to survival curves constructed from data obtained from zoos. Samples of natural and captive populations were compared using phylogenetically independent contrasts, which revealed that extrinsic mortality rates in captive populations are, on average, less than 30% of those of natural populations but that the component of mortality related to aging does not differ significantly between natural and captive birds. This result supports the hypothesis that aging-related mortality is associated with intrinsic causes of death that kill independently of the external environment. A logical implication of this result is that birds in natural populations maintain a high level of physical fitness into old age and do not become more vulnerable to extrinsic mortality factors with increasing age. Additional comparisons showed that the rate of aging in this sample of birds is correlated with body mass, but not with embryonic or postnatal growth rate. These analyses suggest that studies of aging in captive populations can provide powerful tools to help us understand senescence in natural populations.     

Evolutionary ecology of aging: time to reconcile field and laboratory research

Aging is an increase in mortality risk with age due to a decline in vital functions. Research on aging has entered an exciting phase. Advances in biogerontology have demonstrated that proximate mechanisms of aging and interventions to modify lifespan are shared among species. In nature, aging patterns have proven more diverse than previously assumed. The paradigm that extrinsic mortality ultimately determines evolution of aging rates has been questioned and there appears to be a mismatch between intra‐ and inter‐specific patterns. The major challenges emerging in evolutionary ecology of aging are a lack of understanding of the complexity in functional senescence under natural conditions and unavailability of estimates of aging rates for matched populations exposed to natural and laboratory conditions. I argue that we need to reconcile laboratory and field‐based approaches to better understand (1) how aging rates (baseline mortality and the rate of increase in mortality with age) vary across populations within a species, (2) how genetic and environmental variation interact to modulate individual expression of aging rates, and (3) how much intraspecific variation in lifespan is attributable to an intrinsic (i.e., nonenvironmental) component. I suggest integration of laboratory and field assays using multiple matched populations of the same species, along with measures of functional declines.     

Adult hippocampal neurogenesis in aging and Alzheimer's disease

Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. This process is highly regulated by intrinsic and extrinsic factors, which may control the proliferation and/or maturation of neural progenitor cells. Adult-born neurons are integrated in preexisting networks and may have functional implications for adult brain. Here we attempt to summarize relevant findings concerning the physiological role of adult neurogenesis mainly focused on the subgranular zone, and to discuss the reduced neurogenesis observed during aging and the factors that have been involved in this phenomenon. Finally, we focus on hippocampal neurogenesis in Alzheimer's disease, reviewing animal models of the disease used for the study of this process and the conclusions that have been drawn in this context.     

Senescence-associated intrinsic mechanisms of osteoblast dysfunctions

Human aging is associated with bone loss leading to bone fragility and increased risk of fractures. The cellular and molecular causes of age-related bone loss are current intensive topic of investigation with the aim of identifying new approaches to abolish its negative effects on the skeleton. Age-related osteoblast dysfunction is the main cause of age-related bone loss in both men and women beyond the fifth decade and results from two groups of pathogenic mechanisms: extrinsic mechanisms that are mediated by age-related changes in bone microenvironment including changes in levels of hormones and growth factors, and intrinsic mechanisms caused by the osteoblast cellular senescence. The aim of this review is to provide a summary of the intrinsic senescence mechanisms affecting osteoblastic functions and how they can be targeted to abolish age-related osteoblastic dysfunction and bone loss associated with aging.     

Skin aging caused by intrinsic or extrinsic processes characterized with functional proteomics

The skin provides protection against environmental stress. However, intrinsic and extrinsic aging causes significant alteration to skin structure and components, which subsequently impairs molecular characteristics and biochemical processes. Here, we have conducted an immunohistological investigation and established the proteome profiles on nude mice skin to verify the specific responses during aging caused by different factors. Our results showed that UVB‐elicited aging results in upregulation of proliferating cell nuclear antigen and strong oxidative damage in DNA, whereas chronological aging abolished epidermal cell growth and increased the expression of caspase‐14, as well as protein carbonylation. Network analysis indicated that the programmed skin aging activated the ubiquitin system and triggered obvious downregulation of 14‐3‐3 sigma, which might accelerate the loss of cell growth capacity. On the other hand, UVB stimulation enhanced inflammation and the risk of skin carcinogenesis. Collectively, functional proteomics could provide large‐scale investigation of the potent proteins and molecules that play important roles in skin subjected to both intrinsic and extrinsic aging.     

Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo

Skin aging can be attributed to photoaging (extrinsic) and chronological (intrinsic) aging. Photoaging and intrinsic aging are induced by damage to human skin attributable to repeated exposure to ultraviolet (UV) irradiation and to the passage of time, respectively. In our previous report, eicosapentaenoic acid (EPA) was found to inhibit UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Therefore, we investigated the effects of EPA on UV-induced skin damage and intrinsic aging by applying EPA topically to young and aged human skin, respectively. By immunohistochemical analysis and Western blotting, we found that topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease induced by UV light. It was also found that EPA attenuated UV-induced MMP-1 and MMP-9 expression by inhibiting UV-induced c-Jun phosphorylation, which is closely related to UV-induced activator protein-1 activation, and by inhibiting JNK and p38 activation. EPA also inhibited UV-induced cyclooxygenase-2 (COX-2) expression without altering COX-1 expression. Moreover, it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. Together, these results demonstrate that topical EPA has potential as an anti-skin-aging agent.     

Aging in Perennials

Compared with our knowledge of senescence processes in annuals and biennials, relatively little is known about age-related changes in perennials. The study of aging in plants is very complex and there is no consensus in general concepts related to this topic. Furthermore, there is also a problem of scaling up, which makes us wonder whether cells, tissues/organs or whole organisms really age in plants. This is particularly interesting in the case of perennials, which have the ability to make new leaves every year and live for several years or even centuries or millennia. Recent studies indicate that physiological burdens, such as demands on water and nutrient supply, are responsible for reduced growth as plants age. Aside from the extrinsic factors, it is also possible that intrinsic changes in the shoot meristems could occur through repeated cell divisions and could be fixed during plant development, thereby affecting the physiology of leaves that originated from these cells. Additionally, the increased size associated with the aging of woody perennials (trees and shrubs) has also been proposed as a determining factor responsible for the age-related reductions in growth and photosynthetic rates in leaves. This review is aimed at compiling our current understanding of aging in perennials. After defining some fundamental questions and concepts, and introducing the model plants presently used in the study of aging in perennials, the major role meristems play in perenniality and how aging is manifested in the physiology of perennials (changes in phytohormones, water relations, photosynthesis and oxidative stress) are described. Finally, the causes underlying age-related changes in perennials are discussed in detail and a model based on plant plasticity to explain the aging phenomenon in perennials is presented.     

Reproductive aging: insights from model organisms

Aging was once thought to be the result of a general deterioration of tissues as opposed to their being under regulatory control. However, investigations in a number of model organisms have illustrated that aspects of aging are controlled by genetic mechanisms and are potentially manipulable, suggesting the possibility of treatment for age-related disorders. Reproductive decline is one aspect of aging. In model organisms and humans of both sexes, increasing age is associated with both a decline in the number of progeny and an increased incidence of defects. The cellular mechanisms of reproductive aging are not well understood, although a number of factors, both intrinsic and extrinsic to an organism's germline, may contribute to aging phenotypes. Recent work in a variety of organisms suggests that nuclear organization and nuclear envelope proteins may play a role in these processes.     

Intrinsic and extrinsic drivers of succession: effects of habitat age and season on an aquatic insect community

1. Classic studies of succession, largely dominated by plant community studies, focus on intrinsic drivers of change in community composition, such as inter‐specific competition and changes to the abiotic environment. They often do not consider extrinsic drivers of colonisation, such as seasonal phenology, that can affect community change. 2. Both intrinsic and extrinsic drivers of succession for dipteran communities that occupy ephemeral pools, such as those in artificial containers were investigated. By initiating communities at different times in the season and following them over time, the relative importance of intrinsic (i.e. habitat age) versus extrinsic (i.e. seasonal phenology) drivers of succession were compared. 3. Water‐filled artificial containers were placed in a deciduous forest with 20 containers initiated in each of 3 months. Containers were sampled weekly to assess community composition. Repeated‐measures mixed‐effects analysis of community correspondence analysis (CA) scores enabled us to partition intrinsic and extrinsic effects on succession. Covariates of temperature and precipitation were also tested. 4. Community trajectories (as defined by CA) differed significantly with habitat age and season, indicating that both intrinsic and extrinsic effects influence succession patterns. Comparisons of Akaike Information Criteria corrected for sample sizes (AICcs) showed that habitat age was more important than season for species composition. Temperature and precipitation did not explain composition changes beyond those explained by habitat age and season. 5. Quantification of relative strengths of intrinsic and extrinsic effects on succession in dipteran and other ephemeral communities enables us to disentangle processes that must be understood for predicting changes in community composition.     

Relative contributions of offspring quality and environmental quality to adult field performance

Determinants of adult performance, such as growth and survival, are influenced by extrinsic, environmental and intrinsic, phenotypic factors. The relative importance of extrinsic and intrinsic factors, while ecologically relevant, is rarely estimated simultaneously. We estimate the relative contributions of offspring size (intrinsic) and various environmental factors (extrinsic) on adult performance in the marine colonial bryozoan Watersipora subtorquata. We used a variance partitioning approach for both new and previously published data, enabling us to examine the performance of over 1000 individuals in the field. We found offspring size to explain relatively little variation in adult performance. Of the environmental factors taken to account, temporal variation and an environmental gradient had the strongest influences.     

Systematic age‐, organ‐, and diet‐associated ionome remodeling and the development of ionomic aging clocks

Aging involves coordinated yet distinct changes in organs and systems throughout life, including changes in essential trace elements. However, how aging affects tissue element composition (ionome) and how these changes lead to dysfunction and disease remain unclear. Here, we quantified changes in the ionome across eight organs and 16 age groups of mice. This global profiling revealed novel interactions between elements at the level of tissue, age, and diet, and allowed us to achieve a broader, organismal view of the aging process. We found that while the entire ionome steadily transitions along the young‐to‐old trajectory, individual organs are characterized by distinct element changes. The ionome of mice on calorie restriction (CR) moved along a similar but shifted trajectory, pointing that at the organismal level this dietary regimen changes metabolism in order to slow down aging. However, in some tissues CR mimicked a younger state of control mice. Even though some elements changed with age differently in different tissues, in general aging was characterized by the reduced levels of elements as well as their increased variance. The dataset we prepared also allowed to develop organ‐specific, ionome‐based markers of aging that could help monitor the rate of aging. In some tissues, these markers reported the lifespan‐extending effect of CR. These aging biomarkers have the potential to become an accessible tool to test the age‐modulating effects of interventions.     

Protein aggregation as a paradigm of aging

The process of physiological decline leading to death of the individual is driven by the deteriorating capacity to withstand extrinsic and intrinsic hazards, resulting in damage accumulation with age. The dynamic changes with time of the network governing the outcome of misfolded proteins, exemplifying as intrinsic hazards, is considered here as a paradigm of aging. The main features of the network, namely, the non-linear increase of damage and the presence of amplifying feedback loops within the system are presented through a survey of the different components of the network and related cellular processes in aging and disease.     

Analysis of epigenetic aging in vivo and in vitro: Factors controlling the speed and direction

The mechanism of aging is not yet fully understood. It has been recognized that there are age-dependent changes in the DNA methylation pattern of the whole genome. To date, there are several DNA methylation-based estimators of the chronological age. A majority of the estimators use the DNA methylation data from a single tissue type, such as blood. In 2013, for the first time, Steve Horvath reported the DNA methylation-based age estimator (353 CpGs were used) that could be applied to multiple tissues. A refined, more sensitive version that uses 391 CpGs was subsequently developed and validated in human cells, including fibroblasts. In this review, the age predicted by DNA methylation-based age estimator is referred to as DNAmAge, and the biological process controlling the progression of DNAmAge is referred to as the epigenetic aging in this minireview. The concepts of DNAmAge and epigenetic aging provide us opportunities to discover previously unrecognized biological events controlling aging. In this article, we discuss the frequently asked questions regarding DNAmAge and the epigenetic aging by introducing recent studies of ours and others. We focus on addressing the following questions: (1) Is there any synchronization of DNAmAge between cells in a human body?, (2) Can we use in vitro (cell culture) systems to study the epigenetic aging?, (3) Is there an age limit of DNAmAge?, and (4) Is it possible to change the speed and direction of the epigenetic aging? We describe our current understandings to these questions and outline potential future directions.Impact statementAging is associated with DNA methylation (DNAm) changes. Recent advancement of the whole-genome DNAm analysis technology allowed scientists to develop DNAm-based age estimators. A majority of these estimators use DNAm data from a single tissue type such as blood. In 2013, a multi-tissue age estimator using DNAm pattern of 353 CpGs was developed by Steve Horvath. This estimator was named “epigenetic clock”, and the improved version using DNAm pattern of 391 CpGs was developed in 2018. The estimated age by epigenetic clock is named DNAmAge. DNAmAge can be used as a biomarker of aging predicting the risk of age-associated diseases and mortality. Although the DNAm-based age estimators were developed, the mechanism of epigenetic aging is still enigmatic. The biological significance of epigenetic aging is not well understood, either. This minireview discusses the current understanding of the mechanism of epigenetic aging and the future direction of aging research.     

A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy

Human glioma incidence, malignancy, and treatment resistance are directly proportional to patient age. Cell intrinsic factors are reported to contribute to human age-dependent glioma malignancy, but suitable animal models to examine the role of aging are lacking. Here, we developed an orthotopic syngeneic glioma model to test the hypothesis that the age of neural progenitor cells (NPCs), presumed cells of glioma origin, influences glioma malignancy. Gliomas generated from transformed donor 3-, 12-, and 18-month-old NPCs in same-aged adult hosts formed highly invasive glial tumors that phenocopied the human disease. Survival analysis indicated increased malignancy of gliomas generated from older 12- and 18-month-old transformed NPCs compared with their 3-month counterparts (median survival of 38.5 and 42.5 vs. 77 days, respectively). This study showed for the first time that age of target cells at the time of transformation can affect malignancy and demonstrated the feasibility of a syngeneic model using transformed NPCs for future examination of the relative impacts of age-related cell intrinsic and cell-extrinsic factors in glioma malignancy.     

Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches

Aging is unmistakable and undeniable in mammals. Interestingly, mice develop cataracts, muscle atrophy, osteoporosis, obesity, diabetes and cognitive deficits after just 2–3 postnatal years, while it takes seven or more decades for the same age-specific phenotypes to develop in humans. Thus, chronological age corresponds differently with biological age in metazoan species and although many theories exist, we do not understand what controls the rate of mammalian aging. One interesting idea is that species-specific rate of aging represents a ratio of tissue attrition to tissue regeneration. Furthermore, current findings suggest that the age-imposed biochemical changes in the niches of tissue stem cells inhibit performance of this regenerative pool, which leads to the decline of tissue maintenance and repair. If true, slowing down stem cell and niche aging, thereby promoting tissue regeneration, could slow down the process of tissue and organismal aging. In this regard, recent studies of heterochronic parabiosis provide important clues as to the mechanisms of stem cell aging and suggest novel strategies for enhancing tissue repair in the old. Here we review current literature on the relationship between the vigor of tissue stem cells and the process of aging, with an emphasis on the rejuvenation of old tissues by the extrinsic modifications of stem cell niches.     

Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches

Aging is unmistakable and undeniable in mammals. Interestingly, mice develop cataracts, muscle atrophy, osteoporosis, obesity, diabetes and cognitive deficits after just 2–3 postnatal years, while it takes seven or more decades for the same age-specific phenotypes to develop in humans. Thus, chronological age corresponds differently with biological age in metazoan species and although many theories exist, we do not understand what controls the rate of mammalian aging. One interesting idea is that species-specific rate of aging represents a ratio of tissue attrition to tissue regeneration. Furthermore, current findings suggest that the age-imposed biochemical changes in the niches of tissue stem cells inhibit performance of this regenerative pool, which leads to the decline of tissue maintenance and repair. If true, slowing down stem cell and niche aging, thereby promoting tissue regeneration, could slow down the process of tissue and organismal aging. In this regard, recent studies of heterochronic parabiosis provide important clues as to the mechanisms of stem cell aging and suggest novel strategies for enhancing tissue repair in the old. Here we review current literature on the relationship between the vigor of tissue stem cells and the process of aging, with an emphasis on the rejuvenation of old tissues by the extrinsic modifications of stem cell niches.     

The influence of skeletal muscle on systemic aging and lifespan

Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age‐related diseases such as metabolic syndrome, cancer, Alzheimer's and Parkinson's disease. Here, we review recent studies in mammals and Drosophila highlighting how nutrient‐ and stress‐sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle‐derived growth factors and cytokines, known as myokines, modulate systemic physiology. Myokines may influence the progression of age‐related diseases and contribute to the intertissue communication that underlies systemic aging.