Basic Biology Of Aging Research Articles

Mitochondrial Targeted Interventions for Aging.

Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.

Speaking the Same Language: Team Science Approaches in Aging Research for Integrating Basic and Translational Science With Clinical Practice.

Research on aging is at an important inflection point, where the insights accumulated over the last 2 decades in the basic biology of aging are poised to be translated into new interventions to promote health span and improve longevity. Progress in the basic science of aging is increasingly influencing medical practice, and the application and translation of geroscience require seamless integration of basic, translational, and clinical researchers. This includes the identification of new biomarkers, novel molecular targets as potential therapeutic agents, and translational in vivo studies to assess the potential efficacy of new interventions. To facilitate the required dialog between basic, translational, and clinical investigators, a multidisciplinary approach is essential and requires the collaborative expertise of investigators spanning molecular and cellular biology, neuroscience, physiology, animal models, physiologic and metabolic processes, pharmacology, genetics, and high-throughput drug screening approaches. In an effort to better enable the cross-talk of investigators across the broad spectrum of aging-related research disciplines, a goal of our University of Pittsburgh Claude D. Pepper Older Americans Independence Center has been to reduce the barriers to collaborative interactions by promoting a common language through team science. The culmination of these efforts will ultimately accelerate the ability to conduct first-in-human clinical trials of novel agents to extend health span and life span.

FOSTERING MULTIDISCIPLINARY SOLUTIONS IN AGING: THE RESEARCH CENTERS COLLABORATIVE NETWORK

Abstract The NIA supports the Research Centers Collaborative Network (RCCN) to build collaborations between scientists from the 6 NIA-sponsored center programs: Alzheimer's Disease Research Centers, Centers on the Demography and Economics of Aging, Claude D. Pepper Older Americans Independence Centers, Nathan Shock Centers of Excellence in the Basic Biology of Aging, Resource Centers for Minority Aging Research, and Roybal Centers for Translational Research on Aging. RCCN's premise is that researchers from different disciplines are most likely to collaborate when they are addressing common problems. To provide a forum for collaborative exchange, the RCCN has convened 6 workshops on topics that cross-cut the concerns of the various NIA center programs ranging from sustaining behavior change in older adults to measuring biologic age. After each Workshop the RCCN awards pilot funds related to the theme. This symposium will present key learnings from the workshops and present work of four RCCN pilot teams from the third and fourth workshops which focused on resilience and reserve, and life course perspectives on aging. Dr. Ramos will discuss how measurement of psychological resilience may predict physical resilience in older patients with lung cancer, while Dr. Reid will discuss positive affect as a source of resilience for older adults with chronic pain. Dr. White will discuss association between perceived discrimination trajectories and multimorbidity burden among middle-aged and older black adults, while Dr. Brooks will discuss development of a resilience index in chronic musculoskeletal pain. Dr. Kritchevsky will also summarize lessons learned across the first 6 workshops.

San Antonio Nathan Shock Center: your one-stop shop for aging research.

With evolving cores, enrichment and training programs, and supported research projects, the San Antonio (SA) Nathan Shock Center has for 26years provided critical support to investigators locally, nationally, and abroad. With its existing and growing intellectual capital, the SA Nathan Shock Center provides to local and external investigators an enhanced platform to conduct horizontally integrated (lifespan, healthspan, pathology, pharmacology) transformative research in the biology of aging, and serves as a springboard for advanced educational and training activities in aging research. The SA Nathan Shock Center consists of six cores: Administrative/Program Enrichment Core, Research Development Core, Aging Animal Models and Longevity Assessment Core, Pathology Core, Analytical Pharmacology and Drug Evaluation Core, and Integrated Physiology of Aging Core. The overarching goal of the SA Nathan Shock Center is to advance knowledge in the basic biology of aging and to identify molecular and cellular mechanisms that will facilitate the development of pharmacologic interventions and other strategies to extend healthy lifespan. In pursuit of this goal, we provide an innovative "one-stop shop" venue to accelerate transformative research in the biology of aging through our integrated research cores. Moreover, we aim to foster and promote career development of early-stage investigators in aging biology through our research development programs, to serve as a resource and partner to investigators from other Shock Centers, and to disseminate scientific knowledge and enhanced awareness about aging research. Overall, the SA Nathan Shock Center aims to be a leader in research that advances our understanding of the biology of aging and development of approaches to improve longevity and healthy aging.

University of Washington Nathan Shock Center: innovation to advance aging research.

The University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging provides leadership and resources to support the geroscience community locally, nationally, and internationally. Services are provided through our Resource Cores and funds are available annually to support pilot projects by external investigators. Aging-related studies involving proteomics, metabolomics, invertebrate model organisms, and bioinformatics/artificial intelligence are supported by our Cores. The UW Nathan Shock Center also serves as the administrative home for a Geropathology Research Resource. In addition, the Center works in conjunction with the University of Washington Healthy Aging and Longevity Research Institute to organize and support an annual Seminar Series in the Biology of Aging, an annual 1-day Geroscience Symposium, didactic training for the Biological Mechanisms of Healthy Aging Training Program, and other strategic initiatives. Our Center also supports the American Aging Association Annual Meeting, and we have recently partnered with the American Aging Association and the JAX Aging Center to create a set of video lectures on select topics in geroscience as part of the AGE Presents Video Lecture Series.

Fostering Multidisciplinary Solutions in Aging: The Research Centers Collaborative Network

The important problems facing older adults will not be solved through the methods of a single discipline. In recognition of this, the NIA funded the Research Centers Collaborative Network (RCCN) to build collaborations between scientists from the 6 NIA-sponsored center programs: Alzheimer’s Disease Research Centers, Centers on the Demography and Economics of Aging, Claude D. Pepper Older Americans Independence Centers, Nathan Shock Centers of Excellence in the Basic Biology of Aging, Resource Centers for Minority Aging Research, and Roybal Centers for Translational Research on Aging. RCCN’s central premise is that researchers from different disciplines are most likely to collaborate when they are addressing similar problems. To foster collaboration the RCCN has convened 5 workshops on: 1. achieving and sustaining behavior change in older adults; 2. sex and gender in aging research; 3. reserve and resilience; 4. life course perspectives on aging; and 5. promoting the inclusion of older adults in clinical research. After each Workshop the RCCN awards pilot funds related to the theme. This symposium will review key learnings from the workshops and present work of four RCCN pilot teams from the first two workshops which focused on changing and sustaining behavior change in older adults, and sex and gender differences in aging. Dr. Hughes will discuss the value of interdisciplinary research to maintain behavior change while Dr. Lee will discuss social incentives to improve mobility postoperatively. Dr. Stites will discuss cognition and gender trends, while Dr. Ware will discuss sex differences in genetic effects.

Rhesus macaques as a tractable physiological model of human ageing.

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population. This article is part of the theme issue 'Evolution of the primate ageing process'.

Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases.

Aging is the most important single risk factor for many chronic diseases such as cancer, metabolic syndrome, and neurodegenerative disorders. Targeting aging itself might, therefore, be a better strategy than targeting each chronic disease individually for enhancing human health. Although much should be achieved for completely understanding the biological basis of aging, cellular senescence is now believed to mainly contribute to organismal aging via two independent, yet not mutually exclusive mechanisms: on the one hand, senescence of stem cells leads to exhaustion of stem cells and thus decreases tissue regeneration. On the other hand, senescent cells secrete many proinflammatory cytokines, chemokines, growth factors, and proteases, collectively termed as the senescence-associated secretory phenotype (SASP), which causes chronic inflammation and tissue dysfunction. Much effort has been recently made to therapeutically target detrimental effects of cellular senescence including selectively eliminating senescent cells (senolytics) and modulating a proinflammatory senescent secretome (senostatics). Here, we discuss current progress and limitations in understanding molecular mechanisms of senolytics and senostatics and therapeutic strategies for applying them. Furthermore, we propose how these novel interventions for aging treatment could be improved, based on lessons learned from cancer treatment.

ASSESSMENT OF A MICROPLATE SYSTEM FOR MEASURING INDIVIDUAL REAL-TIME RESPIRATION IN SMALL MODEL ORGANISMS OF AGING

The ability to measure oxygen consumption rates of a living organism in real-time provides an indirect method of monitoring dynamic changes in metabolism reflecting organismal level mitochondrial function. In this study, we assessed the Loligo Systems microplate system for measuring individual respiration in small organisms. This included adult nematodes (Caenorhabditis elegans, N2), zebrafish embryos (Danio rerio, AB), and adult fruit flies (Drosophila melanogaster, w1118). Organisms were placed inside 80 µL glass chambers on a 24-well microplate atop a 24-channel optical fluorescence oxygen reading device. Adult nematodes and zebrafish embryos were in liquid culture, M9 buffer and egg water respectively, and the adult flies were in room air. The microplate and reader were placed inside an incubator for temperature control. A silicone gasket with a thin liner was used to seal the chambers. Reference standard oxygen consumption (respiration) of single and multiple adult nematodes (n=1–4 animals/well), zebrafish embryos (n=1–4 animals/well), and adult flies (n=1–2 animals/well) in the microplate system were achieved. Significant differences across numbers of animals/well and by sex were observed. Validation experiments of the oxygen consumption rates measured in C. elegans in parallel with Seahorse extracellular flux (XF) experiments are underway. The Loligo Systems microplate system offers a non-invasive, non-destructive method to measure real-time respiration in smaller organisms. These data provide preliminary evidence for utility of the system for a variety of biomedical applications that relate to organismal and mitochondrial function/dysfunction, including research in the basic biology of aging in these highly-utilized, pre-clinical, genetic model organisms.

P1‐383: APOE‐ε4 IS ASSOCIATED WITH LESS ANTERIOR CINGULATE CORTEX AND INFERIOR FRONTAL GYRUS THICKNESS IN LATE‐ONSET AD

The ApoE-ε4 is a well-proven genetic risk factor for late-onset Alzheimer's disease (LOAD). However, how the epsilon4 allele contributes to disease pathophysiology and the relationship between clinical phenotype are still unclear. This study is aim to explore the association between ApoE-ε4 and regional cortical thickness and brain volume in LOAD to better understand the effect of ApoE-ε4 on LOAD. Patients diagnosed with probable AD by NIA-AA 2011 criteria were recruited from Dementia Clinic in Pecking Union Medical College Hospital. Patients with initial symptoms developed after age of 65 were included. Data including basic population information, history, physical examination, psychological assessment, MRI and ApoE genotype were collected. Using T1-weight imaging, regional cortical thickness and brain volume of whole cerebral were analyzed by DR.BRAIN software. Multiple linear regression models were applied for analyze factors including ApoE-ε4 and disease severity(reflected by ADL score) of affecting the separate regional cortical thickness. 43 LOAD patients were included in this study. As for the analysis of regional cortical thickness: LOAD patient without ApoE-ε4 showed less cortical thickness compared to patients carrying ApoE-ε4 in left pars orbitalis(F(2,36)=3.811 (P<0.05), adjust R2=0.129), left rostral anterior cingulate(F(2,36)=6.078 (P<0.05), adjust R2=0.211), left caudal anterior cingulate(F(2,36)=5.561 (P<0.05), adjust R2=0.194), right pars triangularis (F(2,36)=3.390 (P<0.05), adjust R2=0.112) and right isthmus cingulate cortex thickness (F(2,36)=3.390 (P<0.05), adjust R2=0.120). As for the analysis of regional brain volume: LOAD patient without ApoE-ε4 showed less atrophy compared to patients carrying ApoE-ε4 in left caudal anterior cingulate (F(2,36)=3.589 (P<0.05), adjust R2=0.120), left paracentral (F(2,36)=6.580 (P<0.05), adjust R2=0.227) regions. We found less cortical thickness in bilateral anterior cingulate and inferior frontal gyrus and less atrophy in left caudal anterior cingulate and paracentral regions are associated with the absence of ApoE-ε4 in LOAD patients. These data suggest a region-specific biological effect of the e4 allele in the brains of LOAD patients. This work was supported by CAMS Innovation fund for medical sciences (2016-I2M-1-004), National Natural Science Foundation of China (81550021), 13th Five year National Key Research and Development Program of China (2016YFC1306300), The strategic priority research program (Pilot study)”biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (grant XDPB10).

Ethical perspectives on advances in biogerontology

Worldwide populations are aging with economic development as a result of public health initiatives and advances in therapeutic discoveries. Since 1850, life expectancy has advanced by 1 year for every four.1 Accompanying this change is the rapid development of anti‐aging science. There are three schools of thought in the field of aging science. One perspective is the life course approach, which considers that aging is a good and natural process to be embraced as a necessary and positive aspect of life, where the aim is to improve the quality of existing lifespan and “compress” morbidity. Another view is that aging is undesirable, and that rejuvenation and indeed immortality are possible since the biological basis of aging is understood, and therefore, strategies are possible for engineering negligible senescence. Finally, a hybrid approach is that life span can be extended by anti‐aging medicines but with uncertain effects on health. While these advances offer much promise, the ethical perspectives are seldom discussed in cross‐disciplinary settings. This article discusses some of the key ethical issues arising from recent advances in biogerontology.

Proteomics and metabolomics in ageing research: from biomarkers to systems biology.

Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible 'biomarkers', which are predictors of one's biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying 'endophenotypes' in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity.

Translating the Science of Aging into Therapeutic Interventions.

Life and health span have been extended in experimental animals using drugs that are potentially translatable into humans. Considerable effort is needed beyond the usual steps in drug development to devise the models, and realistic preclinical and clinical trial strategies are required to advance these agents into clinical application. It will be important to focus on subjects who already have symptoms or are at imminent risk of developing disorders related to fundamental aging processes, to use short-term, clinically relevant outcomes, as opposed to long-term outcomes, such as health span or life span, and to validate endpoint measures so they are acceptable to regulatory agencies. Funding is a roadblock, as is shortage of investigators with combined expertise in the basic biology of aging, clinical geriatrics, and investigational new drug clinical trials. Strategies for developing a path from the bench to the bedside are reviewed for interventions that target fundamental aging mechanisms.

Accessing Data Resources in the Mouse Phenome Database for Genetic Analysis of Murine Life Span and Health Span

Understanding the source of genetic variation in aging and using this variation to define the molecular mechanisms of healthy aging require deep and broad quantification of a host of physiological, morphological, and behavioral endpoints. The murine model is a powerful system in which to understand the relations across age-related phenotypes and to identify research models with variation in life span and health span. The Jackson Laboratory Nathan Shock Center of Excellence in the Basic Biology of Aging has performed broad characterization of aging in genetically diverse laboratory mice and has placed these data, along with data from several other major aging initiatives, into the interactive Mouse Phenome Database. The data may be accessed and analyzed by researchers interested in finding mouse models for specific aging processes, age-related health and disease states, and for genetic analysis of aging variation and trait covariation. We expect that by placing these data in the hands of the aging community that there will be (a) accelerated genetic analyses of aging processes, (b) discovery of genetic loci regulating life span, (c) identification of compelling correlations between life span and susceptibility for age-related disorders, and (d) discovery of concordant genomic loci influencing life span and aging phenotypes between mouse and humans.

Aging and Induced Pluripotent Stem Cells

At present, the exact mechanism and biological basis of aging is unknown. The antagonistic pleiotropy theory and competing model of senescence explain the aging occurrence of some physiological functions of human body from different angles. The single nucleotide polymorphisms (SNPs) of genome suggest the individual’s difference of aging process is associated with SNPs-related individual’s sensitivity to diseases. As the naturally occurring DNA damages and age-associated accumulation of DNA damage as well as decline in gene expression regulation indicate individual life expectancy, whereas the shortening mechanism of telomeric terminals of chromosomes and Hayflick limit of cell division determine human life span.

Sponsors of SENS6

Sponsors of SENS6

Forum on aging and skeletal health: Summary of the proceedings of an ASBMR workshop

With the aging of the population, the scope of the problem of age-related bone loss and osteoporosis will continue to increase. As such, it is critical to obtain a better understanding of the factors determining the acquisition and loss of bone mass from childhood to senescence. While there have been significant advances in recent years in our understanding of both the basic biology of aging and a clinical definition of age-related frailty, few of these concepts in aging research have been evaluated adequately for their relevance and application to skeletal aging or fracture prevention. The March 2011 Forum on Aging and Skeletal Health, sponsored by the NIH and ASBMR, sought to bring together leaders in aging and bone research to enhance communications among diverse fields of study so as to accelerate the pace of scientific advances needed to reduce the burden of osteoporotic fractures. This report summarizes the major concepts presented at that meeting and in each area identifies key questions to help set the agenda for future research in skeletal aging.

Biology of Aging Summit Report

Biology of Aging Summit Report

SIRT1: Tumor promoter or tumor suppressor?

Over the past decade, an intensive research on the basic biology of aging has identified individual genes either directly or indirectly involved in regulating the aging process in various model organisms. This allows us to garner all the information available from studies of model organisms and to apply them to better understand aging and cancer in human. Among many genes thus far reported contributing to aging process, the yeast silent information regulator-2 (SIR2) and its homologues in other species, which belong to the family of type III histone and protein deacetylases, have been the subject of active discussion. The demonstrated roles of SIRT1, the mammalian counterpart of the yeast SIR2, reveal that SIRT1 regulates important cellular processes including anti-apoptosis, neuronal protection, cellular senescence, aging and longevity. Based on the observations that SIRT1 is upregulated in tumor cells, the hypothesis is that deregulation of SIRT1 expression may promote tumorigenesis by altering cellular signaling or by inducing modulation of chromatin remodeling leading to promotion of tumorigenesis. Further studies will shed new light on the underlying mechanisms of tumorigenesis mediated by SIRT1.

The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises

There are a handful of biological questions that affect all of us directly in everyday life. How are emotions formed, what is the basis for consciousness, and why do we look the way we do? One that strikes particularly close to home is the question of how we age. The sheer complexity of this problem has had many scientists throw up their hands in frustration and most of the postulated theories have been vague and generally have involved ill-defined wear-and-tear mechanisms. But the pursuit of the biological basis of aging has been revitalized within the last decade by studies in yeast, worms, flies, and mice that have firmly established that there indeed exist specific molecular mechanisms that contribute to the aging process [1]. These efforts point to several distinct, likely interrelated, mechanisms, ranging from improper protein metabolism, to alterations of specific signaling pathways, progressive damage due to generation of oxidative free radicals, and increased genome instability.