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In this issue, Espinoza and colleagues present the design of a 2-year randomized, double-blind, controlled, clinical trial testing whether 2,000 mg/day of metformin retards the advancement of frailty in prediabetic older adults. Demonstrating that any drug can deflect the progression of frailty would be a major milestone in geriatrics, but this study is also important within the larger frame of geroscience which hypothesizes that human health can be improved by directly targeting the biology of aging (1). Support for this hypothesis is found in studies of model organisms, which show that targeting these pathways in a variety of ways—including the administration of metformin—can increase health span and lifespan (2). The study by Espinoza is one of the few rigorously designed trials to test a drug in a context that has direct implications for evaluating the geroscience hypothesis. The geroscience hypothesis is relatively new, and there is uncertainty regarding how to optimally design studies to test it. A key uncertainty is end-point selection. Espinoza and colleagues selected the Fried Cardiovascular Health Study (CHS) frailty phenotype as the primary end-point (3). This measure has good face validity with geriatricians and its use is supported by a great deal of observational data underscoring its robust prediction of health outcomes in older adults. However, the frailty phenotype domains were originally operationalized using data from the CHS study, an on-going observational study. The approach which has worked so well for observational research has limitations from a clinical trial perspective. The Fried CHS frailty phenotype may not be sensitive to change. Participants receive a point for having a value below a threshold cut-point for each of its five components: unintentional weight loss of at least 10 pounds in the past year, slowness, weakness, lack of energy, and low physical activity. This approach makes it relatively insensitive to change because only participants whose measurements actually cross a cut-point during follow-up contribute information. Trials using relatively insensitive measures require more participants or longer follow-up times to detect effects. A person’s classification may change simply due to the passage of time. The phenotype operationalizes the construct of shrinkage as unexpected weight loss over the past year. It is possible that someone who unexpectedly lost weight 11 months previously would no longer meet these criteria at a subsequent follow-up visit even in the absence of any underlying change. Prior weights may not be available when a person enrolls in a trial, so it may be hard to determine if this criterion is met at the baseline of a frailty prevention trial. Interventions could affect component measures without affecting the underlying physiology of frailty. An exercise intervention is likely to show improvement in the physical activity component even if the underlying frailty pathophysiology is unaffected. Conversely, metformin frequently leads to weight loss so unexplained weight loss may end-up being more common in the treated group even if frailty is not exacerbated. There are potential options for adapting the Fried frailty construct for clinical trial use. Ceiling effects and sensitivity to change can be addressed by rescaling the component measures. Sanders and colleagues published a Vigor scale (0–10) which scores the frailty components on an expanded ordinal scale, allowing for better discrimination among non- and pre-frail participants (4). One could adopt an approach similar to that used by Simonsick and colleagues when they adapted the Established Populations for Epidemiologic Studies of the Elderly short physical performance battery (SPPB) for the well-functioning Health Aging and Body Composition Study population (5). The SPPB is based on the performance of three lower extremity tasks, each of which is scored on an ordinal scale from 0 to 4. This results in an SBBP score with integer values from 0 to 12. The SPPB is reasonably sensitive for those with poor mobility function but is insensitive in persons with good function. To adapt the battery, the investigators scored the SPPB components on a continuous 0–1 scale assigning scores based on the ratio of the measured value to the best possible score. The rescaling led to a continuous summary score without a ceiling, better distributional characteristics, and better sensitivity to change (6). The time dependency issue with respect to the shrinkage measure could be addressed in various ways. One might use weight loss since age 50 or 25. This would still be a problem for weight loss interventions, however. One could also consider height loss since age 25. Self-reported adult height is reasonably accurate and height loss would certainly be unintentional and unlikely to be affected by any potential intervention. For trials involving a physical activity intervention, one might consider using accelerometry to quantify sedentary time as an alternative to using a questionnaire to estimate kcals of energy expenditure. These alternatives do not have the depth of data supporting the use of the original measure, but such adaptions could make trials relevant to the underlying physiology of frailty more efficient. An adapted frailty phenotype measure is by no means the only option for geroscience-relevant trials. Potential outcomes fall on a continuum from those that directly test the hypothesis (e.g. emergence of age-related diseases or life-span) to indirect biomarker-based assessments (Figure 1). The National Insitute on Aging’s (NIA) Intervention Test Program evaluates pharmacological agents in mice for their effects at the far right of this continuum (e.g. median lifespan) (7). This end-point is a translational challenge. For example, the Targeting Aging with Metformin (TAME) study, a randomized trial designed to test metformin’s ability to retard the incidence of multiple age-related diseases and death, will require 3,000 people followed for more than 4 years (8). Studies such as TAME will be necessary to definitively test the geroscience hypothesis. But we can anticipate many trials like the one described by Espinoza and colleagues that evaluate interventions relevant to the biology of aging, and which, if promising, might be scaled up. What kinds of measures might be considered for such trials? Evaluation continuum for clinical trials in geroscience. Clinical trials are being designed to test the geroscience. Potential end-points for such trials exist on a continuum, with biomarker-based measures of the underlying aging biology on one end, and rate of occurrence of clinical disease, geriatric syndromes like frailty, and mortality on the other. With increasing levels of assessment from biomarker-based to hard clinical outcomes, the duration required to observe change in the trial endpoint (time), number of research subject and costs to run the trial (expense), and salience of the endpoint to geroscience hypothesis also increases. Reliable biomarkers reflecting changes to fundamental aging processes would be valuable. Currently, NIA is supporting an initiative to develop and validate such biomarkers for clinical trials, but at this point, the data related to options for human studies is insufficient to support their suitability for use in trials. There is a rapidly growing literature on indirect measurements which may have value in the clinical trials context, and some broad strategies have emerged: (a) surrogate markers of individual biological hallmarks or pillars; (b) multivariable biomarker composites; and (c) deficit accumulation indices. Epigenetic age estimators are leading examples of this approach. There are age-related patterns of accumulating DNA methylation. It is possible to calculate a “biological age” based on these patterns. Levine and colleagues extended this idea to calculate a score based on an apparent phenotypic age which was calculated using levels of various age-related blood chemistries (9). Much work is needed to understand the reliability and sensitivity to change of such measures. Recent preliminary reports suggest that epigenetic age estimators are sensitive to short-term administration of a thymotrophic drug combination (recombinant human growth hormone, dehydroepiandrosterone, and metformin) and vitamin D (10,11). Biomarker composites are scores based on age-related biomarkers which can be used to calculate a summary score which may or may not be referenced to an expected age for an individual with that biomarker profile (12). The behavior of these composites in intervention settings may indicate the pace of the aging process. For example, the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy trial tested the effects of 2 years of 25% caloric restriction in healthy, nonobese adults (13). In a post hoc analysis, Belsky and colleagues used a collection of clinical chemistries to calculate a “biological age” score and showed that caloric restriction slowed apparent age-advancement (14). Cumulative deficit indices calculate the proportion of the sum of the number of abnormal clinical signs, symptoms, diseases, or biomarker measures an individual has (numerator) relative to the total number of items included in the index (denominator) to create a score ranging from 0 to 1 (also called Frailty Indices) (15). The trial described by Espinoza and colleagues includes a frailty index as a secondary end-point. Such indices strongly predict mortality and disease outcomes independent of age, and recent data published from the Look AHEAD (Action for Health in Diabetes) trial show that a frailty index is responsive to an intensive lifestyle intervention (16). When the index includes a large number of items the influence of any single component is dampened. This lowers the susceptibility of this approach to items which may be responsive to the intervention for reasons that are not related to the aging process. Being the early days of the geroscience hypothesis, no one is entirely certain what the best end-point might be. The choice might depend on the biological target (e.g. senolytics vs mechanistic target of rapamycin [mTOR] inhibitors) among many other factors. Early guesses may be off-base and as knowledge emerges, investigators may kick themselves for getting it wrong. Until we have a solid empiric foundation laying out which end-points are valid, clinically meaningful, reproducible, and sensitive to change, readers, peer-reviewers, and editors should be open-minded and pay attention to not only the prespecified primary end-point but also to secondary and exploratory end-points. A secondary or exploratory end-point may turn out to be the one that will ultimately be found to be the most useful. To accelerate progress in evaluating the geroscience hypothesis, it will be important that those conducting such studies bank appropriately collected biological samples, obtain potentially useful measures in a standardized way, and be prepared to share data and results in common formats. Sharing how a variety of measures behave across intervention types and settings will help to minimize missteps and inefficiencies. In recognition of the value of this goal, the NIA recently funded the Translational Geroscience Network (R33 AG061456) which has a goal to identify and promulgate standard protocols and data collection instruments to facilitate data sharing across geroscience efforts. Its first work products are expected to appear later in 2020. This work was partially supported by National Institute on Aging Grants: P30 AG21332 and K01..

Research into the basic biology of aging has undergone a seismic shift in the last 10–20 years, moving rapidly from the very descriptive approach focused on the aged that was the predominant focus by the end of the last century, to a more mechanistic (and primarily genetics-driven) phase, focused less on describing the aging phenotype in different models, and more on a definition of the molecular and cellular drivers of the process. This progression was accompanied by an evolution in the concepts and ideas that have dominated the field in the past, namely free radicals, cell senescence, and caloric restriction, each of which became the seed upon which the modern foci of research now stands. Progress in a variety of research areas has crystallized into the beginnings of a conceptualization of the process, including seminal publications that described the major hallmarks or pillars of aging in 2013 and 2014 ( 1 , 2 ). This knowledge is far from complete, and much more research is needed to further refine these pillars, as well as the interactions among them and the interactions between aging and other Gene × Environment elements that, together with aging, determine the health status of the elderly. I would even venture that the description of the major pillars of aging represents the first baby steps in the right direction, but nevertheless, it begins to allow researchers to envision the process of aging as a whole. Aging research is not simply an academic pursuit, it actually holds more promise in terms of helping mankind than most or all other biomedical fields. In terms of health and human suffering, it is well known that four out of five older Americans suffer from at least one chronic disease, and more than half suffer from multiple comorbidities. Aging being the major risk factor for all those diseases, it follows that research into aging could be pivotal in our efforts to reduce the suffering associated with the ravages of old age. In addition to the direct health issues, it has been calculated that care for the elderly currently accounts for 43% of the total health care spending in the United States, or approximately 1 trillion dollars a year ( 3 ), and this number is expected to rise as baby boomers reach retirement age. Reducing these costs is critical for the survival of society as we know it, and indeed it has been calculated that a modest increase in life span and health span (2.2 years) could reduce those expenses by 7 trillion dollars by 2050 ( 4 ). Thus, by delaying aging even by a lesser degree than currently achieved in animal models, there will be significant gains both in terms of health and wealth. The enormous advances in basic aging research, coupled with the promises described in the previous paragraphs, led to the concept of geroscience, a field that aims to understand the molecular and cellular mechanisms responsible for aging being the major risk factor and driver of common chronic conditions and diseases of the elderly. Of course, there is considerable work to be done in order to bring the field forward and move aging biology towards translation. Major areas in need of further development include, in the preclinical space, the development of better, reliable, and predictive biomarkers, as well as development of metrics for health, including resilience. On the clinical side, a major roadblock is the fact that life span—the traditional gold standard in aging research in animal models—is not an option in human studies, and therefore reliable surrogate endpoints need to be developed and characterized. In an effort to take advantage of recent developments in the field, and trying to catalyze further conceptualization of emerging areas, the NIA published in 2011 a Program Announcement (PAR 11–266) titled “Network Infrastructure Support for Emerging Areas of Research in the Basic Biology of Aging.” The PAR called for the establishment of teams that could develop overarching ideas on how to move the field forward, using the R24 mechanism (a resource-related NIH mechanism designed to enhance the capability of resources to serve biomedical research). Several important areas were selected for funding through the usual peer review system, including projects focused on developing the domestic dog as a model system for aging research, a geropathology consortium, and a team, led by Drs. Kirkland, Austad, and Barzilai, to develop a Geroscience Network (see Table 1 ). This latter team tackled the central issue of the geroscience hypothesis: by delaying the aging process, it should be possible to delay not just one, but most chronic diseases affecting the elderly, all at once. Geroscience Network Geroscience Network The accompanying papers describe the work done thus far by this group, as well as a report from an NIA-sponsored workshop on “Resilience in Aging Animal Models”, held at the NIH Campus on August 27, 2014. They Geroscience Network group’s work consisted of 4 separate workshops, each involving between 18 and 35 basic scientists, clinicians, and others. The workshops, held within the space of about 2 years, focused on specific aspects needed to move geroscience from a hypothesis into a reality. While each Geroscience Network workshop focused on specific aspects within the continuum between basic aging biology and clinical practice, many elements of the discussions intersected extensively and consequently, there is considerable overlap in the reports. The paper by Burd and coworkers analyzes the barriers to translation and preclinical development of interventions. The authors discuss possible best approaches along the early stages of the pipeline, starting from drug discovery and lead compound development. In addition to suggestions on best practices at those stages, a discussion is presented concerning existing barriers such as the current lack of efficient communication between basic scientists and clinicians (a gap that geroscience is attempting to narrow), and the difficult issue of funding for these efforts, where a focus on generic drugs may limit financial incentives for industry, despite the potentially large market for these interventions, and where both Federal and philanthropy monies are very tight. Importantly, this report emphasizes the need to develop biomarkers and clinical trial strategies relevant to frailty and resilience, both in humans and in animal models, thus appropriately serving as a nexus between the more basic focus of Huffman and coworkers, and the more clinical ones by Newman and coworkers and Justice and coworkers. The piece by Huffman and coworkers focuses on health span evaluation in preclinical models, with an emphasis on non- or minimally invasive measurements that can be conducted in biomedicine’s animal model of choice, the mouse. This report complements other efforts in the same domain that have appeared recently ( 5 , 6 ), and which aim at attempting a consensus among basic scientists to define what constitutes “health” in mouse models. The focus is on physiological parameters of overall health, including neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory domains. Significantly, Huffman and coworkers also discuss the importance of using stressors to challenge these different physiological domains, so as to assess resilience, rather than simply frailty. The importance of defining and characterizing a panel of health measures that is reliable and robust cannot be overemphasized, since such measurements will form the basis for assessing, at the preclinical stage, whether an intervention is worth considering for a first-in-humans trial. The report by Newman and coworkers deals primarily with strategies needed for translation into the clinic. Purposely, the focus was on how to design studies to delay aging by drugs already approved for human use. Therefore, in addition to discussing the general principles involved in clinical trial design, the participants also discussed the merits and drawbacks of different candidate drugs including metformin, acarbose, rapamycin, resveratrol, and others that are currently being actively investigated. The roadblocks to designing a clinical trial focused on aging as an endpoint are formidable, starting from the obvious impossibility of using life span—the gold standard in preclinical models—in human studies, unless they are observational Phase IV (postmarketing) as was recently reported for metformin ( 7 ). Another major hurdle is the need to define what surrogate measurements might or might not be acceptable to regulatory agencies such as the FDA in the United States. The paper discusses in certain detail some possible approaches to surrogate measurements, including health span, resilience, and diagnosis of a large panel of chronic conditions, which could be used as an endpoint for clinical studies. The report by Justice and coworkers described specific issues and elements that need to be taken into consideration while developing potential clinical trials for aging in humans, including all the elements that characterize a well-designed Phase II clinical trial, and how such a design can be modeled when the goal is to obtain an FDA certification against aging, rather than the more commonly standard of issuing such certifications against disease. Many obstacles will need to be addressed as the field moves from basic biology observations and into the clinical realm, and some of these obstacles differ on whether the intervention involves a previously FDA-approved drug, or a new entity requiring an IND. Interestingly, Justice and coworkers envision at least three possible paradigms that can be used: targeting age-related diseases, targeting geriatric syndromes, and targeting resilience. While many considerations are common to all three scenarios, some are unique, and each scenario presents specific advantages and disadvantages that need to be balanced as the field moves forward. Finally, it is worth noticing that, as stated in the reports, all the discussions of the Geroscience Network involved, to different degrees, an element related to measurements of resilience, either in animal models or in humans. For that reason, and in spite of it being independent of the Geroscience Network, the report from the NIA workshop on Resilience in Aging Animal Models is included in this package as well. The workshop concentrated on identifying practical methods for measuring resilience in mouse models, as a way of accelerating the testing of potential interventions before a full-length longevity analysis was attempted. The group identified a limited number of potential tests that are simple, cheap, and to an extent, measure overall physiological response, as opposed to focusing on a single or few tissues or systems. These potential tests are here being offered to the research community to elicit further studies on optimization of both the stresses and the responses. As a result of the workshop, in 2016, the NIA published RFA AG 16-006, “Short-term Measurements of Improved Physical and Molecular Resilience in Pre-clinical Models.” The reports represent the core of the discussions, which included multiple viewpoints, and are not meant to be the definitive answer to all the related questions. Rather, they represent an offer for the research community to discuss and hopefully improve upon. As stated at the beginning, basic aging research has travelled a long way and the current efforts by several research teams, including those funded through the R24 mechanism, represent the latest—but by no means the last—stage in the progression from the early descriptive phase to finally being able to reap the benefits of basic aging research and apply this knowledge to improve the health and well-being of the burgeoning older population. Drs. Austad, Barzilai, Kirkland, and Sierra are grateful to all the attendees of the R24 retreats for their participation and contributions ( Supplementary Table ).

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Geroscience, a burgeoning discipline at the intersection of aging and disease, aims to unravel the intricate relationship between the aging process and pathogenesis of age-related diseases. This paper explores the pivotal role played by geroscience in reshaping our understanding of pathology, with a particular focus on age-related diseases. These diseases, spanning cardiovascular and cerebrovascular disorders, malignancies, and neurodegenerative conditions, significantly contribute to the morbidity and mortality of older individuals. We delve into the fundamental cellular and molecular mechanisms underpinning aging, including mitochondrial dysfunction and cellular senescence, and elucidate their profound implications for the pathogenesis of various age-related diseases. Emphasis is placed on the importance of assessing key biomarkers of aging and biological age within the realm of pathology. We also scrutinize the interplay between cellular senescence and cancer biology as a central area of focus, underscoring its paramount significance in contemporary pathological research. Moreover, we shed light on the integration of anti-aging interventions that target fundamental aging processes, such as senolytics, mitochondria-targeted treatments, and interventions that influence epigenetic regulation within the domain of pathology research. In conclusion, the integration of geroscience concepts into pathological research heralds a transformative paradigm shift in our understanding of disease pathogenesis and promises breakthroughs in disease prevention and treatment.

Geroscience poses that core biological mechanisms of aging contribute to chronic diseases and disabilities in late life and that health span and longevity can be modulated by pharmacological and behavioral interventions. Despite strong evidence from studies in model organisms and great potentials for translation, most geriatricians remain skeptical that geroscience will help them in the day-by-day battle with the consequences of aging in their patients. We believe that a closer collaboration between gerontologists and geriatricians is the key to overcome this impasse. There is evidence that trajectories of health with aging are rooted in intrinsic and extrinsic exposures that occur early in life and affect the pace of molecular and cellular damage accumulation with aging, also referred to as the "pace" of biological aging. Tools that measure the pace of aging currently allow for the identification of individuals experiencing accelerated aging and at higher risk of multimorbidity and disability. What we term "Translational Geroscience", i.e., the merger of fundamental and translational science with clinical practice, is thus poised to extend the action of geriatric care to a life course perspective. By targeting core mechanisms of aging, gerotherapeutics should be effective in treating patients with multimorbidity and disability, phenotypes that are all too common among geriatric patients nowadays. We call for initiatives that enhance the flow of ideas between gerontologists and geriatricians to facilitate the growth of translational geroscience. This approach can widen the scope of geriatric care, including a new role for geroscience in the promotion and operationalization of healthy longevity.

Geriatricians and others must embrace the emerging field of geroscience. Until recently geroscience research was pursued in laboratory animals, but now this field requires specialized expertise in the care of vulnerable older patients with multiple chronic diseases and geriatric syndromes, the population likely to benefit the most from emerging therapies. While chronological aging measures the inevitable passage of clock time that occurs equally for everyone, biological aging varies among individuals, and importantly, it is modifiable. Advances in our understanding of biological aging, the discovery of strategies for modifying its rate, and an appreciation of aging as a shared risk factor for chronic diseases have jointly led to the Geroscience Hypothesis. This hypothesis states that interventions modifying aging biology can slow its progression-resulting in the delay or prevention of the onset of multiple diseases and disorders. Here we wish to report on the Third Geroscience Summit held at National Institutes of Health on November 4-5, 2019, which highlighted the importance of engaging other disciplines including clinicians. Involvement by scientists with expertise in clinical trials, health outcomes research, behavioral and social sciences, health policy, and economics is urgently needed to translate geroscience discoveries from the bench to clinical care and health policy. Adding to the urgency of broadening this geroscience coalition is the emergence of biological aging as one the most important modifiable factors of COVID-19, combined with the inability of our society to once again recognize and confront aging as a priority and opportunity when facing these types of public health emergencies.

Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This unprecedented paradigm shift requires optimizing the design of future clinical studies related to aging in humans. Researchers will face a number of challenges, including ideal populations to study, which lifestyle and Gerotherapeutic interventions to test initially, selecting key primary and secondary outcomes of such clinical trials, and which age-related biomarkers are most valuable for both selecting interventions and predicting or monitoring clinical responses ("Gerodiagnostics"). This article reports the main results of a Task Force of experts in Geroscience.

Aging is a fundamental biological process characterized by a progressive decline in physiological functions and an increased susceptibility to diseases. Understanding aging at the molecular level is crucial for developing interventions that could delay or reverse its effects. This review explores the integration of machine learning (ML) with multi-omics technologies-including genomics, transcriptomics, epigenomics, proteomics, and metabolomics-in studying the molecular hallmarks of aging to develop personalized medicine interventions. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Using ML to analyze big and complex datasets helps uncover detailed molecular interactions and pathways that play a role in aging. The advances of ML can facilitate the discovery of biomarkers and therapeutic targets, offering insights into personalized anti-aging strategies. With these developments, the future points toward a better understanding of the aging process, aiming ultimately to promote healthy aging and extend life expectancy.

Research in aging has significantly advanced; scientists are now able to identify interventions that slow the biologic aging processes (i.e., the "hallmarks of aging"), thus delaying the onset and progression of multiple diseases, including oral conditions. Presentations given during the 3-part session "Geroscience: Aging and Oral Health Research," held during the 2023 American Association for Dental, Oral, and Craniofacial Research meeting, are summarized in this publication. Speakers' topics spanned the translational research spectrum. Session 1 provided an overview of the geroscience and health span (disease-free and functional health throughout life) concepts. The common molecular mechanisms between oral cancer and aging were discussed, and research was presented that showed periodontal microflora as a potential factor in Alzheimer's disease progression. Session 2 focused on behavioral and social science aspects of aging and their oral health significance. The keynote provided evidence that loneliness and isolation can have major health effects. These social conditions, along with poor oral health, tooth loss, and cognitive decline, could potentially affect healthy eating ability and systemic health in older adults. Research could help elucidate the directions and pathways connecting these seemingly disparate conditions. Session 3 focused on the delivery of oral care in different settings and the many barriers to access care faced by older adults. Research is needed to identify and implement effective technology and strategies to improve access to dental care, including new delivery and financing mechanisms, workforce models, interprofessional provider education and practice, and use of big data from medical-dental integration of electronic health records. Research to improve the "oral health span," reduce oral health disparities, and increase health equity must be tackled at all levels from biologic pathways to social determinants of health and health policies.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.

Although people with HIV are living longer, as they age they remain disproportionately burdened with multimorbidity that is exacerbated in resource-poor settings. The geroscience hypothesis postulates that a discrete set of between five and ten hallmarks of biological ageing drive multimorbidity, but these processes have not been systematically examined in the context of people with HIV. We examine four major hallmarks of ageing (macromolecular damage, senescence, inflammation, and stem-cell dysfunction) as gerodrivers in the context of people with HIV. As a counterbalance, we introduce healthy ageing, physiological reserve, intrinsic capacity, and resilience as promoters of geroprotection that counteract gerodrivers. We discuss emerging geroscience-based diagnostic biomarkers and therapeutic strategies, and provide examples based on recent advances in cellular senescence, and other, non-pharmacological approaches. Finally, we present a conceptual model of biological ageing in the general population and in people with HIV that integrates gerodrivers and geroprotectors as modulators of homoeostatic reserves and organ function over the lifecourse.

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Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been 'compression of morbidity' and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, 'geroscience', is focused on healthspan extension. Superimposed on this background are new attitudes and demand for 'optimal longevity' - living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel 'nutraceutical' compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with ageing, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioural approaches for enhancing adherence to healthy ageing practices in diverse populations, and ongoing analysis of the socio-economic costs and benefits of healthspan extension will be important supporting goals. To meet the demands created by rapid population ageing, a new emphasis in physiological geroscience is needed, which will require the collaborative, interdisciplinary efforts of investigators working throughout the translational research continuum from basic science to public health.

Geroscience is the study of how to slow biological aging to extend healthspan and longevity. Geroscience has not heretofore incorporated behavioral or social-science methods or findings into its agenda, but the current expansion of the agenda to human trials of anti-aging therapies will be greatly aided by behavioral and social science. This article recommends some ways in which geroscience can be augmented through collaboration with behavioral and social science to: accomplish translation from animal models to humans; inform the design of clinical trials of anti-aging therapies; develop outcome measures for evaluating efficacy of anti-aging therapies, and reduce and not exacerbate health disparities.

Aging remains the most pervasive risk factor for a wide range of chronic diseases that afflict modern societies. In the United States alone, incidence of age-related diseases (e.g., cardiovascular disease, stroke, Alzheimer's disease, vascular cognitive impairment and dementia, cancer, hypertension, type-2 diabetes, chronic obstructive pulmonary disease, and osteoarthritis) is on the rise, posing an unsustainable socioeconomic burden even for the most developed countries. Tackling each and every age-related disease alone is proving to be costly and ineffective. The emerging field of geroscience has posed itself as an interdisciplinary approach that aims to understand the relationship between the biology of aging and the pathophysiology of chronic age-related diseases. According to the geroscience concept, aging is the single major risk factor that underlies several age-related chronic diseases, and manipulation of cellular and systemic aging processes can delay the manifestation and/or severity of these age-related chronic pathologies. The goal of this endeavor is to achieve health improvements by preventing/delaying the pathogenesis of several age-related diseases simultaneously in the elderly population by targeting key cellular and molecular processes of aging instead of managing diseases of aging as they arise individually. In this review, we discuss recent advances in the field of geroscience, highlighting their implications for potential future therapeutic targets and the associated scientific challenges and opportunities that lay ahead.

Treatments that target fundamental processes of aging are expected to delay several aging-related conditions simultaneously. Testing the efficacy of these treatments for potential anti-aging benefits will require clinical trials with endpoints that reflect the potential benefits of slowing processes of aging. There are several potential types of endpoints to capture the benefits of slowing a process of aging, and a consensus is needed to standardize and compare the results of these trials and to guide the analysis of observational data to support trial planning. Using biomarkers instead of clinical outcomes would substantially reduce the size and the duration of clinical trials. This requires validation of surrogate markers showing that treatment induced change in the marker reliably predicts the magnitude of change in the clinical outcome. The surrogate marker must also reflect the biological mechanism for the effect of treatment on the clinical outcome. "Biological age" is a superficially attractive marker for such trials. However, it is essential to establish that treatment induced change in biological age reliably predict the magnitude of benefits in the clinical outcome. Reaching consensus on clinical outcomes for geroscience trials and then validating potential surrogate biomarkers requires time, effort, and coordination that will be worthwhile to develop surrogate outcomes that can be trusted to efficiently test the value of many anti-aging treatments under development.

Population aging is unprecedented, without parallel in human history, and the 21st century will witness even more rapid aging than did the century just past. Improvements in public health and medicine are having a profound effect on population demographics worldwide. By 2017, there will be more people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60 (http://unfpa.org/ageingreport/). Although we can reasonably expect to live longer today than past generations did, the age-related disease burden we will have to confront has not changed. With the proportion of older people among the global population being now higher than at any time in history and still expanding, maintaining health into old age (or healthspan) has become a new and urgent frontier for modern medicine. Geroscience is a cross-disciplinary field focused on understanding the relationships between the processes of aging and age-related chronic diseases. On October 30-31, 2013, the trans-National Institutes of Health GeroScience Interest Group hosted a Summit to promote collaborations between the aging and chronic disease research communities with the goal of developing innovative strategies to improve healthspan and reduce the burden of chronic disease.

Research on the biology of aging has accelerated rapidly in the last two decades. It is now at the point where translation of the findings into useful approaches to improve the health of the elderly population seems possible. In trying to fill that gap, a new field termed geroscience will be articulated here that attempts to identify the biological underpinnings for the age-dependency of most chronic diseases. Herein, I will review the major conceptual issues leading to the formulation of geroscience as a field, as well as give examples of current areas of inquiry in which basic aging biology research could lead to therapeutic approaches to address age-related chronic diseases, not one at a time, but most of them in unison.