Considering the Future of Geroscience: Goals and Opportunities Stemming From the Fourth Geroscience Summit

The population of older individuals is rapidly increasing across the globe. Although this demographic shift reflects important advances in science, medicine, and policy, it is also likely to bring about major societal and economic challenges. One such challenge involves health disparities of aging that primarily affect under-represented or underserved populations (1). At present, it is not understood why some older individuals experience poorer health outcomes with age, and there are not many clinical options to address this problem. Geroscience offers the potential to gain insights into these questions because it facilitates new partnerships across disciplines and is focused on improving health and quality of life as we age across the whole lifespan. New partnerships forged through geroscience will result in increased knowledge about the interactions and impact of genetic, molecular, environmental, behavioral, and social factors as we age.

Geroscience is a field of research built upon the hypothesis that interventions that slow or reverse molecular drivers of aging will simultaneously delay functional decline and the onset of multiple age-associated diseases (2). Given the urgent need for approaches that can yield better health at older ages, for all individuals, the field of geroscience has seen rapid growth in recent years. Early on, the U.S. National Institutes of Health (NIH) recognized the promise of this area and formed a collaborative Geroscience Interest Group (GSIG) that brought together staff from multiple NIH institutes and centers (3). The GSIG became a critical forum for discussion in this rapidly evolving field, with the group hosting a series of landmark scientific summits, the most recent of which took place on April 24–26, 2023. The Fourth Geroscience Summit convened researchers from diverse disciplines to examine the state of science and consider the future of the field and how to address specific challenges and barriers. A high-level overview of the summit is presented below through the lens of goals and opportunities for the field. This special issue of The Journal of Gerontology contains additional perspective papers that describe specific topics discussed at the summit in greater detail.

Goal: Design Multilevel Approaches to Address Age-Related Health Disparities

Many social, structural, and environmental factors affect the health of individuals and populations and can drive health inequities. Individuals’ experiences and exposures can become biologically embedded and accumulate over the life course, resulting in health disparities that ultimately affect rates and outcomes of aging. Several speakers at the summit stressed the need for the Geroscience research community to increase its efforts to facilitate the understanding of heterogeneity in aging and find ways to address the differences in health outcomes and lifespan that exist between different populations.

Social determinants of health (SDOH) and structural factors such as racism, low socioeconomic status, and limited educational attainment may cause health disparities, accelerate aging, and shorten life expectancy through multiple mechanisms from behavioral to biological, including poor health literacy, substance use, low physical activity, and poor diet, as well as deleterious changes in gene expression, immune responses, DNA repair, and in the epigenome. The NIH is investing in research to understand how SDOH and structural factors affect biology and behavior to influence clinical outcomes across the lifespan. Speakers at the summit emphasized the value of multilevel research and interventions that consider SDOH and structural factors to delay the onset of multiple age-related diseases and monitor the differential risks and benefits of those interventions across racial and ethnic groups. Conceptual research frameworks, such as those from the National Institute on Minority Health and Health Disparities and the National Institute on Aging, can be useful for guiding research on the interactions among multiple domains (eg, biology, behavior, physical environment, sociocultural environment, and health care system) and levels (eg, individual, interpersonal, community, and societal) of influence on health outcomes. Pèrez-Stable et al., and McDougle et al. provide deeper insights about multilevel approaches to addressing age-related health inequities in their perspective papers within this special issue (4,5).

Goal: Ensure Inclusion of Diverse Populations in All Aspects of Geroscience Research

To facilitate new discoveries about the fundamental mechanisms of aging, summit speakers discussed the value of studying specific populations with unique characteristics such as centenarians, individuals residing in nonindustrialized contexts, and individuals affected by certain chronic diseases and health experiences. For example, the greater lifespans of centenarians and their offspring occur despite having similar lifestyle factors (eg, physical activity and dietary habits) to those in the general population (6,7). Studies of centenarians have linked certain genetic variants with increased longevity, serving as motivation for new research such as the SuperAgers Family Study, which aims to enroll 10 000 centenarians and uncover inherited and natural factors that slow aging (8). Indigenous populations that live in native, nonindustrialized environments offer rare opportunities to learn about the aging process and consider new gerotherapeutic avenues. This is because Indigenous populations are often more or less affected by age-related disease and dysfunction than the more-frequently studied populations in industrialized nations. One example is the Tsimané population, native to Bolivia, who tend to live longer and develop fewer chronic diseases than are found among individuals living in industrialized environments, whether from indigenous or nonindigenous groups (9,10).

Another important element to moving geroscience forward in an equitable and inclusive way involves training a more diverse research and clinical workforce with the necessary knowledge and skills. Ensuring diversity in aging research and geroscience clinical trials, specifically from under-represented populations and older adults, requires intensive efforts to build trust and engage with community members. The importance of training a diverse workforce and including under-represented groups in aging research are 2 topics also covered by the included articles from Pèrez-Stable et al. and McDougle et al (4,5).

Goal: Explore Geroscience Interventions for Chronic Disease Patients and Survivors

Several health conditions have a bidirectional relationship with aging: susceptibility to those health conditions increases with age, and the presence of (or treatment for) those conditions also accelerates aging processes. Moreover, although mortality rates are declining in older adults, prevalence of certain age-related conditions and thus of multimorbidity and disability rates are rising, with the attendant decrease in quality of life. Although therapeutic treatments for cancer and human immunodeficiency virus (HIV) have improved significantly and can extend lifespan, cancer and HIV survivors experience elevated risks of developing age-related phenotypes such as declines in physical and cognitive functions. Intensive care unit (ICU) survivors also experience accelerated aging and are an important population to study further.

Geroscience offers an alternative health care approach that focuses on slowing or reversing biological aging processes to prevent or delay a wide spectrum of diseases and disability. For example, senescent cells are a driver of aging and chemotherapy can increase senescent cell burden. To address this, cancer treatments could employ a “one-two punch” approach and combine senolytic and chemotherapeutic treatments. Similarly, to lessen the impact of age-related pathologies in individuals living with HIV, antiviral treatments could also incorporate senolytic therapies (11).

Goal: Further Develop Research Models to Understand and Treat Multimorbidity

Despite progress in our understanding of aging mechanisms and treatments for specific diseases, the prevalence of multimorbidity, the presence of 2 or more chronic medical conditions, is on the rise (12). Multimorbidity is challenging to study in humans, however, model organisms offer an excellent opportunity for learning more about the underlying biological mechanisms and conducting preclinical studies. To translate insights from animal models to the clinic, summit speakers emphasized the need for a shared vocabulary that describes aspects of healthspan that are measurable across species. Furthermore, there is a need to identify and validate cross-species mechanisms and biomarkers of aging that permit longitudinal, in vivo assessments of interventions. A variety of model organisms, including rodents, dogs, and nonhuman primates (NHPs), share aging characteristics with humans and display variable levels of resilience in response to stressors and thus are useful in this line of research.

Goal: Identify and Implement the Use of Aging-Related Health Outcome Measures

Identifying measures that correlate with both aging and health would greatly advance the field of Geroscience by helping to stratify patients by physiological characteristics, in addition to age (as time elapsed since birth). These characteristics could be used to develop new interventions to optimize care of older adults which would benefit greatly from being able to anticipate clinical changes. Summit speakers explored some promising measures of aging and health, including assessments of frailty and mobility, including Frailty Indexes, the Physical Function Component 10 (PF-10), the 6-minute and 400-meter walking tasks, and the Short Physical Performance Battery (SPPB). Frailty Indexes share the feature of a “fraction” defined as the proportion of functional and physiological deficits out of total possible deficits (13). Animal and human studies of the Frailty Index have shown that this measure reliably increases in late life. Interventions, such as exercise, angiotensin-converting enzyme (ACE) inhibitors, and reduction of polypharmacy can slow the rate at which frailty increases with age.

Although overall SPPB scores predict mobility, disability, and mortality, SPPB gait speed scores have the highest predictive power for these outcomes (14). Because mobility scores on various batteries predict age-related outcomes across mice, rats, nonhuman primates, and humans, the application of these translatable measures will fuel future geroscience discoveries and the assessment of gerotherapeutic agents. However, since molecular changes underlying frailty and mobility deficits can be present before the clinical manifestations, additional research is needed to develop quantifiable and predictive measures of the molecular changes.

Goal: Identify and Validate Predictive Biomarkers of Aging

Geroscience would benefit from a validated toolbox of aging-related biomarkers. Ideally, these biomarkers would precede aging-related functional decline and would be measurable in the short-term (ie, within the span of a clinical trial), sensitive to change, and predictive of disease/dysfunction or mortality. These biomarkers should be scalable, easy to collect (ideally from bodily fluids) and provide information about different health states and trajectories of aging. The development of surrogate biomarkers of aging-related processes will be essential for determining the optimal timing of gerotherapeutic interventions. As part of this special issue Bartolomucci et al., highlight the value of animal models for informing the development of relevant biomarkers of human aging (15).

Current promising avenues for aging biomarkers include epigenetic clocks, gene expression and proteomic data, and measures of other hallmarks of aging, including mitochondrial function and cellular senescence. Based on DNA methylation, first- and second-generation epigenetic clocks predict chronological age and survival, respectively. Newer epigenetic clocks, such as DunedinPACE, can measure the rate of aging (16,17). Unlike other epigenetic clocks that were trained on cross-sectional data, DunedinPACE is derived from analysis of longitudinal data collected from a cohort of same-chronological-age individuals and tracks changes in those individuals in early adulthood. The predictive power of tools like DunedinPACE may help facilitate analyses when data from longitudinal studies are not available.

In addition to changes in DNA methylation, changes in gene and protein expression may also correlate with biological aging. Advances in the ability to detect protein variants (proteoforms) may bolster our understanding of age-related changes in protein expression and the development of new aging biomarkers. Machine learning and other advances in technology may facilitate investigation of gene and protein expression changes. Within this special issue, Zhavoronkov et al. describe how artificial intelligence-based approaches can be leveraged to create models of aging that predict health status and disease risk and may ultimately inform and accelerate therapeutic development (18).

Mitochondrial dysfunction is also known to be an important driver of aging, making it both a biomarker and potential therapeutic target because of its association with loss of mobility, accumulation of beta-amyloid and neurodegeneration, mild cognitive impairment, and dementia. Mitochondria also appear to tightly regulate age-related signal transduction pathways. Notably, various tissue types and body systems demonstrate age-sensitive phenotypes that can be used to study the impact of interventions that may alter lifespan or healthspan. Thus, the development of organ system- or tissue-specific epigenetic clocks could be very useful for clinical trials of specific geroscience interventions.

There are many resources available to guide geroscientists in the development of biomarkers of aging. These include the Biomarkers of Aging Consortium, a cross-disciplinary group focused on developing, validating, and implementing biomarkers of aging and longevity, and the NIA Predictive Biomarkers Initiative. There is also a wealth of biological data available for future studies, collected across different cell and tissue types to measure specific aging phenotypes. These data can be used to feed computational models and generate powerful bioinformatic tools that may predict age or specific features of aging. Establishing measures or biomarkers of aging is an iterative process, and once predictive tools are generated, they must be tested and validated in a variety of settings.

Goal: Provide Clear Communication and Training in Geroscience

The current medical landscape is largely disease-specific, but geroscience provides an opportunity to make health care less siloed. Given that many specialists contribute to care for older adults, medical practitioners should integrate geroscience perspectives into training and treatment of disease. Geroscience can specifically be leveraged for the prediction, treatment, and management of multimorbidity and geriatric syndromes. As individuals age, reductions in biological resilience can increase susceptibility to disease, creating a vicious cycle of aging and the development of multimorbidity. Geroscience may provide tools for predicting the health trajectories of aging patients before and after both chronic stressors, such as dialysis, and acute stressors, such as knee replacement surgery. Furthermore, there is evidence that geroscience-based interventions such as moderate exercise, senolytics, and rapamycin can improve the treatment of disease. For geroscience to advance toward implementation, summit speakers discussed the need for developing shared terminology and providing clear and realistic messaging about the goals, knowledge gaps, and advances in this field. This includes a consistent definition of the term “geroscience” and educational materials for clinicians, researchers, medical and graduate students, and the lay public. Al-Naggar et al., and Forman et al., expand upon these topics in their perspectives in this special issue (19,20).

Conclusion

The NIH Fourth Geroscience Summit examined a wide range of recent advances and initiatives taking place across the field. The summit participants, across disciplines and disease fields, are approaching their work through a geroscience lens, which represents a major step forward. However, there is still work to be done to address challenges related to geroscience clinical trials, education and workforce development, and communication, along with the critically important issue of addressing health disparities in aging. Hearing from many talented early career investigators working in geroscience was an especially encouraging highlight of this most recent summit.

Geroscience brings together researchers and clinicians across multiple fields and shifts the focus from specific age-associated diseases toward a “gestalt understanding” of how the basic biology of aging, combined with genetic, environmental, behavioral, and social factors, can be leveraged to extend the quality of life for all individuals as they age. The ultimate goal of geroscience is to provide translational researchers a path forward to testing such interventions in clinical trials, implementing validated approaches in the clinic, as well as informing/training clinicians on how to best provide care in health settings where older individuals meet providers.

Funding

None.

Conflict of Interest

None.

Acknowledgments

We authors wish to thank all of the speakers and participants of the Fourth Geroscience Summit for the stimulating discussion, particularly the facilitators who provided overviews of each session.

Disclaimer

The participation of these individuals or the materials should not be interpreted as representing the official viewpoint of the U.S. Department of Health and Human Services, the National Institutes of Health, or the National Institute on Aging, except where noted.

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