Ilsa Rovira Arya Biragyn LaVerne Brown Zorina S Galis Malgorzata Klauzinska Svetlana Kotliarova Janine M Simmons Anil Wali Ronit Yarden Dan Xi Gabriela Riscuta ^*

• National Institutes of Health (NIH), Bethesda, United States

Many cultures throughout history have pursued the quest to improve longevity (1). Scientific advances, implementation in public health, and the use of vaccines and antibiotics have enhanced life expectancy over the last century (2). These interventions have reduced mortality but may have led to a concomitant rise in age-related multimorbidity. As we learned from the Struldbruggs in Jonathan Swift's Gulliver's Travels, who continue to age despite being immortal, a longer lifespan without good health is not ideal (3). The development of interventions needs to refocus on preventing age-related decline and extending healthspan. Healthspan is defined as the period of life spent in good health, free from chronic diseases and disabilities (4) At its most essential, aging can be considered impaired regulation of homeostasis, with a diminished cell's ability to repair damage which would normally ensure that the organism remains functional, a gradual decline in physiological functions, and accumulation of dysregulated and senescent cells over time. As such, aging is linked to increased vulnerability to chronic diseases and aging-associated syndromes, such as cancer, cardiovascular disease (CVD), neurodegenerative disorders, pulmonary conditions, and frailty. Preventing these or delaying their onset would improve the quality of life of our increasingly aging population. Identifying factors that promote healthy aging and preserve functional abilities and well-being has become a priority as the world's population ages (. Understanding the commonalities and differences of the biological pathways involved in natural aging and age-related diseases is critical for influencing resilience outcomes, promoting health, and effective prevention or disease management (5). Each individual's biological aging path is unique and shaped by a known and unknown array of determinants. As we age, we encounter shared and competing risks in age-related chronic diseases that lead to multiple aging trajectories and influence health outcomes (6)(7)(8). These risks include genetics and the exposome -the lifetime exposure to internal factors and external environmental influences such as pollution and climate change. Critical psychosocial and lifestyle factors include diet, exercise, sleep patterns, and stress levels. Geroscience seeks to understand how the aforementioned factors impact common cellular and molecular processes that influence the emergence of physiological dysfunction and chronic diseases to identify novel approaches that can help slow down or even reverse genetic, molecular and cellular hallmarks of aging and extend healthspan and longevity (9)(10)(11)(12)(13).Resilience is believed to decrease with age and the development of age-related conditions (14). The definition of resilience for living systems adopted by the trans-NIH Resilience Working Group encompasses their capacity to resist, adapt to, recover, or grow from a challenge (15). An enhanced understanding of aging processes and resilience factors could facilitate strategies focused on improving early detection and intervention with the aim to delay the onset of age-related conditions, mitigate their severity, decrease morbidity and frailty, and foster healthier aging trajectories (8,16). This manuscript summarizes the authors' take on the knowledge gaps and current barriers, as they have emerged from a workshop organized on the topic of: "Health and Aging Trajectories: Shared and Competing Risks & Resiliencies for Chronic Diseases Associated with Aging" (17). We are also including novel research opportunities, ongoing efforts to address these gaps, and strategies for future research that emphasize the inclusion of diverse populations and leverage advanced technologies (Figure 1). The consensus highlights the need for multi-disciplinary, collaborative efforts to develop interventions that enhance resilience and prevent chronic diseases, extend the healthy lifespan and improve quality of life ( 17). Unlike chronological aging, evenly measured in all individuals, biological aging does not affect individuals uniformly, being influenced by a person's genetics, external factors, and lifestyle choices, from conception to death, and even before conception (5). A complex interplay between inherent genetic factors and a range of external and lifestyle factors impact the course of biological aging and the onset of age-related chronic diseases. These Several biological processes -briefly described below -have been shown to contribute to various aging trajectories and are inextricably linked to the emergence of age-related chronic diseases (8). Improving our understanding of healthy aging will help discern effective ways to modulate some of the manifestations of the aging process that can improve resilience outcomes and extend healthspan (23,24).Manifestation of aging-associated morbidities coincides with dysregulation of the immune system, such as the generation and function of both innate and adaptive cells. At the generation step, hematopoiesis is shifted towards myelopoiesis at the expense of lymphopoiesis in the bone marrow, reducing the output of lymphocytes (25)(26)(27). Together with thymic involution and a life-long antigen exposure, naïve B cells and T cells are reduced, and antigen-experienced memory B cells and T cell subsets are increased in the periphery (28)(29)(30)(31), thereby limiting responses to infections, tissue impairments and cancer. Aging-associated B cells (32,33) inhibit survival of pro-B cells in the bone marrow (34) as well cause polarization of peripheral Th17 and Th1 cells (35), while aging-activated innate B1 B cells promote insulin resistance in the elderly (36) and induce potentially autoimmune CD8+ T cells (37). Myeloid cells, such as monocytes and macrophages, show impaired phagocytosis, thus inefficiently clearing apoptotic cells and pathogens in aging (38,39). The dysregulation as well as decline in immune function (termed immune senescence) increases in advanced age, contributing to the increased incidence of CVD, cancer, and degenerative conditions. Cellular senescence is a fundamental aspect of aging where a growing number of cells with increasingly anti-apoptotic mutations continue to exist within the tissue ecosystem but cease to divide (40,41). These cells are implicated in a range of age-related conditions, in part by fostering inflammation and disrupting normal cell function across various bodily systems (42). Within the central nervous system, senescent cells contribute to structural brain changes and cognitive decline (43). They can also tilt the scale towards the development of cancer (44)(45)(46). Cellular senescence is also associated with reduced resilience and a shortened lifespan, and represents a potential therapeutic target to reduce severity and morbidity in COVID-19 infections (47).Consequently, there is a burgeoning interest in the development of senolytics, a category of drugs aimed at targeting and eliminating senescent cells. This therapeutic strategy holds the potential to mitigate age-related chronic diseases, thereby enhancing resilience and extending healthspan (48)(49)(50)(51)(52).The exploration of senolytics has yielded promising results, though it remains premature to draw definitive conclusions (53,54). Enhancing the specificity of these compounds and optimizing treatment protocols, including dosage, is critical to mitigate adverse effects. Interestingly, senolytics have been identified in natural compounds, indicating the potential for nutraceutical approaches in managing aging-related diseases (55).Endothelial dysfunction marks a key aspect of aging-related metabolic shifts, leading to arterial stiffness, fibrosis, and inflammation, all contributing to vascular and organ decline (56). This dysfunction underpins the progression of CVD, cancer, and degenerative conditions like vascular dementia and impacts aging pathways (57)(58)(59)(60)(61). Age-driven vascular changes in the brain which are more frequently observed in women can diminish cognitive function and brain volume, potentially marking early signs of brain aging (62). Early intervention in people with mild cognitive impairment (MCI), an intermediate stage between the expected declines in memory common during normal aging and Alzheimer's dementia, could potentially reduce or prevent the progression of cognitive decline and dementia (63,64). Utilizing biomarkers like plasma amyloid and tau alongside neuroimaging can reveal the neurocognitive impacts of aging, concomitant with the contribution of various risk factors such as hypertension, genetics, and lifestyle on health outcomes (65,66).Accumulating evidence demonstrates the gut microbiome's role in age-related changes in metabolism, digestion, immunity, mood, and cognition, influencing individuals' health. Aging can shift the microbiome towards pro-inflammatory bacteria, affecting metabolism, weakening intestinal integrity, and leading to low-grade inflammation (67). This microbiome evolution, linked to brain health via the gut-brain axis, may contribute to neurodegenerative diseases (68). Given its sensitivity to diet, medication, and environment, influencing the microbiome offers a potential strategy for preventing and treating age-related conditions (69)(70)(71)(72).The transition from normal to malignant cells, as outlined by the somatic evolution theory, establishes a connection between aging and the development of cancer (73). As we age, our DNA repair mechanisms become less efficient, leading to an accumulation of mutations. These mutations, combined with changes in the immune system, can contribute to the onset of cancer, atherosclerosis, and other chronic diseases. Aging and cancer share several key features, including genomic instability, alterations in metabolism, changes in telomeres, and cell senescence, all of which present potential targets for therapeutic intervention (74)(75)(76).The body's cellular responses to stress often begin in the brain. Neurotransmitters and chemokines trigger the mobilization of immune cells from the bone marrow. These immune cells play a crucial role in maintaining homeostasis and triggering inflammatory and atherosclerotic processes. The decline in immune function with age is mechanistically connected to increased morbidity (77). Additionally, clonal hematopoiesis, which is characterized by the accumulation of somatic mutations in hematopoietic stem cells, has also been implicated in the onset of various age-related diseases (78)(79)(80)(81).Brain-body circuits play a pivotal role in mediating interactions between lifestyle, biological aging, and the psychogenic aging and have the potential to influence various biological aging processes (82). Psychogenic aging encompasses the molecular-level of psychological aging clocks including all psychological traits, cognitive processes, motivations, and emotional responses of an individual (82) .The identification of biomarkers associated with the psychogenic aging p could reveal the profound effects of depression and loneliness on age-related morbidity, enhancing our comprehension of psychosocial resilience and its contribution to longevity and healthspan.The debate around whether aging should be classified as a disease or a normal biological process significantly influences regulatory oversight of antiaging interventions. Regulatory bodies can only oversee treatments if aging is categorized as a disease. This has prompted alternative strategies, such as testing drugs aimed at age-related diseases as indirect means of addressing aging. It has also led to the development of unregulated approaches that often lack robust scientific basis and potentially pose health risks. There is an urgent need for a standardized definition of normal aging versus age-related chronic diseases, along with associated biomarkers, and the creation of innovative models for studying biological aging. These measures are crucial for establishing reliable and effective intervention strategies (1). A pressing research priority in the field is the identification, stratification, and management of overlapping and distinct disease risks, with an emphasis on understanding how these risks interplay and can be mitigated to improve healthspan. Pleiotropic interventions which produce multiple positive effects on health represent an efficient path to improve health outcomes (83)(84)(85)(86). For example, patients with anxiety or depression, rheumatoid arthritis, diabetes, hypertension, and cancer have demonstrated positive health improvements following weight loss (87,88). Moreover, applying weight reduction strategies early in adolescence and childhood delays the onset of multiple chronic conditions later in life (89) which underscores the need to consider known interventions and their optimal timing to enhance protective pathways, versus the traditional approach of mitigating known disease pathways (90). Exercise has been demonstrated to both slow disease progression and prevent chronic diseases (90). Mental stimulation and physical activity have also been shown to reduce the risk of MCI (64). Improved sleep duration is also known to ameliorate inflammatory cytokines, mental health problems, and other outcomes of interest for healthy aging (92). In addition, factors such as reliable access to health care, social support, adherence to medications, reducing environmental air pollution, and activities such as mindfulness meditation have proven effective in improving risk factors and long-term negative health outcomes (93)(94)(95)(96)(97)(98). The potential to combine multiple effective interventions, in addition to identifying the optimal time of life and intervals to test for chronic diseases is a promising path to develop effective preventive strategies and promote better health.Many age-related conditions share risk factors and often coexist as multimorbidities (MM) requiring simultaneous management in individuals (99). MM prevalence is higher among minorities and disadvantaged groups (100). African Americans and Hispanics face heightened risks and mortality rates from these conditions. The COVID-19 pandemic highlighted the increased risk and health disparities in older adults with MM (101). Furthermore, African Americans have a higher incidence of neurodegenerative diseases (102,103). An understanding of the mechanisms and factors that may allow some stressed or disadvantaged groups to maintain healthy aging despite adverse exposures might provide insights into the protective role of lifestyle interventions or other interventions against cognitive decline and age-related diseases to improve health trajectories. Clinical trials focused on aging research need to ensure inclusive representation of minorities, older adults, and individuals from disadvantaged groups to unravel the complexities of health span and diverse aging pathways.Multiple detailed longitudinal measurements are essential to better evaluate an individual's health and disease status. The analysis of extensive data sets necessitates the use of machine learning (ML), artificial intelligence (AI), and large language models (LLMs) (104). These technologies hold significant promise for personalized care, early disease detection, and targeted interventions, thereby providing new avenues for preventing and managing age-related diseases and identifying individual aging pathways. Technological advancements, such as wearable devices that offer continuous health monitoring, can focus on the unique interplay of genetics, environment, and lifestyle factors. This approach facilitates the development of personalized preventive and treatment strategies for age-related chronic diseases ( 105) . Closing the gap between lifespan and healthspan requires the creation of novel strategies to make age-related diseases more predictable, preventable and manageable. Gaining insights into the essential elements that maintain balance throughout life and the factors that disrupt this balance could lead to the identification of novel diagnostic markers and treatment targets (106, 107). Implementing longitudinal studies in clinical research is expected to identify critical periods for effective interventions. The use of cutting-edge technologies to compile comprehensive and diverse datasets throughout life will accelerate discoveries and their application in clinical settings. Achieving the ambitious research goals set forth in this workshop demands interdisciplinary collaborations to address the complexities of aging and early disease detection. Prioritizing the inclusion of patient perspectives and those from marginalized communities in all research phases is essential, as is the commitment to moving research findings from the laboratory into clinical practice. Representation of minorities and marginalized groups Best practices multimorbidities Impact of lifestyle changes across different life stages and populations Identify optimal times for sustainable interventions