Healthy Aging As part of our series on emerging life sciences, the editor speaks with Drs Vince C. Marconi MD and Kris Ann Oursler MD, principal investigators at Emory University and Virginia Tech, respectively, about their research pathway into healthy aging and their passion for advancing whole-body health. Drs Marconi and Oursler reflect on personal and professional experiences motivating their research and the road ahead as we begin 2023. 1. Can you share a life event or activity that informs your view on healthy aging? VCM: After returning from overseas military deployment to Iraq and relocating to a new job in Atlanta, I struggled with both physical and psychosocial challenges. The usual, siloed strategies to address these challenges fell short. After discovering a body of literature demonstrating the biological impact of the experience of stress on the immune system through neuroendocrine pathways,[1-7] I shifted my approach to incorporate an integrative strategy in my personal and professional life. Of particular interest, the interplay, history and mechanistic details of immune response to viral infections (HIV, SARS-CoV-2), psychological trauma, and long-term comorbid burden have broad implications for healthy aging. Following these collective insights, we began an exploration of whether stress and trauma experienced by patients with HIV in our clinic might be mitigated by a special kind of meditation and mindfulness practice known as Cognitively-Based Compassion Training (CBCT®), developed by a team working with the Dalai Lama and Emory University investigators. In the initial randomized, active attention-control trial, we found increasing CBCT practice time reduced objective levels of circulating inflammatory factors and subjective psychological stress.[8] Demonstrating a mechanistic link between psychological experience and biological markers for patients from an inner city HIV clinic and the benefits of using a non-pharmacologic intervention. These data were convincing enough for me to continue pursuing this general approach in my health sciences research. KAO: My career path has also been informed by my research on patients with HIV. Effective antiretroviral therapy was just becoming feasible when I joined the faculty in the Department of Medicine at the University of Maryland. I observed firsthand as middle-aged veterans with HIV would succumb to cancer and myocardial infarction after successfully controlling viral burden, a task that frequently required first overcoming drug addiction and home insecurity. I was fortunate to have the opportunity to explore the phenotype of biological aging in people with HIV (PWH) in the Veterans Cohort Study (VACS) under the mentorship of Amy Justice. Trained as an Infectious Diseases physician, the complexity of aging as a process was new to me. This quickly changed when the late Andrew Goldberg invited me to join the Division of Geriatrics and Gerontology, which championed physical activity and exercise training modalities as a strategy for healthy aging. A pivotal life event for me was when a veteran named Mr. K. who had HIV, diabetes and peripheral vascular disease volunteered for an exercise trial we were conducting. The trial's screening treadmill test showed previously undiagnosed ischemic heart disease which led to open heart surgery, and, because of the early diagnosis, Mr. K. had a remarkable recovery. Mr. K. returned to complete the exercise trial, resulting in complete resolution of his arterial claudication and improved diabetes. Multiple benchmarks of healthy aging are improved with exercise – from sarcopenia to polypharmacy. I was also struck by the positive impact that exercise had on Mr. K, not just his comorbidity and quality of life, but also his resilience. 2. What scientific insights have informed your view that life in the modern era is often characterized by chronic un-wellness? VCM: Most low and middle-income countries have a greater proportion of deaths due to infectious diseases and nutritional deficiencies.[9] As these countries increase their economic well-being, chronic non-communicable diseases (NCD) and mental health conditions emerge as an important cause of death. A debate persists as to whether this reflects a survivor bias whereby individuals avoiding infectious disease deaths then live long enough to develop age-related comorbidities or if technological advancements have resulted in more sedentary lives, increased psychological stress, more processed foods, and disintegrated social networks increasing the prevalence of NCDs and mental health disorders. Since the late 1930's, the U.S. has climbed to the top globally in gross domestic product per capita without relinquishing this spot in nearly 100 years. Despite this standing, NCD's and mental health conditions continue to increase, in contrast with our success in treating malaria, smallpox, yellow fever, tuberculosis, and diarrheal diseases. Notably, deaths from cardiovascular disease (CVD), influenza, and pneumonia have substantially decreased since 1950 while cancer deaths remained stable. However, dementia, suicide, drug, and alcohol related deaths have substantially increased over the past 20 years. Along with these changes, the U.S. (the only high-income country to do so) has experienced a decline in life expectancy since 2008, well before COVID-19 had an appreciable impact. 3. Can you elaborate on healthy aging as a holistic outcome? KAO: Viewpoints on holistic outcomes are as diverse as the definitions of the word holistic. One I favor is by Patrick Pietroni who defined the patient as “a multidimensional being, possessing body, mind and spirit, all inextricably connected, each part affecting the and whole and the whole being greater than the sum of the parts”.[10] Older clinicians will recall the “biopsychosocial model”.[11] Younger clinicians more often spend questionable time looking at the computer screen rather than their patient's face or life history. For me, healthy aging is more than the absence of disease. It requires more than multidimensional integrated treatment. Relating back to my first lesson in gerontology, healthy aging in an individual requires consideration of “quality” in the biology of aging in concert with social determinants of health and, of course, prevention of disease and disability. VCM: Because neurohormonal pathways that connect psychosocial experience with the immunologic milieu determine disease emergence, progression, and response, I think that approaches that address the synergistic relationships between mind (cognitive/behavioral), body (motor/sensory/autonomic/cellular/molecular), and spirit (affective) domains will be most successful at optimizing quality of life and healthy aging. In this synergy model, alterations in one domain invariably create a disruption in the other. Therefore, any intervention affecting one of these areas could be potentially offset or be augmented through compensatory changes in other domains. 4. Where do you see progress in mechanistic pathways that underlay healthy aging? VCM: Substantial progress has been made in translational geroscience over the past decade due in part to advances in systems biology and multi-omics technology. Over the next decade, we anticipate the discovery of composite markers that capture both global senescence and organ-specific aging phenotypes. These composite markers should incorporate functional assessments, multi-morbidity, and biological profiles with special attention to bioenergetic, immunologic, neurologic, and hormonal mechanistic pathways. Concurrent with these efforts, proof-of-concept trials of interventions targeting these pathways (hypothalamic-pituitary-axis, mTOR, Jak-STAT, NF-kB, etc.) will provide invaluable insight into the strategic design of therapeutics with the express purpose of mitigating adverse aging outcomes. 5. As guest editors of the upcoming special issue, “Healthy aging: linking causal mechanisms with holistic outcomes”, how do you measure success? KAO: Aging transcends all clinical disciplines and is driven by mechanisms from basic science to behavioral health. Therefore, my first goal of the issue is to encourage collaboration across not just across disciplines but also research approaches. Funding, and thus research opportunity, tends to be placed in a single area of one of these domains and needs updating to accommodate the growth in interdisciplinary research in aging. This objective would be realized by more announcements akin to the Paul B. Beeson Emerging Leaders Career Development Award in Aging. A second goal relates to my research focus, and personal interest, in exercise. I would like to see translational research in diverse areas coalesce into major advances that prioritize healthspan over lifespan. Another personal measure of success would be for me to continue to ride my bike over mountains for the next 2 decades. VCM: A key challenge for researchers pursuing holistic approaches to scientific inquiry is the need to connect seemingly disparate disciplines and concepts, which requires innovative paradigms and novel perspectives. Since each discipline possesses a unique culture and intellectual foundation, bridging these divides is compulsory for cross-cutting investigation to thrive. It is conceivable that this thematic issue could serve as an incubator for investigators to explore and cultivate these collaborations. Measures of success would include (1) funded grants and calls for proposals employing these strategies, (2) publications which arise beyond this thematic issue, and (3) conferences or meetings which include a focus on holistic science and that embrace complexity. A podcast based on this interview and a special collection of papers related to healthy aging will be published in our partner journal Aging Cell in mid-2023.