My research program lies in one more focused and two broad and interconnected areas of aging research and intervention. a. Infection and immunity with aging. Over the past 15 years my group has systematically investigated alterations with aging of the immune system and its interactions with acute and persistent microbial pathogens. In the process, we have discovered and described multiple and cumulative defects in microbial detection, initial recognition and uptake by the innate immune system, processing, presentation and initiation of the adaptive immune response, generation of effector immunity and of memory responses and homeostasis and long-term regulation of lymphocyte subsets. We have followed up that work with attempts to correct molecular and cellular defects using novel vaccination and thymic rejuvenation models in mice and non-human primates, and by validating the observations from these models in humans, as well as deriving primary data from human subjects on these same topics. . There is no doubt that I will continue this work on both tracks: primary, basic research will be performed in the mouse, human or NHP model, and, depending on suitability, may be also validated in other models. Translation will be performed in human or NHP models, where we will seek to intervene therapeutically to improve outcomes of infection in older adults. The ultimate goal for the next decade of my career and beyond will be to produce palpable improvement in the immune system of older adults so as to increase success of vaccination and resistance to infection. b. Inflammation in aging: causes and consequences. This is a broader interest of mine, that intersects not only with the immune system, but also with microbial colonization, gut barrier function, metabolism, adiposity and energy sensing. Why do older adults exhibit increased signs and markers of systemic inflammation? Is this inflammation multifactorial, or does it lie in an overexcitable immune system, or increased proinflammatory adipose mass or altered microbial colonization and increased permeability of different (mostly mucosal) barriers? Or a combination thereof? Can we conclusively intervene against diseases of aging and, perhaps, normal aging itself, by modulating inflammation? Microbiome sequencing, deliberate colonization with specific microflora, depletion of different immune cell subsets and/or antibiotic and anti-inflammatory treatments as well as metabolic intervention will all be combined to understand and treat these conditions and their impact upon aging. c. Interventions to extend healthspan and longevity. Advances in the biology of aging have now reached the point where it is no longer unrealistic to put the incredible promise of health-prolonging anti-aging intervention to use in humans. One must: (i) understand effects of life extension in model organisms upon healthspan and end organ function; (ii) carefully dissect signaling pathways that lead to the measured outcomes and validate them in higher primates or humans; and (iii) intervene along these pathways to apply life and healthspan extension treatments. We are currently in the process of multidisciplinary collaborative studies to understand end-organ function and quality of life in the course of different mTOR pathway manipulations in adult and aged mice. Drug discovery program will follow to optimize treatments, and translation will be attempted subsequently in primates and humans.
