The world's population is growing older and this is accompanied by increasing incidence in health decline and greater risk for disease. A goal of the proposed study is to develop an accelerated aging model in SIV- infected rhesus macaques undergoing antiretroviral therapy (ART) and test proof-of-concept for delaying or reversing the rate of aging, inflammation, and disease. This strategy is based on the observation that while ART is tremendously successful in extending the survival of HIV-infected individuals, there occurs an accelerated aging process exemplified by earlier onset of chronic inflammatory diseases compared to uninfected individuals of similar age. Macrophages are key cells involved in innate immunity, are central to regulating inflammation and contribute to pathogenesis during both aging and HIV infection. During aging, macrophages become dysfunctional and are less able to maintain homeostasis leading to increased susceptibility to infectious and non-communicable diseases. An accelerated model of aging in rhesus macaques will reduce the experimental timeline for testing anti-aging strategies in an animal model that is directly applicable to humans. Our hypothesis is that SIV-infected and ART-treated rhesus macaques undergo accelerated aging similar to humans, and that short-term depletion of senescent macrophages will reverse or delay the onset of accelerated aging sequelae.
The specific aims are:
Aim 1. Develop a model of accelerated aging in SIV-infected and ART-treated rhesus macaques. Rhesus macaques of 10-12 years of age (~30-40 years of age in humans) will be infected with SIV and administered ART. Based on preliminary results, we hypothesize that initiating ART after blood monocyte turnover rate increases 20% over baseline levels will result in a faster rate of aging based on time until and level of inflammation, tissue damage, and disease. Conversely, we expect that if ART is initiated before blood monocyte turnover increases, the rate of aging and immune senescence will be slower. The results will determine which ART initiation schedule will be applied for targeting senescent or dysregulated macrophages.
Aim 2. Determine if replacement of senescent dysregulated macrophages ameliorates inflammation in SIV-infected macaques undergoing ART to reverse accelerated aging. The ?middle-aged? rhesus macaques will be infected with SIV and given ART before or after monocyte turnover increases, depending on which ART timing produces the most accelerated rate of aging. We will then administer liposome-alendronate /clodronate (bisphosphonates) and hypothesize that this will remove senescent long-lived macrophage and stimulate endogenous cell recruitment or trafficking (e.g. monocytes) for replacement with fresh functional macrophages that will better regulate inflammation and reverse the rate of accelerated aging.
The proposed research is relevant to public health for further developing a model of accelerated aging that utilizes the nonhuman primate model of SIV infection and antiretroviral therapy (ART). This is based on observations that humans infected with HIV and administered ART exhibit accelerated aging, and tests an approach to remove dysfunctional long-lived macrophages in attempt to reverse or delay the onset of accelerated aging and inflammatory disease. The results will move work forward to reduce the risk for developing chronic diseases in the elderly.
|He, Ziyuan; Allers, Carolina; Sugimoto, Chie et al. (2018) Rapid Turnover and High Production Rate of Myeloid Cells in Adult Rhesus Macaques with Compensations during Aging. J Immunol 200:4059-4067|