Connecting surgical stress to sex-dependent vulnerabilities in aging and aging hallmarks

Abstract It is becoming clear that studies relying solely on animals housed under conventional, unprovoked conditions, rather than the same variety of stressors normally encountered by free-living humans, has limited our understanding of how the exposome impacts aging biology. Physiologic resilience, which is a dynamic process defined by the ability for biologic systems to cope following a stress-induced perturbation to restore homeostasis, may represent an important determinant of how stressors impact aging hallmarks. Resilience declines with age, can be further compromised by stressful stimuli, and deterioration of multiple aging hallmarks likely underlie in part this phenomenon. Our unpublished data have established an approach to quantify resilience to a single surgical stress episode that can predict aspects of later life healthspan and lifespan. Moreover, we demonstrate that a single surgical stress episode at mid age can significantly shorten male, but not female lifespan. This is accompanied by evidence of persistent changes in male aging hallmarks 7 months at the inflammatory, metabolic and epigenetic level. Here, we hypothesize that alterations to aging hallmarks by surgical stress is a function of resilience, modified by sex differences, and triggered by inflammation to drive destabilization of other hallmarks. Moreover, gerotherapeutics capable of dampening early triggers could act to improve resilience and preserve aging hallmarks. In the R61 phase, we will first establish the spatial, temporal, and sex-dependent impact of surgical stress on aging hallmarks and relationship to dynamic resilience for prioritizationThis will be done by quantifying relative resilience to surgical stress in CB6F1 hybrid mice and determine the impact of surgery performed at either 8, 13 or 18 mo of age on the accumulation of deficits to aging hallmarks at 22 mo age for prioritization of age of surgery, hallmarks and tissues to examine. We will further develop a chemically-induced mid-aged mouse model of female menopause for studies on sex differences to surgical stress. Based upon these studies, the R33 phase will determine the ability of gerotherapeutics to counteract surgically-induced impairments to aging hallmarks and healthspan prioritized in Aim 1 and survival in mice. Moreover, we will evaluate the role of menopausal status on dynamic resilience, hallmarks, healthspan and in mitigating the detrimental effects of survival observed in male mice.