Geriatrics - The NOMIS Foundation

Disease tolerance is a defence strategy essential for survival of infections, limiting physiological damage without killing the pathogen^1,2. The disease course and pathology an infection may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Because successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defence strategy would change with age. Animals infected with a 50% lethal dose (LD₅₀) of a pathogen often show distinct health and sickness trajectories due to differences in disease tolerance^1,3 and can be used to define tolerance mechanisms. Here, using a polymicrobial sepsis model, we found that, despite having the same LD₅₀, aged and young susceptible mice showed distinct disease courses. In young survivors, cardiac Foxo1 and its downstream effector Trim63 (MuRF1) protected from sepsis-induced cardiac remodelling, multi-organ injury and mortality. Conversely, in aged hosts, Foxo1 and Trim63 acted as drivers of sepsis pathogenesis and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and indicate that disease tolerance genes show antagonistic pleiotropy.

Geroprotectors are compounds that slow the biological aging process in model organisms and may therefore extend healthy lifespan in humans. It is hypothesized that they do so by preserving the more youthful function of multiple organ systems. However, this hypothesis has rarely been tested in any organisms besides C. elegans and D. melanogaster. To determine if two life-extending compounds for Drosophila maintain a more youthful phenotype in old mice, we asked if they had anti-aging effects in both the brain and kidney. We utilized rapidly aging senescence-accelerated SAMP8 mice to investigate age-associated protein level alterations in these organs. The test compounds were two cognition-enhancing Alzheimer’s disease drug candidates, J147 and CMS121. Mice were fed the compounds in the last quadrant of their lifespan, when they have cognitive deficits and are beginning to develop CKD. Both compounds improved physiological markers for brain and kidney function. However, these two organs had distinct, tissue-specific protein level alterations that occurred with age, but in both cases, drug treatments restored a more youthful level. These data show that geroprotective AD drug candidates J147 and CMS121 prevent age-associated disease in both brain and kidney, and that their apparent mode of action in each tissue is distinct.

Publications in Geriatrics by NOMIS researchers

Disease tolerance and infection pathogenesis age-related tradeoffs in mice

Geroprotective effects of Alzheimer’s disease drug candidates