Aging is a fundamental and dynamic process that occurs in all complex life forms. Yet, little is known about the mechanisms that drive aging. We recently identified a novel anti-inflammatory pathway associated with a small peptide hormone, PEPtide Inhibitor of Trans-Endothelial Migration (PEPITEM), circulating in the plasma of healthy individuals. PEPITEM plays an important role in systemic homeostasis of the immune system by maintaining a stable internal state. Moreover, the natural waning of PEPITEM expression during human ageing in the immune system is associated with diseases of old age1. Importantly, synthetic PEPITEM can restore homeostasis in ex vivo assays using cells from patients with these diseases, as well as in animal models of disease.
Unfortunately, gerontology, the study of aging, does not yet possess an understanding of the integrated function of such pathways across different organs and tissues. Here we aim to use the biology of the PEPITEM pathway to develop unique in silico models of systemic homeostasis, which can be applied to the ageing process.
A fascinating aspect of the differences in the healthspan of the human population is the possibility that during evolution specific pathways have arisen to counteract the functional degradation of critical metabolic and immune pathways. Crucially, the premature loss of these leads to the onset of chronic disease with an associated burden of morbidity and an increased risk of early death. Such mechanisms would have to be systemic and involve cross talk between numerous organ systems, including the immune system, to counter aging processes at the level of the whole organism.
To date our understanding of systemic homeostasis in gerontology is rudimentary. However, the existence of ‘anti-senescent’ pathways is evidenced by the discovery of the protein hormone, α-klotho, loss of which in mice is associated with accelerated senescence and early death, while over-expression is associated with a 30% extension of lifespan2. Interestingly, both PEPITEM and klotho circulate in a secreted form so that they can interact with a number of physiological systems to achieve systemic homeostasis.
Currently we have no integrated models of the systemic function of anti-senescent hormones and although we and others have identified important functions of PEPITEM, much remains unknown. Hypothesis: PEPITEM is a central node in a network of inflammatory cells and molecules that controls homeostasis. Changes in the network prematurely drive the ageing process and increase susceptibility to age-related diseases, including sarcopenia (the loss of muscles) and osteoporosis (deterioration of bone) and Immune mediated inflammatory diseases ( IMIDs). Mathematical models have delivered insight into signalling pathways in other systems (e.g. the cell cycle) by complementing experimental studies of individual molecules and providing network level perspective of the interacting elements.
We will construct the first mathematical model of the PEPITEM signalling network to deliver mechanistic insight into peptide interactions with upstream and downstream molecules and to predict how the network is reprogrammed during aging. Models of different cell types that can interact via chemical signalling will be generated. In combination these models will explain how molecular and cellular networks ensure resilience to perturbations in homeostasis, and how network changes during aging decrease this capacity, and increase the risk of loss of homeostasis and chronic inflammation.
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