A single lung contains dozens of distinct cell types, and each one handles protein damage in a surprisingly different way—a discovery that overturns the long-held assumption that all cells respond uniformly to stress. This matters because as we age, proteins increasingly misfold and clump together, a hallmark of frailty and age-related disease. Current knowledge of how cells manage this problem comes almost entirely from fast-growing cancer cells, which behave nothing like the diverse, non-dividing cells in real human tissues. The researchers have also found that senescent cells—aged cells that accumulate with age and drive inflammation—rewire their protein quality control systems, but in ways that depend on the cell type they came from. Indiscriminately removing all senescent cells, as some experimental therapies do, could backfire because some of these cells help with tissue repair. If successful, this work will identify both universal and cell-type-specific weaknesses in how lung cells handle protein stress. That could yield precise targets for drugs that protect healthy cells or selectively kill diseased ones—including senotherapeutics and protein-degrading drugs already of high pharmaceutical interest. The project also creates new human cell-culture models that could reduce reliance on mouse studies in ageing research.
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A cell is an incredibly complex machine, with billions of highly-dynamic components whose production and destruction must be tightly regulated. Proteins, arguably the most diverse components, first must fold into their correct structures to function. Misfolded proteins not only fail to do their jobs; they also interfere with other cellular processes. Consequentially, cells have evolved a vast repertoire of protein quality control (PQC) systems to minimise disruption by misfolded proteins and restore protein homeostasis (‘proteostasis’). As imbalanced proteostasis is a hallmark of ageing and ageing-related diseases, interventions that boost ailing proteostasis capacities are highly sought-after for promoting healthy ageing across the lifecourse (BBSRC priority). Given the evolutionary conservation and vital importance of PQC for maintaining health, it is assumed that different cells respond uniformly to environmental stresses that increase protein misfolding. However, we recently discovered that PQC systems of different human cell types from the same tissue respond in strikingly distinct manners to the same stressor. Therefore, our current knowledge of human PQC—which stems largely from rapidly-dividing cancer models—needs re-evaluation to realise the promise of proteostasis-boosting interventions. Furthermore, with ageing, tissue composition drifts, including the accumulation non-dividing ‘senescent’ cells that drive chronic inflammation. Based on studies demonstrating that senescent-cell removal improves mouse healthspan, lifestyle and therapeutic interventions to remove senescent cells in humans are in various stages of pre-clinical and clinical testing. However, certain senescent-cell populations serve protective roles in tissue repair and stress-resilience, suggesting that indiscriminate removal of senescent cells will be detrimental to long-term health. Importantly, we have discovered that stress-induced PQC is re-wired in senescent cells—but this re-wiring differs depending on the cell-type of origin. Our findings suggest distinct PQC strategies operate in different cell-types to mitigate protein misfolding stresses in complex tissue environments. Here, we will identify both universal and cell-specific vulnerabilities that these distinct PQC strategies leave exposed. This work focuses on the lung: a tissue with clear ageing-related functional decline and susceptibility to senescent-cell-associated diseases currently being targeted in ‘senotherapeutic’ clinical trials. We will combine multi-dimensional proteomics, high-resolution live-cell imaging, and specialised 2D/3D primary human cell-culture systems, to evaluate PQC and resilience at cell and tissue levels. Addressing BBSRC’s “frontier bioscience: understanding the rules of life” remit, we will establish the diversity, mechanisms, and consequences of distinct PQC across cell-types. First, we will characterise the PQC diversity in a complex tissue environment. Next, we will determine whether distinct PQC is caused by differences in the identity of the proteins that misfold upon stress between cells, or by the same misfolded proteins being handled differently by PQC systems. Finally, we will define novel cell-specific stress vulnerabilities, and identify the underlying PQC mechanisms. These objectives will lay the groundwork for interventions to rescue vulnerabilities in healthy cells, or exploit those inherent to pathologic cells, with the ultimate goal of promoting life-long health and resilience. We will generate novel, actionable targets for emerging therapeutic modalities of great pharmaceutical interest (e.g. senotherapeutics; PROTACs and other targeted protein-degraders). This research tackles the interplay between two well-established drivers of age-associated frailty, exemplifying BBSRC’s “integrated understanding of health” priority, especially “the biological basis of ageing”. Furthermore, the novel human senescent-cell co-culture models will aid the priority for “refinement, replacement, and reduction in research using animals” across the senescence and ageing fields, which are currently dominated by mouse studies.
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