Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults’ immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.
Actinic keratosis (AK) is a skin disease that is characterized by clinical and subclinical cutaneous lesions in sun-exposed areas. It is a considerable burden due to its high occurrence in middle-aged and older populations, as well as its propensity to progress to invasive cutaneous squamous cell carcinoma. The mammalian target of rapamycin (mTOR) pathway is critical in carcinogenesis and tumor development, and it has been shown to be over-activated during skin tumorigenesis, particularly upon ultraviolet (UV) radiation exposure, the key risk factor for AK. However, the ability of mTOR inhibitors to treat AK is not well documented. Herein, we evaluated the effect of oral mTOR inhibitors in vitro and in vivo and found that mTOR inhibitors lower keratinocyte cell proliferation in vitro and both clear and prevent AK and cutaneous squamous cell carcinoma (cSCC) in a UV-B induced SKH1 hairless mouse model of disease. mTOR inhibition reduced the number and size of skin lesions and the frequency of cSCC, resulting in a considerable reduction in disease severity. mTOR inhibition prevented lesion occurrence in areas of field cancerization, without affecting epidermal thickness, keratinocyte proliferation in vivo, or the presence of p53+ cells. Our findings indicate that, when appropriately dosed, oral mTOR inhibitors provide a safe home-based systemic treatment alternative with significant benefits to patients over current topical treatment options.
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