{
  "abstract": "Introduction Age is a major risk factor for cardiovascular disease. Chronic inflammation and declining immunity are considered central to this risk. Macrophages play a key role in pathogen clearance, arterial lipid handling and tissue homeostasis, but show a functional decline in phagocytosis and chemotaxis with age. We showed macrophages from older individuals show reduced function and identified declining transcription factors MYC and USF1 drive this aged phenotype in primary human and mouse cells. Therapies such as statins and metformin, as well as supplements like fisetin, appear to offer protection from multiple age-associated diseases. We hypothesised that so-called ‘geroprotective’ therapies act to restore macrophage MYC or USF1 and functional decline with age.Methods Human monocyte-derived macrophages (hMDMs) isolated from peripheral blood mononuclear cells (PBMCs) were taken from healthy older donors (≥50 years), and from younger donors (20-30 years). hMDMs were treated with geroprotector drugs including metformin, statins and fisetin, every 2 days for 7 days. Transcription factors (including MYC) and target gene expression were quantified by RT-qPCR. Macrophage functions were assessed for phagocytosis by fluorescent bead uptake and for chemotaxis by transwell migration.Results Several of 11 geroprotectors tested, including simvastatin, fisetin and rapamycin, upregulated macrophage transcription factor expression in older donors. Fisetin treatment restored MYC expression in MDMs from older donors, while USF1 remained unaffected. This MYC restoration was accompanied by improved phagocytosis and chemotaxis, towards the levels seen in young donor MDMs.Conclusion MYC appears a central target for improving the function of macrophages from older individuals, with fisetin and other geroprotective therapies offering potential interventions to reduce immunosenescence and associated chronic cardiovascular diseases.",
  "authors": [
    {
      "affiliations": [
        "University of Sheffield, Sheffield, United Kingdom"
      ],
      "name": "Martha Clements"
    },
    {
      "affiliations": [
        "University of Sheffield, Sheffield, United Kingdom"
      ],
      "name": "Joshua Kimble"
    },
    {
      "affiliations": [
        "University of Sheffield, Sheffield, United Kingdom"
      ],
      "name": "Sheila Francis"
    },
    {
      "affiliations": [
        "University of Sheffield, Sheffield, United Kingdom"
      ],
      "name": "Endre Kiss-Toth"
    },
    {
      "affiliations": [
        "University of Sheffield, Sheffield, United Kingdom"
      ],
      "name": "Heather Wilson"
    }
  ],
  "title": "223 Improving the decline in age-related macrophage function using geroprotective therapies",
  "uid": "ded53aba-f9a1-5bd6-9971-95e29857561b"
}