Department of Biology, Colgate University, 13 Oak Dr., Hamilton, NY, 13346, USA.
Stanford Law School, Crown Quadrangle, 559 Nathan Abbott Way, Stanford, CA, 94305, USA.
Geroscience. 2024 Apr;46(2):1895-1908. doi: 10.1007/s11357-023-00942-y. Epub 2023 Sep 28.
Aging and cancer seem to be closely associated, such that cancer is generally considered a disease of the elderly in both humans and dogs. Additionally, cancer is a metabolic shift in itself towards aerobic glycolysis. Larger dog breeds with shorter lifespans, and increased glycolytic cellular metabolic rates, die of cancer more often than smaller breeds. The tumor suppressor p53 factor is a key suppressor oncogene, and the p53 pathway arrests cellular proliferation and prevents DNA mutations from accumulating during cellular stress. The p53 pathway is also associated with the control of cellular metabolism to prevent cellular metabolic shifts common to cancerous phenotypes. SIRT1 deacetylates the p53 tumor suppressor protein, downregulating p53 via effects on stability and activity during stress. Here, we used primary fibroblast cells from small and large puppies and old dogs. Using UV radiation to upregulate the p53 system (100 J/m), control cells and UV-treated cells were used to measure aerobic and glycolytic metabolic rates using a Seahorse XFe96 oxygen flux analyzer. We also quantified p53 expression and SIRT1 concentration in canine primary fibroblasts before and after UV treatment. We demonstrate that, due to a higher p53 nuclear to cytoplasmic ratio in large breed dogs after UV treatment, p53 could have a more regulatory effect on large breed dogs' metabolism compared with smaller breeds. Thus, there may be a link between p53 upregulation and inhibition of glycolysis in large breed dogs during times of cellular stress compared with small breed dogs. However, SIRT1 concentrations decrease with age in domestic dogs of both size classes, suggesting a possible release of inhibition of p53 through the SIRT1 pathway with age. This may lead to increased incidences of cancer, especially due to the more pronounced upregulation of p53 with cellular stress.
衰老和癌症似乎密切相关，因此癌症通常被认为是人类和犬类老年人群的一种疾病。此外，癌症本身就是一种向有氧糖酵解转变的代谢变化。寿命较短、糖酵解细胞代谢率较高的大型犬种比小型犬种更容易死于癌症。肿瘤抑制因子 p53 是一种关键的抑癌基因，p53 途径可阻止细胞增殖，并防止细胞应激过程中 DNA 突变的积累。p53 途径还与控制细胞代谢有关，以防止与癌症表型常见的细胞代谢转变。SIRT1 去乙酰化 p53 肿瘤抑制蛋白，通过影响稳定性和活性来下调 p53 在应激过程中的表达。在这里，我们使用从小型和大型幼犬以及老年犬中分离的原代成纤维细胞。使用紫外线辐射上调 p53 系统（100 J/m），用 Seahorse XFe96 氧气通量分析仪测量对照细胞和紫外线处理细胞的有氧和糖酵解代谢率。我们还在紫外线处理前后定量了犬原代成纤维细胞中的 p53 表达和 SIRT1 浓度。我们证明，由于大型犬种在紫外线处理后 p53 的核质比更高，p53 可能对大型犬种的代谢产生更具调节作用，而对小型犬种则不然。因此，与小型犬种相比，在细胞应激期间，大型犬种的 p53 上调可能与糖酵解的抑制有关。然而，两种体型的犬类的 SIRT1 浓度都会随着年龄的增长而降低，这表明随着年龄的增长，通过 SIRT1 途径对 p53 的抑制作用可能会减弱。这可能会导致癌症发病率的增加，特别是由于细胞应激时 p53 的表达上调更为明显。
