Step 1: Preheat oven to 375°F (190°C). Grease a 9×13 inch baking dish.
Step 2: Cook pasta according to package directions until al dente. Drain well and set aside.
Step 3: In a large pot or Dutch oven, melt 4 tablespoons of butter over medium heat.
Step 4: Whisk in the flour and cook for 1-2 minutes, stirring constantly, until a smooth, pale roux forms.
Step 5: Gradually whisk in the warm whole milk and heavy cream until smooth. Continue whisking until the sauce thickens and begins to simmer, about 5-7 minutes.
Step 6: Remove the pot from heat. Whisk in the Dijon mustard, salt, black pepper, garlic powder, onion powder, and nutmeg.
Step 7: Add 3 cups of shredded sharp cheddar and 1.5 cups of shredded Gruyere (or Colby Jack) to the sauce, a handful at a time, stirring until completely melted and smooth after each addition. Reserve the remaining cheese for the topping.
Step 8: Add the cooked and drained pasta to the cheese sauce. Stir gently until all the pasta is thoroughly coated.
Step 9: Pour the mac and cheese mixture into the prepared baking dish, spreading evenly.
Step 10: In a small bowl, melt the remaining 2 tablespoons of butter. Stir in the Panko breadcrumbs and the reserved 1 cup of sharp cheddar and 0.5 cups of Gruyere (or Colby Jack) cheese.
Step 11: Sprinkle the breadcrumb-cheese mixture evenly over the top of the mac and cheese.
Step 12: Bake for 20-25 minutes, or until the topping is golden brown and the mac and cheese is bubbly around the edges. Let rest for 5-10 minutes before serving.