1. Diet/Lifestyle
A poor lifestyle and diet can leave even those who excercise and have good genetics in an unhealthy situation.
Exposure to chemicals, i.e. tobacco, alcohol, chemical solvents, etc can cause harm even to the most genetically gifted individual. E.g. a chemical worker exposed to benzene has an increased cancer, a worker who had been exposed to asbestos has an increased cancer, a smoker has an increased cancer risk
Poor diet would lead to vitamin and mineral deficiencies that could not be overcome if the diet were to continue.
Even the most genetically gifted individual is doomed if they are exposed to the wrong environmental contaminate.
2. Genetics
Pick any genetic disease.
3. Excercise
Those who excercise probably follow number 1.
4. Hormone Optimization
Most times homeostasis is broken by those who have the mentality that more is better. Hormone optimization does not ultimately determine optimum health and fitness.