Amish who carried the null SERPINE1 mutation lived about 10 years longer:
That’s a huge increase in lifespan, arguably much greater than almost any single factor we know in humans.
The carriers of the gene mutation produce less PAI-1, which results in a greater tendency for blood clots to break down. Those who are homozygous (-/-) for the mutation have an even greater tendency to break down blood clots, which results in a bleeding disorder. That’s the immediate consequence of less PAI-1.
However, the heterozygous (+/-) carriers had longer telomeres, which is a sign of slower aging. They also had less diabetes risk, a 0% diabetes rate compared to 7% in non-carriers, even though body mass index was the same. And they had better cardiovascular risk markers, including lower blood pressure and lower carotid artery thickness, a measure of atherosclerosis.
Clearly, PAI-1 does a lot to promote aging, and having less of it appears to result in longer life.
Amish eat three huge meals per day but do hard manual labor and walk wherever they go (when not in a buggy). No sedentary lifestyle for them.