L-leucine

Leucine is the amino acid that switches on muscle protein synthesis, and that is not a marketing claim. It activates mTORC1 through the Sestrin2 sensor, and a meal's leucine content predicts the size of the post-meal synthetic response better than its total protein does.

That mechanism is what got it into a lifespan study, though pointing in an awkward direction. Restricting mTOR signalling is the single most reproducible way to extend mouse lifespan, and rapamycin does it pharmacologically. Leucine does the opposite. The Interventions Testing Program tested it anyway, in the 2017 cohort, on the healthspan reasoning that preserving muscle in old age might extend life even if the signalling direction looked wrong.

It did not. In that cohort the combination of rapamycin plus acarbose started at 9 months produced longer male lifespan than either drug alone had in previous cohorts, and captopril produced a small significant female benefit. Leucine was one of four agents that produced no lifespan benefit at all.

The human evidence is more interesting than the null. Pooling 16 trials in 999 older people, leucine supplementation increased lean body mass by 0.99 kg and body weight by 1.02 kg against controls, with the effect concentrated in participants who were already sarcopenic. It did not increase muscle strength. And in 30 healthy elderly men given 7.5 g daily for three months, there was no change in muscle mass or strength at all.

The pattern is consistent: leucine helps when the problem is inadequate protein stimulus, and does nothing when it is not.

A lifespan null from this programme is a real, expensive, well-powered finding, and it is narrower than it sounds. What was tested was one concentration in the diet, started at one age, in one mouse strain, with death as the endpoint. A null tells you that this dose, in these animals, did not move that endpoint. It does not tell you the compound is inert, that a different dose would also fail, that the mechanism is wrong, or that the reason people actually take it has been refuted. Those are separate questions and most of them were never asked. The failure mode this site is trying to avoid runs in both directions: treating a mouse lifespan positive as proof that a supplement works, and treating a mouse lifespan null as proof that it does nothing.

Leucine also raises a tension worth stating openly, because most supplement content picks one side of it and pretends the other does not exist.

The most reproducible lifespan-extending intervention in mice is inhibition of mTOR, whether by rapamycin, by protein restriction or by restriction of specific amino acids. Leucine is the most potent dietary activator of mTORC1 that exists. If mTOR signalling is the lever, leucine is pulling it the wrong way.

Against that, muscle mass in older adults predicts function and independence, and sarcopenia is a real clinical problem that mTOR activation addresses. Both things can be true. What the ITP result adds is that in mice, at the dose tested, taking leucine did not shorten life either. The cohort simply showed no lifespan effect in either direction, which is a less dramatic finding than either camp would prefer.

The Interventions Testing Program is funded by the National Institute on Aging and run in parallel at three independent laboratories, in Bar Harbor, Ann Arbor and San Antonio. It uses UM-HET3 mice, a four-way genetic cross, so no result can be an artefact of a single inbred background. Both sexes are studied, cohorts are sized to detect roughly a 10 percent shift in lifespan, compounds are fed in the diet from a stated starting age, and the programme commits in advance to publishing negative results alongside positive ones. That last commitment is why this batch can exist at all: almost no other part of ageing research reliably tells you what did not work.