Fruit flies fed less protein as larvae lived longer, and a storage protein carried the “memory”

Eating less, without going hungry for nutrients, makes many laboratory animals live longer. A less familiar idea is that the diet of the very young can matter for the rest of life. Nearly a century ago, restricting food early in life was already suggested to lengthen life in rats and in water fleas, and similar effects have since been seen in fruit flies and mice. What nobody knew was how the body “remembers” a diet it ate long ago, especially in an insect that rebuilds its whole body when it turns from a maggot-like larva into a fly.

A team with corresponding authors at RIKEN in Japan now proposes an answer in flies: a protein the larva stockpiles, which ends up limiting how much protein the young adult can make. Making proteins from the instructions in genes is called translation; it happens on ribosomes, small machines in the cell that are themselves built from dozens of proteins.

What they did

• The diet switch. Flies normally get their protein from yeast. Partway through larval life (about 68 hours after the egg was laid) the team moved larvae from food with 8% yeast to food with only 2% or 1%. Once the flies emerged as adults, all of them ate the same standard food. The team calls this “early-life protein restriction”.
• Tracing the food. Larvae were raised on a synthetic diet in which two amino acids (the building blocks of protein) carried a slightly heavier, harmless form of their atoms. Adults then got a differently labelled version. A mass spectrometer, which weighs molecules, could then tell which proteins in the adult head were built from larval food and which from adult food.
• Testing a suspect. The team switched off the gene for a storage protein called Lsp2 in the fat body, the fly's combined liver and fat tissue, at different stages, and checked protein-making and lifespan. They also tried larval diets low in single amino acids.

What they found

• Longer lives. Flies of both sexes that had been protein-restricted as larvae lived longer, even though they ate normally as adults. Adding a mix of amino acids back to the poor larval food removed the benefit, pointing to protein itself rather than other parts of yeast.
• A cost. These flies were smaller (females weighed up to 28% less), paler, and the females laid fewer eggs early on.
• Larval food lingers. Three days into adult life, about 64% of the proteins in the head were still made with larval amino acids; by day six it was about 46%. Ribosome proteins were prominent among them.
• Fewer ribosomes, less protein-making. Protein-restricted flies had fewer ribosome proteins and made less protein during their first week as adults. After that the difference faded.
• Lsp2 is the link. Restricted flies had less Lsp2, both carried over from the larva and newly made. Switching off Lsp2 copied the key effects: fewer ribosome proteins, less protein-making and a longer life. Combining it with the larval diet did not add extra years, which suggests both work the same way. Unlike the diet, it did not reduce egg-laying.
• Specific building blocks. Lsp2 is rich in two amino acids, phenylalanine and tyrosine (about 2 and 2.7 times more than the average fly protein). Cutting tyrosine, phenylalanine or histidine from the larval diet lowered Lsp2 and lengthened life; cutting isoleucine, which is scarce in Lsp2, did not.

What to keep in mind

• A missing link, by the authors' own account. The team could not directly show that fewer ribosome proteins cause the longer life, because no tool exists to raise ribosome proteins on their own. That step rests on earlier work showing that damping protein-making in a fly's first ten adult days extends lifespan.
• Not all good news. Switching off Lsp2 only in the first adult week lengthened life, but combined with the poor larval diet it shortened it. The diet also lost its benefit when adult food had no amino acids or three times the usual amount.
• Open questions. How the stored amino acids are released and used remains unclear. The protein measurements show relative, not absolute, changes, and most experiments were not blinded (the person who planned them also did them), though lifespan tests were run by someone else where possible.
• Flies, not people. Mammals have no direct counterpart of Lsp2. The authors only speculate that abundant blood proteins such as albumin might play a similar role. Nothing here suggests that children or adults should eat less protein.

Why it matters

It has long been known in people that nutrition early in life can affect health decades later. This study offers a concrete, testable mechanism in an animal: a stockpiled protein that records the juvenile diet and sets how hard the young adult's protein factories run. The authors link it to the observation that rapamycin, a prescription drug with side effects that dampens the mTOR growth signal, extends lifespan in many species, most strongly when given early in life. Whether anything like this works in mammals is still an open question.