Knocking out Lsp2, a fat body adipokine that drives ribosomal protein overproduction after protein feeding, extended fly lifespan by 14–28% without fertility cost and sidestepped rapamycin, the only geroprotector in large-scale trials
Knocking out Lsp2, a fat body adipokine that drives ribosomal protein overproduction after protein feeding, extended fly lifespan by 14–28% without fertility cost and sidestepped rapamycin, the only geroprotector in large-scale trials
On September 23 Nature published a paper by Zongzhao Zhai's group at Hunan Normal University (China). In the same issue an independent group led by Fumiaki Obata published a second study on the same protein, approaching it through larval nutrition. Both papers describe Lsp2 as a node connecting diet, ribosomal protein synthesis, and fly lifespan.
For nearly half a century Lsp2 was an unremarkable protein: Drosophila larvae stockpile it in the fat body, an organ that combines the functions of the liver and adipose tissue, as raw material for the pupal stage. The Chinese group compared gene expression in fly heads after a protein meal and during aging: both processes shifted the same genes in a similar pattern, and Lsp2 stood out, with its synthesis in adult flies rising 80-fold within seven hours. It is an adipokine, a hormone that the fat body secretes into hemolymph, the fly counterpart of blood.
The familiar signaling network drives it: essential amino acids activate the insulin pathway and mTORC1, the cellular sensor of nutrient abundance. Lsp2, however, has a narrow effect: when it is overexpressed, only 35 genes change compared with 684 under mTORC1 activation. It works through translation: it increases phosphorylation of 4E-BP, a brake that blocks synthesis of TOP mRNAs encoding nearly all ribosomal proteins. By releasing this brake, Lsp2 forces the cell to produce ribosomal proteins beyond its actual need, an expensive and dispensable task.
Knocking out the gene (two mutant lines, including a CRISPR knockout) extended median lifespan by 14–28%. Longevity usually costs fertility, but flies lacking Lsp2 laid eggs at normal rates, and on days 8–10 even exceeded controls, while retaining resistance to starvation, oxidative stress, and infection. The authors explain that ribosomal proteins are already made in excess of what ribosome assembly requires, so trimming their synthesis saves energy without impairing functional ribosomes. In double mutants lacking both Lsp2 and 4E-BP the effect nearly disappeared: the entire benefit runs through the translational brake.
Rapamycin acts on the same mTORC1 network but far less predictably: in flies, a single change in food composition reversed its effect from +5.4% to −51.3% median lifespan. Here one gene reverses the sign: rapamycin extended the lifespan of normal flies and shortened it in flies lacking Lsp2 on the same diets.
Unlike rapamycin, which cannot reduce 4E-BP phosphorylation in vivo, Lsp2 appears to be an endogenous regulator of 4E-BP activity.
Obata's paper in the same issue resolved a century-old puzzle: experiments in rats and daphnia had shown that restricting food during early life extends adult lifespan, but the mechanism remained unclear. Isotope labeling showed that some amino acids from larval food survive metamorphosis and end up incorporated into adult Lsp2. When a larva is deprived of protein, adult Lsp2 remains persistently low, and that alone is sufficient for longevity: Lsp2 stores the trace of childhood nutrition in the adult body. Two independent routes converged on a single gene and a single translational brake.
The authors suggest that insect hexamerins like Lsp2 are functionally reminiscent of immunoglobulin G, the most abundant blood protein in humans, whose production in B cells also depends on mTORC1 and whose excess has been linked to aging. There is no direct vertebrate homolog of Lsp2, and the resemblance remains the authors' hypothesis.
Our serendipitous discovery of a mechanism that tunes global ribosomal protein translation motivates us to search for similar regulators in mammals as a means of extending lifespan.