High-protein diets may speed aging through one amino acid — in fruit flies

Protein is having a moment — shakes, bars, and powders marketed to everyone from teenagers to grandparents. A new study doesn't dispute that protein is essential. But it traces, step by step, how sustained excessive protein can quietly erode the very thing longevity seekers care about: mitochondrial function. In fruit flies, diets with 30% of energy from protein shortened median lifespan from 75 to 54 days compared with a moderate 10% protein diet — and the damage ran through a single gene.

How excess protein got to the mitochondria

The team, led by Xiaoqing Xu and Ying Li, fed flies six isocaloric diets ranging from 5% to 30% protein energy. Lifespan followed an inverted U: 10% protein lived longest; both extremes shortened life. Multi-omics — transcriptomes at day 18 and day 48, proteomics, amino-acid profiling — pointed to the glycine–serine–threonine pathway and one hub gene: CG6415, the fly homolog of the human AMT gene. Deleting CG6415 extended the high-protein flies' median lifespan by 15.7% and restored antioxidant enzymes; forcing its expression on a normal diet shortened life by 22%.

In human embryonic kidney 293T cells, overexpressing AMT cut respiratory-chain complex I, II, III, and V activity, collapsed mitochondrial membrane potential, lowered ATP, and flooded cells with mitochondrial superoxide — while silencing AMT reversed those effects. The amino-acid screen then fingered isoleucine as the key dietary trigger: it upregulated CG6415, and cutting isoleucine within a high-protein diet extended lifespan in normal flies (but not in CG6415-overexpressors).

The watchdog caveats

This is flies plus human cells in a dish — not people. Individual amino-acid supplementation only partly reproduced the full high-protein effect, and mammalian studies remain to be done. And the finding cuts both ways: too little protein (5%) also shortened life, and protein remains indispensable for muscle, immunity, and bone. The authors frame CG6415/AMT as a potentially druggable node and isoleucine as a precision-nutrition lever — not a verdict against protein itself. Study: Journal of Advanced Research, 2026.

Where the evidence stands

• Established: Protein restriction extends lifespan in many organisms, from yeast to mice; very high protein intake is linked to higher all-cause mortality in human epidemiology.
• Preliminary: The CG6415/AMT mechanism was demonstrated in fruit flies with verification in human cells; mammalian and human evidence is still missing.
• Contested: Optimal protein intake for humans remains debated — needs differ by age, activity, and health status; this study doesn't define a human target.
• Absent: No human trial has tested isoleucine restriction or AMT modulation for healthspan.