High-protein diet promotes aging by activating the CG6415/AMT gene and disrupting mitochondrial homeostasis

Dietary protein has multiple physiological functions. However, high-protein diets have been proven to elevate the risk of all-cause mortality. Aging is a dynamic and complex process, but the impact of dietary protein on aging remains unclear.

To explore the effects of high-protein diets on aging at multiple life stages and the underlying mechanisms.

Drosophila were used to assess the effects of diets with 5%, 10%, 15%, 20%, 25%, and 30% protein energy supply on lifespan. Transcriptomic and proteomic analyses at multiple life-stage points screened pathways and key genes consistently affected by high-protein diets. Knockout and overexpression of the key gene CG6415 in Drosophila verified its mediating role in high-protein diets' impact on aging. Based on the insights from the omics data of gene-knockout Drosophila, the mechanism by which the human homologous AMT gene of CG6415 affects aging was verified in the mammalian genetic background using the human embryonic kidney 293T cell. According to the effects of high-protein diets on Drosophila's amino acid profiles, lifespan observations with individual supplementation of 20 amino acids, and verification using CG6415 gene-knockout Drosophila, the amino acids that play key roles in the impact of high-protein diets on aging were identified.

There is an inverted U-shaped relationship between lifespan and dietary protein energy ranging from 5% to 30%. Glycine, serine, and threonine metabolism pathway and the CG6415 gene can be activated by high-protein diets of various proportions at multiple life-stage points. The CG6415/AMT gene inhibits oxidative phosphorylation, disrupts mitochondrial homeostasis, and subsequently activates the p53-p21 pathway, promoting aging and stress-induced damage. Supplementing isoleucine can partially simulate the role of high-protein diets in regulating CG6415-mediated aging.

High-protein diet promotes aging, partly via activation of the CG6415/AMT gene and subsequent disruption of mitochondrial homeostasis. Isoleucine plays a relatively key role in this process.