A research team led by Prof. KONG Qingpeng from Kunming Institute of Zoology of the Chinese Academy of Sciences reported that ETS1-regulated ribosome function reduction is an important mechanism for human healthy aging and longevity. This study was published in Science Advances.
Healthy aging study is closely related to the national economic development and people's well-being. The “Healthy China Action Plan (2019-2030)” issued by the State Council in 2019 proposes to change the focus from treating diseases to preventing diseases. Long-lived people with an average of much longer life span but without major age-related diseases are regarded as the best model of human healthy aging. Therefore, studying the longevity mechanisms would offer people an opportunity to identify the protective factors for human health, which in return will have high potential to be directly applied to health interventions and to provide some theoretical basis for “healthy aging” in China.
Healthy aging and longevity results from a combination of intrinsic genetic and extrinsic environmental factors. Previous studies have shown that longevity heritability is relatively low (about 25%), and only a few longevity-related genetic variants have been observed in longevity people even at the genomic DNA level. These findings suggest that their health protective factors may exist at the gene expression regulation level.
Recently, a team of researchers from Kunming Institute of Zoology of the Chinese Academy of Sciences, Xiangya Hospital Central South University and Hainan Medical College, obtained and analyzed the peripheral blood leukocyte transcriptome data (RNA-seq) in 185 long-lived individuals (LLIs) and 86 spouses of LLI-children (F1SPs) in Lingshui (LS) Prefecture and Lingao (LG) Prefecture, Hainan Province.
The researchers found a new but very significant signal in the LLIs, viz. ribosomal pathway genes were markedly downregulated in both LS and LG longevity cohorts, besides the similar observation that the team has ever reported, viz. the significantly upregulated signals on the autophagy-lysosomal pathway. They showed that the observed downregulation of ribosome protein-coding genes (RPGs) is most likely regulated by a transcriptional regulator ETS1.
Further functional assays using different replicated senescent cells showed that knockdown of ETS1 reduced RPG expression and alleviated cellular senescence. Therefore, the study showed that the decreased ribosome function plays an important role in human healthy aging/longevity, and the transcriptional regulator ETS1 is involved in the regulation of this process.
Protein translation proceeds at ribosomes and is one of the most energy-consuming process in cells. Decreased ribosome function has been shown to prolong the lifespan of lower animals, such as worms and mice, etc. Here, this study first reveals that the reduction of ribosome function is a new mechanism of human healthy aging and longevity, and thus complements the chain of evidence that the ribosome function decline should be a conserved life-extension mechanism.
The decline of ribosome function in the LLIs may be an important way to cope with inadequate energy supply caused by mitochondrial damage with age and may promote human healthy aging and longevity through energy redistribution. This study provides support for the hyperfunction theory of aging.
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