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Researchers Find Age-Related Protein Changes Differ Across Organs in Rats

NEW YORK (GenomeWeb) – Researchers from several institutions — including the Salk Institute for Biological Studies, the European Molecular Biology Laboratory, and the University of California, Berkeley — have used a multi-omics approach to show that different organs in rats degenerate at different rates.

Scientists have known for some time that aging is associated with the decline of protein, cell, and organ function. However, a recent large-scale study showed that most proteins across different organs don't change in abundance during aging, so it's unclear how aging affects cellular proteins and whether these protein changes differ across organs.

To find this out, the research team took an integrated approach — using genomic and proteomic techniques together — to characterize gene expression, bulk translation, and cell biology in the brains and livers of young and old rats. 

As described in detail this week in Cell Systems, the researchers began by comparing age-related protein changes in the liver and brain by harvesting these organs from three 6-month-old rats and three 24-month-old rats. The samples were split at the transcription, translation, and proteome levels for subsequent analysis by next-generation RNA sequencing, ribosome profiling, and tandem shotgun mass spectrometry. RNA sequencing and ribosome profiling were prepared using an Illumnia TruSeq kit and sequenced using the Illumina HiSeq platform. The researchers then compared the mRNA abundance and translation output of 9,875 brain and 6,490 liver transcripts between young and old animal samples. The changes in translation efficiency were inferred by comparing these measured values.

To increase proteomic coverage and obtain insights into subcellular localization, the organ samples were fractionated into nuclei, post-nuclear fraction 1 (enriched for mitochondria); post-nuclear fraction 2 (enriched for cytoplasmic membranes); and soluble cytosolic proteins, according to previously established procedures. The researchers analyzed all samples with shotgun mass spectrometry, which enabled them to perform 14,131 comparisons of protein abundances across two age groups and four sub-cellular fractions, covering 4,714 protein groups. 

The researchers identified 468 differences in protein abundance between young and old animals, mainly due to changes in protein synthesis. Another set of 130 proteins showed age-related changes expected to affect function or activity level of the proteins within cells, phosphorylation state, or splice form.

"Our study showed that organs have different aging mechanisms and that aging is largely driven by changes in protein production and turnover," Martin Hetzer, co-author and Salk Institute professor, said in a statement

Interestingly, most age-related protein differences were specific to the brain, rather than the liver. Since cells in the liver are frequently replaced throughout adulthood, this organ has ample opportunity to replenish its proteins. However, most neurons in the brain are non-dividing cells that must survive throughout the animal's entire lifetime which makes them more vulnerable to the accumulation of damage and loss of function over time. Consequently, a larger fraction of proteins in the brain was affected by aging compared to the liver. 

"Based on our findings, we would define aging as an organ-specific deterioration of the cellular proteome," said Hetzer. In the older brain, researchers found perturbations in the levels of 12 protein kinases from different families that control cell growth, neuronal morphogenesis and plasticity, and memory function. In the older liver, they found effects on the phosphorylation of proteins involved in several metabolic processes and energy production. 

The researchers plan to analyze other organs, such as the heart, to further examine the general and organ-specific effects of aging. They also hope to investigate how and why these changes occur. "We expect these organs to have specific aging signatures, like the brain and liver," said Hetzer. "An interesting open question is whether one organ can affect the aging of another organ, that is, is aging sensed at the organismal level? Answering this question would give us a more comprehensive understanding of the aging process and how it relates to disease."