Mapping Proteomic Changes with Aging in Rats

This open access paper describes data on epigenetic and protein abundance changes with age in the liver and brain in rats. It is a good introduction to just how much data is yet to be cataloged in detail when looking at all tissue and cell types and how their operations change with aging. The sheer complexity of our biochemistry is why shortcuts that enable us to evade waiting on more data are essential to rapid progress towards rejuvenation treatments. At present, for example, the forms of damage that distinguish old tissue from young tissue are well enumerated and well understood. So the research community can work towards repair therapies without needing to fill in any of the blanks regarding exactly how this damage produces the very complex set of alterations and wide range of age-related diseases seen in old tissues.

Here, we present an integrated comparison of gene expression, translation, protein abundance, and phosphorylation in organs from young and old rats. Our work expands the list of proteins that are affected by chronological age in mammals. Although some of the functional modules discussed above were previously identified as hallmarks of aging, we identified hundreds of molecular events underlying these processes that were previously unknown to be affected by age. We thus provide a rich resource that should stimulate the generation of new, experimentally testable hypotheses, leading to a better understanding of aging on the organism level.

The comparison of two organs with different physiology and regenerative capacity enabled us to distinguish organ-specific effects from more systemic effects of aging. Intuitively, our results suggest that organ-specific effects of age are tightly linked to the organ function. For example, in brain, multiple alterations of key signaling mediators are observed. We speculate that these alterations might be part of a progressive functional deterioration that affect the maintenance of neuronal plasticity in old brains and other phenotypes observed the aging brain. Notably, 45 of the changes that we identified in old rat brains are consistent with a previous transcriptomics study of aging human brains, suggesting that age-related changes in the proteome and transcriptome are to some extent conserved from rat to humans.

The systemic impact of chronological age on proteome homeostasis manifests on many levels. In the liver, the majority of age-dependent changes are driven by alteration of transcript abundance (58% of the affected transcripts versus only 25% in brain), suggesting the occurrence of age-related changes in transcriptional regulation. In contrast, the brain appeared to be affected by age largely at the translational level. Our data suggest that an age-associated remodeling of the translation machinery in the brain may ultimately lead to alterations of the translation efficiency of a subset of transcripts in old animals. Specifically, we identified 15% of the brain transcripts to be affected by a change in translation (versus only 2% in liver).

Despite the correlation between translation output and protein abundances, not all the observed changes of protein abundance could be explained by changes in translation output, particularly in brain. This phenomenon strongly indicates a higher degree of post-translational control in the brain as compared to the liver. Indeed, our proteomic analysis revealed that key regulators of protein homeostasis were altered in aged brain, including several components of the ubiquitin-proteasome and autophagy systems. These findings imply that altered protein homeostasis, which has been shown to affect organism longevity under stress-response conditions, also leads to detectable proteomic alterations that occur between young and old animals. The exact consequences and targets of such alterations are likely complex and remain to be explored in detail.

Link: http://dx.doi.org/10.1016/j.cels.2015.08.012

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