A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to posttranscriptional mechanisms that account for over 40% of the ageregulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging by using the short-lived vertebrate Nothobranchius furzeri and combining transcriptomics, proteomics and thermal proteome profiling. We found that the 25 correlation between protein and mRNA levels is progressively reduced during aging, and that post-transcriptional mechanisms are responsible for over 40% of these alterations. These changes induce a progressive stoichiometry loss in protein complexes, including ribosomes, which have low thermal stability in brain lysates and whose component proteins are enriched in aggregates found in old brains. Mechanistically, we show that reduced proteasome activity occurs early 30 during brain aging, and is sufficient to induce loss of stoichiometry. Our work thus defines early events in the aging process that can be targeted to prevent loss of protein homeostasis and agerelated neurodegeneration.

Chen et al. identify Rad21/cohesin as a critical mediator of inflammation/NF-κB–induced differentiation of hematopoietic stem cells (HSCs). Aging-associated increases in inflammation select for HSCs with disrupted or naturally reduced Rad21/cohesin expression exhibiting increased self-renewal and myeloid-biased differentiation: two hallmark features of the aging hematopoietic system.

Highlights d Proteomes of aged MuSCs and skeletal muscles reveal altered communication d 183 extracellular proteins change abundance in different skeletal muscles during aging d FAPs are the main source of niche proteins affected during aging d Injection of Smoc2 into regenerating muscle of young mice hampers regeneration

Recently discovered acylation by reactive acyl-CoA species is considered a novel regulatory mechanism in epigenetics and metabolism. Established analytical methods like Western blotting and proteomics fail to detect the plethora of acylation structures in a single analysis and lack the ability of absolute quantitation. In this paper, we developed an HPLC–MS/MS method for the simultaneous detection and quantitation of 14 acylated lysine species in biological samples. Extensive effort was invested into method validation resulting in recovery rates between 75 and 93% and levels of detection in the nanomolar range. Thus, we were able to quantitate 8 acylation structures in mouse liver, kidney, heart, and brain. Further enrichment by repetitive HPLC fractionation resulted in the quantitation of 6 additional acylation structures including 4 novel modifications: N 6-acetoacetyl lysine, N 6-isovaleryl lysine, N 6-(2-methylbutyryl) lysine, and N 6-tiglyl lysine.