The murine transcriptome reveals global aging nodes with organ-specific phase and amplitude

Abstract

Aging is the single greatest cause of disease and death worldwide, and so understanding the associated processes could vastly improve quality of life. While the field has identified major categories of aging damage such as altered intercellular communication, loss of proteostasis, and eroded mitochondrial function 1 , these deleterious processes interact with extraordinary complexity within and between organs. Yet, a comprehensive analysis of aging dynamics organism-wide is lacking. Here we performed RNA-sequencing of 17 organs and plasma proteomics at 10 ages across the mouse lifespan. We uncover previously unknown linear and non-linear expression shifts during aging, which cluster in strikingly consistent trajectory groups with coherent biological functions, including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Remarkably, these gene sets are expressed similarly across tissues, differing merely in age of onset and amplitude. Especially pronounced is widespread immune cell activation, detectable first in white adipose depots in middle age. Single-cell RNA-sequencing confirms the accumulation of adipose T and B cells, including immunoglobulin J-expressing plasma cells, which also accrue concurrently across diverse organs. Finally, we show how expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to aging of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter-and intra-organ progression of aging, thereby providing a foundation to track systemic sources of declining health at old age.

A nutritional memory effect counteracts the benefits of dietary restriction in old mice

“…Although we only had access to scRNA-seq profiles of AL-fed mice, the switch-resistant repression of inflammatory genes under DR (such as interferon response genes) could, in this model, represent a way of maintaining plasticity in the adipose tissue through prevention of sterile inflammation. Interestingly, the WAT of AL-fed mice exhibits-prior to any other tissue-major age-related expression shifts, most notably of inflammatory genes, at 15 months of age 57 . It is noteworthy that ex vivo WAT explant cultures from DR-fed mice still retained clear differences in TG and membrane lipogenesis after 72 h incubation in a medium with all nutrients in abundance and without exposure to the systemic DR environment, thus supporting the role of tissue-and/or cell-type-specific effects as mediators of the transcriptional memory.…”

Sample multiplexing for targeted pathway proteomics in aging mice

“…One limitation of the current study lies in the limited resolution within each tissue, given that certain reports have claimed particular regions (37) or cell subpopulations (18) may contribute distinctively to tissue aging or aging-related diseases. In addition, we believe adding more age groups could be of future interest and potentially improve temporal resolution and be beneficial in investigating correlations between transcription and translation, given the corresponding transcriptome study has just become available (38).…”

Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

“…In order to study factors that could potentially influence susceptibility to SARS-CoV-2 infection, we investigated the expression of the coronavirus receptor ACE2. We first assessed the expression of ACE2 in a variety of post-mortem rodent and human tissues (Figure S1 and Table S1) 15–18 . ACE2 was consistently expressed at high levels in mouse, rat, and human kidneys, consistent with its role as a regulator of the RAS pathway.…”