Transcriptome analysis of human ageing in male skin shows mid-life period of variability and central role of NF-κB

Abstract

Age is well-known to be a significant factor in both disease pathology and response to treatment, yet the molecular changes that occur with age in humans remain ill-defined. Here, using transcriptome profiling of healthy human male skin, we demonstrate that there is a period of significantly elevated, transcriptome-wide expression changes occurring predominantly in middle age. Both pre and post this period, the transcriptome appears to undergo much smaller, linear changes with increasing age. Functional analysis of the transient changes in middle age suggest a period of heightened metabolic activity and cellular damage associated with NF-kappa-B and TNF signaling pathways. Through meta-analysis we also show the presence of global, tissue independent linear transcriptome changes with age which appear to be regulated by NF-kappa-B. These results suggest that aging in human skin is associated with a critical mid-life period with widespread transcriptome changes, both preceded and proceeded by a relatively steady rate of linear change in the transcriptome. The data provides insight into molecular changes associated with normal aging and will help to better understand the increasingly important pathological changes associated with aging.

Rejuvenating Strategies for Stem Cell-Based Therapies in Aging

“…In the mammalian skeletal muscle, an age specific increase in niche-derived NF‐κB signaling impairs satellite cells function, which can be attenuated by systemic administration of sodium salicylate, an FDA‐approved NF‐κB inhibitor (Oh et al, 2016). Observations in humans, in turn, suggest a central role for NF-κB activation and TNFα signaling in skin aging (Haustead et al, 2016). Evidence from heterochronic parabiosis also suggests that several serum-derived factors contributing to the age-related loss of regenerative capacity are molecules involved in the regulation of inflammation.…”

Transcriptional Signatures of Aging

“…Whereas the gene expression profiles of very old and young individuals highly correlate with other individuals in those groups, individuals within the middle aged group did not resemble each other, and instead correlated more strongly with either the young or old group [26]. Additionally, there are greater transcriptional changes between middle age and young or old samples in some human tissues, as compared with young versus old [32]. Importantly, the transcriptional signature of aging within blood from individual human patients is significantly associated with aging-associated phenotypes such as blood pressure, waist-hip ratio and smoking [8].…”

“…For example, increased expression of genes involved in stress response and oxidative damage is observed in aging human brain, retina, skin and fibroblasts (Table 1) [26, 27, 30, 32, 53]. Similarly, genes involved in stress response and inflammation show increased expression with age in rodent brain, kidney, liver, muscle, and pancreatic cells, and in fruit flies [34, 37, 39, 54].…”

“…For example, an increase in oxidative stress in aging cells could induce the increased DNA binding shown by the transcription factor NF-κb in aging mouse cardiac muscle [64]. Notably, NF-kb is also implicated in the age-related transcriptional changes observed in human skin [32]. In addition, since environmental stresses could influence the timing and level of upregulation of stress response genes, inducible upregulation of these genes could explain much of the heterogeneity observed both between individual cells in a tissue, and between different individuals in a population.…”

Mutation accumulation differentially impacts ageing in mammalian tissues

“…Normalization. Affymetrix .CEL files from 23 datasets 15,24,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] were downloaded from NCBI Gene Expression Omnibus (GEO) 51,52 with accession number and EBI Array Express 53 . These raw datasets were processed using the Bioconductor "affy" package "expresso" function 54 .…”