Transcriptional Profiling of Human Familial Longevity Indicates a Role for ASF1A and IL7R

Abstract

The Leiden Longevity Study consists of families that express extended survival across generations, decreased morbidity in middle-age, and beneficial metabolic profiles. To identify which pathways drive this complex phenotype of familial longevity and healthy aging, we performed a genome-wide gene expression study within this cohort to screen for mRNAs whose expression changes with age and associates with longevity. We first compared gene expression profiles from whole blood samples between 50 nonagenarians and 50 middle-aged controls, resulting in identification of 2,953 probes that associated with age. Next, we determined which of these probes associated with longevity by comparing the offspring of the nonagenarians (50 subjects) and the middle-aged controls. The expression of 360 probes was found to change differentially with age in members of the long-lived families. In a RT-qPCR replication experiment utilizing 312 controls, 332 offspring and 79 nonagenarians, we confirmed a nonagenarian specific expression profile for 21 genes out of 25 tested. Since only some of the offspring will have inherited the beneficial longevity profile from their long-lived parents, the contrast between offspring and controls is expected to be weak. Despite this dilution of the longevity effects, reduced expression levels of two genes, ASF1A and IL7R, involved in maintenance of chromatin structure and the immune system, associated with familial longevity already in middle-age. The size of this association increased when controls were compared to a subfraction of the offspring that had the highest probability to age healthily and become long-lived according to beneficial metabolic parameters. In conclusion, an “aging-signature” formed of 21 genes was identified, of which reduced expression of ASF1A and IL7R marked familial longevity already in middle-age. This indicates that expression changes of genes involved in metabolism, epigenetic control and immune function occur as a function of age, and some of these, like ASF1A and IL7R, represent early features of familial longevity and healthy ageing.

Identifying the genomic determinants of aging and longevity in human population studies: Progress and challenges

“…This approach has been applied in the LLS to explore the transcriptome in whole blood for association with human familial longevity. Genes belonging to the mTOR pathway, as well as ASF1A and IL7R , were differentially expressed between offspring and controls 59, 60. In addition, the expression of mTOR genes in blood associated to prevalent diabetes and serum glucose.…”

Identification of Pharmacodynamic Transcript Biomarkers in Response toFGFRInhibition by AZD4547

“…Global gene profiling analysis via microarray or RNAsequencing has limitations when screening large numbers of samples due to the cost and time taken to generate data. In contrast, medium throughput targeted profiling can be performed using platforms such as the BioMark HD/Fluidigm Array (12)(13)(14). This enables profiling of a large number of samples across key pathway transcript biomarkers, enabling higher throughput and reducing costs and analysis time.…”

Gene expression analysis of mTOR pathway: association with human longevity

“…Recently, we have identified 360 genes, the expression of which was associated with human longevity (Passtoors et al, 2012). MTOR (also known as FRAP1) was among these, suggesting a role for the mTOR signalling pathway in human longevity.…”