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Degenerative Diseases Dominate Over Cancer in Transcriptomic Signature of Aging

NEW YORK (GenomeWeb) – There's an antagonistic relationship between cancer and degenerative chronic diseases as organisms age, even at the transcriptome level.

While cancer is the greatest contributor to mortality among 60-year-old people, its dominance declines with age and is replaced among the elderly by degenerative chronic diseases. Researchers led by Christian-Albrechts-University Kiel's Christophe Kaleta speculated that this shift could be due to changes in gene transcription. He and his colleagues examined the transcriptomes of four vertebrate species over time to develop a transcriptomic signature of aging. As they reported in Nature Communications today, they found that as organisms age, their transcriptomic signatures shift and become less like those observed in cancer and more like those observed in degenerative diseases.

"These results reveal a fundamental trade-off between cancer and degenerative aging diseases that sheds light on the pronounced shift in their epidemiology during aging," Kaleta and his colleagues wrote in their paper.

The researchers analyzed 531 samples collected from four tissues from four organisms — humans, mice, zebrafish, and killifish — at five time points to search for a conserved aging-associated transcriptomic signature. Because previous studies have noted little overlap in aging-linked genes between species, the researchers instead focused on expression differences affecting similar functional processes, as derived from Gene Ontology, KEGG Pathway, and a genome-wide reconstruction of human metabolism.

They noted that the number of differentially regulated processes rose with age, and used the first and last two aging time points to develop their aging-associated transcriptomic signature. This signature highlights the upregulation of the immune system as well as the down-regulation of cell cycle and cell differentiation processes in the elderly.

Kaleta and his colleagues developed what they dubbed an aging-mediated disease alignment score (AMDA) to gauge the overlap between aging and disease transcriptomes. With this, they analyzed 22 aging-related and 30 disease-related datasets to find that the expression patterns of older individuals are shifted toward that of people with cardiovascular, neurodegenerative, and type 2 diabetes, as compared to younger individuals. They further noted that aging moves the transcriptome away from gene-expression signatures linked to cancer.

Similarly, when the researchers examined transcriptomic data collected from the same mouse and killifish individuals over time, they again found a shift from cancer to degenerative disease-associated signatures as they got older.

Kaleta and his colleagues sought to tease out the processes that drive these aging-related transcriptomic shifts by developing a disease alignment contribution (DAC) score. They found that the top ranking DAC score processes show the same direction of change in chronic degenerative disease, but an opposite one in cancer. That is, they found that processes that are induced in cancer are downregulated in degenerative diseases, and vice versa.

The researchers also wanted to determine whether this antagonism plays out on the genomic level. They gathered a list of all SNPs associated with aging-related diseases from the GWAS catalog and examined how they overlapped with cancer risk SNPs. They uncovered a dozen genomic loci with 40 shared risk SNPs between cancer and degenerative aging-related diseases. They found that 36 of these SNPs were antagonistic: one allele gives a predisposition to cancer while another gives a predisposition to degenerative disease.

Interestingly, the researchers noted that the locus with the largest number of shared risk SNPs is the long non-coding RNA ANRIL, which regulates a number of cell cycle regulators. The locus also includes risk variants for cardiovascular disease, type 2 diabetes, and neurodegenerative diseases.

"While we mostly report on associations and cannot infer causal relationships, these results represent an important basis for future functional studies that examine the mechanisms that mediate the antagonism between cancer and degenerative aging diseases," Kaleta and his colleagues added.