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Researchers Uncover Gene Expression Signature of Healthy Aging

NEW YORK (GenomeWeb) – A signature based on the expression of 150 genes is associated with healthy aging, according to a new study.

James Timmons from King's College London and his colleagues uncovered 150 probe sets that could distinguish healthy 25-year-olds from healthy 65-year-olds, as they reported this week in Genome Biology. After validation, they developed a healthy age gene score based on that signature, noting that higher scores were associated with better health. They also reported that their classifier could potentially be used as a diagnostic for Alzheimer's disease.

"Our discovery provides the first robust molecular 'signature' of biological age in humans and should be able to transform the way that 'age' is used to make medical decisions," Timmons, who also serves as director and CSO of XRGenomics, a firm developing RNA-based diagnostics for age-related disease, said in a statement. "This includes identifying those more likely to be at risk of Alzheimer's, as catching those at 'early' risk is key to evaluating potential treatments."

While previous studies of human aging have typically focused on related diseases or extreme longevity, Timmons and his colleagues instead examined healthy 65-year-olds. To uncover a pattern of RNA expression linked with health in older people, they applied machine-learning methods to RNA expression data obtained from muscle tissue from a cohort of sedentary, but healthy 25-year-olds and 65-year-olds. The research participants, they noted, had good aerobic fitness and did not have diabetes.

This training set of RNA expression data from 15 young and 15 older research participants whittled the 54,000 probe-set list down to 150 RNAs that could distinguish between young and old muscle tissues.

These 150 probe sets could also classify young and old muscle samples from four additional datasets with an average 93 percent accuracy. Further, the researchers reported that this expression signature could also accurately classify brain and skin tissue by age, even on different platforms.

Based on both gene ontology and Ingenuity Pathway analysis, the researchers were unable to uncover an association between the 150 genes in the signature and any biological processes or signaling pathways in particular.

Timmons and his colleagues applied this classifier to a set of gene expression profiles from 108 muscle samples obtained from participants in the Uppsala Longitudinal Study of Adult Men. They ranked each participant on each of the genes and turned those rankings into a summed median gene score.

Despite each participant being about 70 years of age, the researchers noted a wide distribution of gene scores. This, they said, suggests that their healthy aging gene score is distinct from chronological age.

They also noted that the gene score was unrelated to lifestyle biomarkers like blood pressure, glucose or cholesterol levels, and renal function.

In addition, the healthy aging gene scores appear to be predictive of later health. The researchers profiled RNA obtained from healthy participants from the Uppsala cohort at age 70 as well as follow-up data.

A higher gene score was associated with better cognitive and renal function across a 12-year span, the researchers reported. Cognitive decline and decreased renal function, they noted, are key determinants of all-cause mortality.

In particular, the researchers found that their gene score could help uncover people at risk of developing Alzheimer's disease.

The researchers calculated healthy aging gene scores for two independent case-control studies of Alzheimer's and two case-control studies of lifestyle-related diseases. Alzheimer's patients, they reported, had lower median scores, suggesting that the signature could act as a diagnostic for the disease.

"This is the first blood test of its kind that has shown that the same set of molecules are regulated in both the blood and the brain regions associated with dementia, and it can help contribute to a dementia diagnosis," Timmons said.

The scores were unrelated to diabetes or vascular disease status, he and his colleagues noted.

Early detection of people at risk of Alzheimer's is thought to be key to slowing the disease's progress, and the researchers said that their gene score could be used to identify people at higher risk of the disease, as well as middle-aged people who could be enrolled in preventative clinical trials before the clinical onset of disease.

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