A number of lines of research indicate that coordination of gene expression within and between cells deteriorates with age. If any two genes are tightly correlated in the expression levels in youth, that correlation tends to decline in strength with age. On the one hand there is increased noise in the distribution of behaviors from cell to cell in response to the same environmental circumstances. Further, where systems of regulation interact with one another, those interactions drift out of synchronization, such as the loss of coordination between central and peripheral circadian clocks. We can hypothesize on how these changes might arise from a stochastic distribution across cell populations of the well known forms of damage associated with aging, including mutations in nuclear DNA, mitochondrial dysfunction, and cellular senescence. But clear chains of cause and effect are at present challenging to establish in the complexity of the biochemistry of a single cell, never mind in tissues and organisms made up of countless such cells.
Nonetheless, measures of loss of coordination of gene expression might prove to be useful biomarkers of aging. This is the conclusion of today's open access paper on the topic. Many age-related changes are visible and interesting in large study populations, but are too varied in their behavior and relationships with the rest of biology to use effectively as biomarkers for individuals. Telomere length measured in immune cells from a blood sample is a good example. The researchers involved in the study noted here conclude that loss of coordination in gene expression is not like this, and does in fact correlate well with other measures of aging on an individual basis. They go on to speculate on whether this loss of coordination is pathological, a cause of age-related dysfunction. Are specific aspects of age-related changes in gene expression meaningfully harmful in and of themselves, or are they a reaction to other harms that do not in and of themselves cause much further damage? That is an ongoing debate, and it won't be settled here.
Aging is characterized by widespread dysregulation across various biological levels, including a decline in gene-to-gene transcriptional coordination. This decline leads to reconfigured interrelations within gene transcriptional networks, which warrants study to better understand the biological system disorders in the aging process. However, the gene pair coordinated expression relationships (CERs) in past analyses were estimated using correlation coefficients across a bulk of samples, capturing only population-level trends. Changes in CERs within individuals during aging remain unclear. Especially since such an analysis cannot determine whether two genes are coordinated in a single individual, it is difficult to connect the gene coordination to personalized biological functioning and health status, thus limiting its potential as an indicator or biomarker of an individual's biological aging or even disease risk. Therefore, a study focusing on gene-to-gene transcriptional coordination at an individual-specific level is urgently needed to gain deeper insights into its biological significance in aging and even age-related outcomes.
To systematically explore the individual-level gene-gene expression coordination dynamics during aging, we constructed 15,933 personalized transcriptional networks in 26 tissues from 967 donors (ranged from 20 to 80 years old), sourced from the Genotype-Tissue Expression (GTEx) project. We revealed that the loss of gene coordination is positively correlated to an individual's senescence-related molecular traits (e.g., senescence-associated secretory phenotype (SASP) and immune cell infiltration) and biological functioning processes (e.g., reactive oxidative species (ROS) and oxidative phosphorylation). Notably, we provided evidence showing that age-related CER loss has the potential to serve as an indicator of an individual's biological aging and health status. Moreover, we found that gene-to-gene relationship loss during aging leads to disrupted gene expression coordination in key pathways, such as proteolysis, which are closely related to longevity and healthy aging. Further analysis indicated that the aging-related CER loss may be pathogenic in a gene dosage-dependent manner.
View the full article at FightAging
