RNA sequencing and gene network data are used to identify candidate genes that could turn back the “transcriptome clock” that reflects the biological age of distinct human cell types.

Technology has the potential to treat major age-related diseases including cardiovascular disease, cardiovascular disease, and cancer. More than 150,000 people die each day across the globe, about two-thirds of them from age-related causes like cancer, neurodegenerative diseases, strokes, and cardiovascular disease. If the process of aging could be slowed or reversed, the incidence of these conditions would be dramatically reduced, and more humans would live longer, healthier lives. However, aging is a complex process involving multiple biological systems – there is no single biomarker for aging. Therefore, developing treatments that target the root causes of aging is very challenging. Ichor is a Validation Project at the Wyss Institute of Harvard that aims to address this problem using high-throughput genetic screening to identify networks of genes that are strongly implicated in aging processes and develop RNA-based therapies that can make old cells young again.

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Alzheimer’s Disease (AD) is probably more diverse than our traditional models suggest. Postmortem, RNA sequencing has revealed three major molecular subtypes of the disease, each of which presents differently in the brain and which holds a unique genetic risk.  Such knowledge could help us predict who is most vulnerable to each subtype, how their disease might progress and what treatments might suit them best, potentially leading to better outcomes. It could also help explain why effective treatments for AD have proved so challenging to find thus far.

“The mouse models we currently have for pharmaceutical research match a particular subset of AD,  but not all subtypes simultaneously. This may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalised human trials across all AD subtypes,”  say the authors. “Therefore,” the authors conclude, “subtyping patients with AD is a critical step toward precision medicine for this devastating disease.”

Traditionally, AD is thought to be marked by clumps of amyloid-beta plaques (Aβ), as well as tangles of tau proteins (NFTs) found in postmortem biopsies of the brain. Both of these markers have become synonymous with the disease, but in recent years our leading hypotheses about what they actually do to our brains have come under question. Typically, accumulations of Aβ and NFT are thought to drive neuronal and synaptic loss, predominantly within the cerebral cortex and hippocampus. Further degeneration then follows, including inflammation and degeneration of nerve cells‘ protective coating, which causes signals in our brains to slow down.

Strangely enough, however, recent evidence has shown up to a third of patients with a confirmed, clinical diagnosis have no Aβ plaques in postmortem biopsies. What’s more, many of those found with plaques at death did not show cognitive impairment in life. Instead of being an early trigger of AD, setting off neurodegeneration and driving memory loss and confusion, in some people, Aβ plaques appear to be latecomers. On the other hand, recent evidence suggests tau proteins are there from the very earliest stages.

In light of all this research, it’s highly likely there are specific subtypes of AD that we simply haven’t teased apart yet. The new research has helped unbraid three major strands. To do this, researchers analysed 1,543 transcriptomes – the genetic processes being express in the cell – across five brain regions, which were collected post mortem from two AD cohorts.

Source: https://advances.sciencemag.org/