Summary: Researchers report certain genes and pathways that regulate slicing factors play a critical role in the aging process. Disrupting these genetic processes, researchers say, could reverse signs of aging in human cells.
Source: University of Exeter.
Research has shed new light on genetic processes that may one day lead to the development of therapies that can slow, or even reverse, how our cells age.
A study led by the University of Exeter Medical School has found that certain genes and pathways that regulate splicing factors – a group of proteins in our body that tell our genes how to behave – play a key role in the ageing process. Significantly, the team found that disrupting these genetic processes could reverse signs of ageing in cells.
The study, published in the FASEB Journal, was conducted in human cells in laboratories. Aged, or senescent, cells are thought to represent a driver of the ageing process and other groups have shown that if such cells are removed in animal models, many features of ageing can be corrected. This new work from the Exeter team found that stopping the activity of the pathways ERK and AKT, which communicate signals from outside the cell to the genes, reduced the number of senescent cells in in cultures grown in the laboratory. Furthermore, they found the same effects from knocking out the activity of just two genes controlled by these pathways – FOX01 and ETV6.
Professor Lorna Harries, of the University of Exeter Medical School, who led the research, said: “We’re really excited by the discovery that disrupting targeted genetic processes can bring about at least a partial reversal of key elements of the ageing process in human cells. This suggests that they could be an important aspect in designing therapies that could keep us healthier as we age. Our ultimate goal is to help people avoid some of the diseases partially caused by ageing cells, such as dementia and cancer.”
The ERK and AKT pathways are repeatedly activated throughout life, through aspects of ageing including DNA damage and the chronic inflammation of ageing.
The research suggests that this activation may hinder the activity of splicing factors that tell genes how to behave. This, in turn, could lead to a build-up of senescent cells – those which have deteriorated or stopped dividing as they age.
To stop the activity of the ERK and AKT pathways, the study used inhibitors which are already used as cancer drugs in clinics. When the pathways were disrupted, the team observed an increase in splicing factors, meaning better communication between protein and genes.
They also noted a reduction in the number of senescent cells. Researchers saw a reversal of many of the features of senescent cells that have been linked to the ageing process, leading to a rejuvenation of cells.
Dr Eva Latorre, of the University of Exeter Medical School, who carried out the research, said: “This study is part of a fast-evolving body of work into how we age. We used compounds that are already widely available in clinics for cancer – and are known to be relatively safe. It’s still early days and we need to understand far more about the complex relationships of how our cells and genetic processes influence ageing, yet it’s an exciting contribution to how we may one day be able to influence healthier ageing.”
Funding: Funding provided by Dunhill Medical Trust.
Source: Louise Vennells – University of Exeter
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Original Research: Abstract for “FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence” by Eva Latorre, Elizabeth L. Ostler, Richard G. A. Faragher, and Lorna W. Harries in FASEB Journal. Published August 8 2018.
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Cellular plasticity is a key facet of cellular homeostasis requiring correct temporal and spatial patterns of alternative splicing. Splicing factors, which orchestrate this process, demonstrate age-related dysregulation of expression; they are emerging as potential influences on aging and longevity. The upstream drivers of these alterations are still unclear but may involve aberrant cellular signaling. We compared the phosphorylation status of proteins in multiple signaling pathways in early and late passage human primary fibroblasts. We then assessed the impact of chemical inhibition or targeted knockdown of direct downstream targets of the ERK and AKT pathways on splicing factor expression, cellular senescence, and proliferation kinetics in senescent primary human fibroblasts. Components of the ERK and AKT signaling pathways demonstrated altered activation during cellular aging. Inhibition of AKT and ERK pathways led to up-regulation of splicing factor expression, reduction in senescent cell load, and partial reversal of multiple cellular senescence phenotypes in a dose-dependent manner. Furthermore, targeted knockdown of the genes encoding the downstream targets FOXO1 or ETV6 was sufficient to mimic these observations. Our results suggest that age-associated dysregulation of splicing factor expression and cellular senescence may derive in part from altered activity of ERK and AKT signaling and may act in part through the ETV6 and FOXO1 transcription factors. Targeting the activity of downstream effectors of ERK and AKT may therefore represent promising targets for future therapeutic intervention.