Minnesota team determines that senescent immune cells are the most dangerous type of senescent cell, making them key target for senolytic drugs.
Cellular senescence is the very definition of killing with kindness; when a cell realises it should stop dividing because it’s reached the division limit (the Hayflick Limit), or has developed a cancerous mutation that could lead to runaway multiplication and become a tumour, it becomes senescent. Damage can also trigger senescence, which alerts the body to the harm.
Longevity.Technology: Like purgatory, senescence should be a transitional state, a stop on the way to death, as the self-destruct countdown to apoptosis (cell death) should start when cellular senescent begins. However, this doesn’t always happen and the cell remains in permanent limbo, not dividing, growing or being useful, but hanging around, encouraging other cells into senescence and also pumping out a harmful cocktail of proteins and other damaging chemicals.
This toxic excretion can damage other cells, causing inflammation, aging and cell death and driving most age-related diseases, such as arthritis, cardiovascular disease and diabetes. Research into senolytics and senotherapeutics is trying to find ways of tacking cellular senescence.
The research team — led by Dr Laura Niedernhofer, MD, PhD, a professor in the Department of Biochemistry, Molecular Biology and Biophysics — discovered that senescent immune cells drive tissue damage all over the body and shorten lifespan. Therefore, senescent immune cells are particularly detrimental and should be a top target for senolytic therapy.
“Now that we have identified which cell type is most deleterious, this work will steer us towards developing senolytics that target senescent immune cells,”
U of M researchers, including Niedernhofer and collaborators at the Mayo Clinic, previously identified this new class of drugs back in 2015, coining the term senolytics; these drugs , which selectively remove senescent cells from the body. However, senolytic drugs must be targeted towards a specific cell type, so a senolytic drug that can kill senescent brain cells is no good against senescent liver cells.
The U of M defined the contribution of immune system aging to organism aging by selectively deleted Ercc1, a gene which encodes a crucial DNA repair protein in mouse haematopoietic cells (the cells that form blood and immune cells). This deletion had the effect of increasing the amount of endogenous DNA damage (damage caused by reactive oxygen species or metabolic processes) and therefore the number of cells becoming senescent.
The mice in the experiment were healthy into adulthood, but then displayed premature onset of immunosenescence characterised by attrition and senescence of specific immune cell populations; they also demonstrated impaired immune function, similar to changes that occur during aging in mice in the wild .
“Now that we have identified which cell type is most deleterious, this work will steer us towards developing senolytics that target senescent immune cells,” said Niedernhofer, who is also the director for the Institute on the Biology of Aging and Metabolism at the U of M Medical School, one of the state-sponsored Medical Discovery Teams.
“We also hope that it will help guide discovery of biomarkers in immune cell populations that will help gauge who is at risk of tissue damage and rapid aging, and therefore who is at most need of senolytic therapy .”