Hematopoietic stem cells (HSC) are the factory that produces all our blood cells: red blood cells, white blood cells, and platelets. With age, they function less and less, and damage the immune system, energy and immunity. A new study published in Nature Communications by Prof. Yuta Yamada and his colleagues identified the surprising culprit: MLKL, a protein known mainly for its role in "killing" cells, turns out to be also the cause of stem cell aging, and in an unexpected way.
Who is MLKL and what does he usually do?
MLKL (Mixed Lineage Kinase domain-Like) is the operator of the process called necroptosis, a type of "programmed cell death" different from apoptosis. When the cell is severely damaged or infected, MLKL is activated, moves to the cell's membrane, and tears it apart. It is a protective process, removing damaged cells from the system.
The surprising discovery: MLKL is active even without killing
Yamda's team used mice engineered with a fluorescent sensor that lights up when MLKL is activated. They identified a new phenomenon: in blood stem cells, MLKL is active but does not kill the cell. Instead, it accumulates in the mitochondria, where it is:
- Damages mitochondrial membranes
- Reduces energy production (poor glycolysis)
- Reduces the self-renewal capacity of the stem cell
- Harms the production of lymphoid cells (lymphoid lineage), which produce the immune B and T cells
The factors that activate MLKL
The team identified three key factors that activate MLKL in stem cells without killing:
- Chronic inflammation (inflammaging): low levels of inflammatory cytokines that increase with age
- Replication stress: high demand for stem cell division, which causes DNA damage
- Oncogenic stress: potential initiations of cancerous mutations that are activated but the system inhibits them
Relation to longevity
In aged mice, MLKL showed increased activity, and stem cell function significantly deteriorated. When MLKL was genetically removed, the same mice maintained a younger immune system and lived longer. That is, MLKL is not only a sign of old age, it is the cause of some of it.
What are the consequences for humans?
Pharmaceutical companies are already developing MLKL inhibitors for use in inflammatory diseases. If this research is confirmed in humans, the same inhibitors could also be used as longevity supplements:
- Immune system is stronger in adults
- Normal blood production over a longer period of time
- Reducing the risk of myelodysplastic syndromes and leukemia
The bottom line
The protein whose function is to "kill dangerous cells" turns out to be one of the main causes of loss of function with age, even without killing. This is an example of what longevity research is beginning to understand: Aging is not one big system failure. It is an accumulation of small processes, each of which works a little differently than it should. And now we have another target for treatment.
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