SIRT3 in blood stem cells limited chronic inflammation and age-related functional decline in mice

The SIRT3 enzyme in blood stem cells from old mice reduced inflammation and improved performance in tests of muscle function, lung structure, and memory

Bone marrow continuously produces immune cells. The authors showed that, with age, this source can establish an inflammatory program in its descendants, and that SIRT3 can weaken this program at the level of the hematopoietic stem cell.

On July 16, a team from the University of California, Berkeley, the Buck Institute, and other centers published a study in Nature Aging. The researchers examined hematopoietic stem cells, which are rare bone marrow cells that produce blood and immune cells throughout life.

With age, these stem cells increasingly produce myeloid cells, including macrophages, monocytes, and other cells of the innate immune system. These cells can respond rapidly to infection, but during aging they may retain an inflammatory program and sustain excessive alarm signals in the blood. A study of EP2 in tissue macrophages examined another part of this process: an inflammatory receptor prevented the macrophages from clearing aged neutrophils. The SIRT3 study looks further upstream, at the stem cells that produce myeloid descendants.

This persistent reprogramming is called trained immunity. After an infection, it helps the body respond more quickly. The authors tested a different situation: repeated damage in an old organism may turn this response into a chronic state in which stem cell descendants carry inflammation into tissues for years.

The study focused on SIRT3, a mitochondrial enzyme that helps cells manage oxidative stress. Its level in hematopoietic stem cells declines with age. The researchers genetically increased SIRT3 expression in mice and found lower levels of the inflammatory factors TNF and IL-6 in the blood, fewer inflammatory macrophages in tissues, and better performance in strength and endurance tests.

The team then transplanted bone marrow from young mice with increased SIRT3 expression into ordinary young mice and allowed the recipients to age. Two years later, the recipients had better muscle function, remained more active, had smaller pulmonary alveoli, and showed changes in measures of spatial memory. Their tissues also contained fewer markers of cellular senescence.

Bone marrow transplantation and the transfer of specific immune cell populations helped identify the intermediary. Stem cells with increased SIRT3 expression produced less inflammatory myeloid cells, and transferring these cells into young mice improved their performance in physical tests. T-cells did not produce the same effect. In this model, the sequence is as follows: aging blood stem cell → inflammatory myeloid descendants → inflammation and functional decline in other organs.

The experiments used mice with genetically increased SIRT3 expression. The next step is to reproduce this sequence in human cells and find a way to modify it without bone marrow transplantation.