Cyclic FOXM1 Upregulation Extends Life in Aged Mice

The team here notes a recent study in which researchers carefully induced greater expression of FOXM1 in aged mice, showing extension of life as a result. FOXM1 overexpression is known to induce greater stem cell activity, but also to push somatic cells towards a more cancer-like phenotype, meaning more growth, more regeneration, more activity. Cancer and regeneration are two sides of the same coin. Regeneration and tissue maintenance are controlled processes, while a cancer is driven by the same mechanisms when they run wild.

Given these connections, it is not too surprising to find that FOXM1 is downregulated in older individuals, perhaps a part of the general decline in stem cell function, regeneration, and growth that is characteristic of aging. There is a trade-off in later life between tissue maintenance and risk of cancer, due to rising levels of molecular damage, and evolution has selected for a slow decline rather than a longer period of vitality with greater risk of sudden death by cancer. As the successes of stem cell treatments and various other pro-regenerative approaches to therapy make clear, it is nonetheless possible to push the body towards greater tissue maintenance without causing a greatly increased risk of cancer.

Forkhead box (FOX) genes are transcription factors: genes that drive the expression of other genes and are known to play an important role in cell proliferation and longevity. FOXM1 is another forkhead box gene that has gained the attention of aging researchers as an important oxidative stress response regulator and one of the major players in tumorigenesis. Previous studies have shown that FOXM1 is decreased in the cells of older healthy people as well as people whose aging is accelerated by Hutchinson-Gilford progeria syndrome.

In this study, the researchers set out to check if it's possible to delay aging by increasing the expression of FOXM1 in progeroid and naturally aged mice. However, instead of inducing the fully functioning FOXM1, a modified gene that did not contain an N-terminal part was chosen. The C-terminal side of FOXM1 plays an important role in transcriptional activity, and the N-terminal side plays a role in the regulation of intracellular processes, such as controlling the segregation of genetic material during cell division. The N-terminal side was also shown to have an autoinhibitory function repressing the activity of the protein at specific cell cycle stages.

Although promising, the results from experiments in progeroid mice might not translate into naturally aging animals. Therefore, the researchers applied truncated FOXM1, using a 3-day-on and 4-day-off scheme, for 80 weeks to 8-week-old naturally aging mice. Remarkably, the treatment extended the lifespan of aged mice by almost 30% compared to controls. Tissue examination revealed that truncated FOXM1 induction rejuvenated multiple organs: aorta, skin, fat, and muscle. The researchers observed reduced muscle atrophy and a higher number of muscle stem cells, along with increased muscle strength. In addition, decreased aortic fibrosis and wall thickening, as well as increased subcutaneous fat, were demonstrated. Confirming previous results, naturally aging mice had downregulated senescence biomarkers in skin, kidney, fat, and muscle following truncated FOXM1 induction.


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