Four Transcription Factors Rejuvenate Old Cells in Mice

As we age, many bodily functions become slower or less effective, including the regeneration of tissue. A new study describes a potentially promising way to accelerate this essential repair process again.

Researchers at the University of California, San Francisco, have identified four transcription factors – proteins that regulate the activity of other genes – that appear to rejuvenate cells.

Four transcription factors linked to cell rejuvenation

To pinpoint the four crucial transcription factors, the researchers first used a computational model to compare old and young human fibroblast cells, examining how gene expression changes with age.

They produced a shortlist of 200 transcription factors that might govern cellular ‘youthfulness’, then systematically switched these factors on and off to alter which transcription factors were produced.

This process ultimately narrowed the candidates to four transcription factors that were investigated in greater depth: E2F3, EZH2, STAT3, and ZFX. Adjusting the levels of these factors in mouse liver cells and in human fibroblast cells cultured in laboratory dishes moved the cells towards a more youthful state.

Effects in older mice and human fibroblast cells

When the team increased production of one of these transcription factors in the liver cells of elderly mice, they observed several improvements. Fat and scarring were substantially reduced, while glucose tolerance improved – all indicators of a younger organ.

The researchers also adjusted the levels of all four transcription factors in laboratory-grown human fibroblast cells. Fibroblasts form connective tissue and create structural support around other cells and organs. This too produced several markers of youthfulness, including greater cell division and higher energy levels.

"By altering gene expression using the transcription factors we identified, old fibroblasts behaved as if they were younger, and improved the health of old mice," says biochemist Hao Li.

Because these proteins produced effects in two distinct species and cell types, they may represent a kind of universal blueprint that could be applied more widely to restore youthful states in older cells.

"These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species," write the researchers in their published paper.

Safety and long-term research questions

The research remains at an early stage. It does not yet point to extended lifespans, replacement limbs or rejuvenation of the entire body, as the findings currently cover only a small number of cell types.

Long-term safety will also need careful assessment. The mouse experiments ran for only a few weeks, meaning the consequences of rejuvenating cells this way over longer periods remain unknown. Excessive cell growth associated with EZH2 has been linked to cancer.

Yet, as the global population ages and people live longer, possible approaches for maintaining healthier bodies for more years merit further study.

"Our work opens up exciting new opportunities to understand and ultimately reverse aging-related diseases," says biochemist Janine Sengstack.

The research has been published in PNAS.