Called the 'DREAM complex,' these proteins may determine how fast humans age

Cells age for many reasons, but one idea keeps resurfacing. As the years pass, small DNA changes stack up inside tissues and slowly tilt biology off balance. A new set of analyses points the finger at a single control hub for that stack up.

The DREAM complex is named for its components Dp, Rb-like, E2F, and Muv. This group of proteins work together to shut down certain genes, including many involved in DNA repair.

Scientists say that DREAM resembles a built-in “brake” on DNA repair – when that brake presses harder, mutations rise and age related problems follow.

DREAM complex blocks DNA repair

The DREAM complex is a multiprotein repressor that limits the expression of many DNA repair genes in nondividing cells. Its job in quiescent cells is to keep growth programs quiet, but that silence also reaches repair pathways.

This work features Trey Ideker from the University of California San Diego (UCSD).

His lab and collaborators assembled evidence that links measured DREAM activity to mutation levels in cells, differences in lifespan across mammal species, and signs of Alzheimer’s risk in people.

“We show that the DREAM complex transcriptionally represses essentially all DNA repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA repair capacities,” wrote Ideker.

In 2023, investigators showed that DREAM suppresses a wide span of repair programs in worms and human cells. 

When DREAM complex is chemically inhibited in cells, repair genes pick up speed and tissues cope better with damage stressors. That response offers a clue to how cells balance growth, rest, and repair across the lifespan.

What new data shows

A new preprint maps DREAM activity in single cells from mouse tissues, across 92 mammal species, and in brains from large human datasets.

One signal repeats across those scales, lower DREAM activity goes with fewer mutations and longer life.

“DREAM knockout protects against mutation accumulation in vivo, reducing single base substitutions by 4.2 percent and insertion or deletions by 19.6 percent in brains of mice,” reported Ideker.

The team engineered mice so the complex cannot form after early development. 

Cells and tissues with higher DREAM complex activity carried more mutations at any given age. That was true across many organs, not just one cell type, and it held up after accounting for how fast cells divide.

In human brain datasets, individuals with higher inferred DREAM activity tended to be diagnosed with Alzheimer’s earlier.

The same score tracked with more severe neuropathology and with a higher per cell mutational load.

How DREAM complex controls repair

DREAM is not the only player in this story. Other cellular pathways can guide when it turns on or off, especially during stress.

One of the important repair genes affected is BRCA2, which normally helps fix DNA with high accuracy. When DREAM suppresses BRCA2, cells rely on less precise repair methods, increasing the risk of errors.

Another key factor, called DYRK1A, helps assemble DREAM in resting cells. When DYRK1A is blocked, DREAM loses its grip and repair genes become more active, allowing cells to better handle DNA damage.

The fact that one complex can shut down so many repair systems explains why mutations build up with age, even in tissues that divide very little.

It also shows scientists a potential target for adjusting how fast those mutations accumulate.

Mutation matters for lifespan

Species differ wildly in lifespan, but late life mutational burden does not. A cross species study showed that the rate at which somatic mutations accumulate each year tends to be lower in long lived mammals.

The DREAM complex analyses echo that pattern. Species with lower DREAM activity have longer maximum lifespans and lower measured mutation rates in sequenced tissues.

If a conserved brake controls repair capacity, that could be one mechanism behind the scaling of mutation with lifespan. It fits with other observations that long lived species invest more in genome maintenance.

The link does not prove that mutation alone sets lifespan, but it shows a plausible lever that biology already uses. That lever can now be measured in tissues and compared across species.

DREAM complex and Alzheimer’s angle

Neurons handle a lot of DNA stress. Independent pathology work shows that neurons in Alzheimer’s brains accumulate double strand breaks early in disease.

The new analyses tie higher DREAM activity to earlier diagnosis and to worse pathology scores. That pattern matches the idea that less repair capacity leaves neurons with more persistent damage over time.

The study also found that human cells with higher DREAM activity pick up more mutations per year. That includes brain cells, which normally divide rarely and depend on accurate repair to stay stable.

The convergence of human neuropathology, single cell mutation counts, and a repair repressor makes a coherent story. It does not close the case, but it raises the stakes for testing DNA repair control in neurodegeneration.

Where the science still needs work

Not every result points one way. In the mouse experiment, knocking out DREAM complex late did not extend lifespan, and the authors note that the design was not tuned for that test.

Correlation is not causation. High DREAM activity could track with other stress pathways that drive aging, so careful perturbation studies will be needed in different tissues and at different life stages.

Some biologists argue that mutation accumulation explains cancer risk well but does not yet account for many normal aging traits. Others counter with data from progeroid syndromes that link weak repair to rapid aging.

The next step is clear, change DREAM activity at the right time and in the right cells, then watch longevity, function, and side effects with a cold eye. That is the sort of test that can separate signal from story.

Targeting DREAM complex with drugs

If partial DREAM inhibition safely raises repair, that could slow the pace at which tissues accumulate mutations.

Any such approach would need to preserve normal cell cycle control and avoid pushing cells toward unwanted growth.

Drugs that modulate DYRK1A or that block DREAM assembly already exist in research settings. Early work shows they can lift repair gene expression and reduce damage markers in some models.

Therapies will have to find a middle path. Too much inhibition could interfere with essential control of the cell cycle, while too little might not meaningfully change mutation rates.

For now, the value is conceptual and practical. A measurable control point for repair gives aging research a sharper tool and a testable hypothesis for diseases of late life.

The study is published in bioRxiv.

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