How fast you age may be controlled by a DNA repair boss in your cells

Recent findings suggest that a specific clump of proteins in our cells manages the extent of DNA repair, determining the pace at which mutations accumulate over time. This process may significantly influence not just how we age, but our overall longevity as well.

According to Trey Ideker from the University of California, San Diego, the level of repair can reliably indicate lifespan both in humans and various animal species. His team is exploring pharmacological interventions that could enhance lifespan by improving DNA repair mechanisms.

While some researchers find the evidence linking this protein complex—known as DREAM—with mutation rates compelling, they emphasize that further studies are necessary to fully understand its relationship with aging and longevity.

The prevailing theory of aging suggests a connection to the gradual accumulation of mutations within cellular DNA. As these mutations proliferate, cellular functions deteriorate, triggering a cascade of health issues.

Even though our cells are equipped with dedicated repair systems to address DNA damage, they often fall short in numbers, with the efficiency of DNA repair tasks being primarily influenced by genetics.

Ideker’s research has brought to light compelling evidence that the DREAM protein complex acts as a critical regulator of DNA repair levels—essentially steering the repair workforce. Each DREAM complex can exist in various identical copies within a cell and is constructed from several distinct proteins, from which the name DREAM is derived.

Initially, DREAM was believed to oversee cell division. However, it is now recognized to inhibit hundreds of genes essential for DNA repair, including the BRCA2 gene, which is associated with increased breast cancer risk upon mutation.

The methodology adopted by Ideker’s team involved measuring DREAM activity by examining over 300 genes it regulates; lower activity in these genes indicates higher DREAM activity levels. “Our study aims to establish that elevated DREAM activity is detrimental to aging and longevity, while reduced DREAM activity correlates positively with longevity,” Ideker explains.

In their investigations, data was analyzed from over 100,000 mouse cells across various tissues, showing that higher DREAM activity led to an increased number of mutations. They also reviewed data from 92 mammal species, where a significant correlation between lower DREAM activity and extended maximum lifespans was observed.

Additionally, by studying the cells of 90 individuals—including 80 diagnosed with Alzheimer’s disease—the researchers identified a connection between DREAM activity and Alzheimer’s risk.

The research team attempted to genetically modify mice to eliminate DREAM, although this posed a significant challenge. Each protein in the DREAM complex serves vital functions, and disrupting the entire complex during early developmental stages resulted in non-viable offspring. To circumvent this, they administered a drug to knock out DREAM in 8-week-old mice, showing a notable reduction in mutations—specifically, 20% fewer deletions and insertions in their brain cells by the time of natural death. While these knockout mice did not live longer, Ideker insists this limitation is tied to the experimental setup, stating, “The design wasn’t optimal for assessing longevity, and we need to refine it to explore lifespan extension effectively.”

Despite the challenges, Ideker believes the evidence consolidates a compelling narrative. “Our findings affirm that DREAM significantly influences aging and the buildup of mutations throughout life,” he asserts.

João Pedro de Magalhães from the University of Birmingham acknowledges, “Their data from mice indicates a causative relationship between DREAM and mutation levels.” However, de Magalhães highlights that a direct causative link to aging remains unproven. “To establish this link, they would need to demonstrate that mice with lower mutation levels also enjoy longer lifespans, which has not been accomplished yet.”

Thus, while the hypothesis that mutation accumulation is a primary factor in aging is yet to be conclusively proven, advocates like Ideker argue that instances such as progeria—characterized by premature aging due to inadequate DNA repair—support the theory. Conversely, critiques from de Magalhães maintain that there lacks comprehensive evidence linking mutational accumulation to regular aging beyond its association with cancer risk.

Even if the DREAM complex plays a pivotal role in the aging process, its multifaceted functions could complicate therapeutic applications. “It is possible that a complete loss of DREAM function, as we observed, is too extreme,” suggests Zane Koch, part of Ideker’s team. “A more nuanced approach involving partial DREAM inhibition might hold the key to lifespan extension.”