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Can research into a rare, accelerated aging disease and “zombie cells” teach us something about the normal aging process?

Did you know that a small molecule called NAD⁺ plays a critical role in our ageing process? A deficiency of this molecule may cause you to age much faster than normal. Imagine your cells stopping energy production or your DNA struggling to repair itself. This is the harsh reality of aging, as well as the experience of individuals with Werner syndrome, a rare and severe genetic disorder that leads to premature aging.

Now, in groundbreaking studies, researchers have found that NAD⁺ supplementation could be a potential treatment for these accelerated aging diseases. The study on NAD+ deficiency in Werner syndrome was published in the leading aging journal Aging-US.

The reality of Werner syndrome

“Werner syndrome is an adult-onset progeria where individuals age more rapidly. By their 20s and 30s, the patients start to show greying and loss of hair, wrinkles, and appear much older than their actual age,” explains Dr. Sofie Lautrup, a postdoctoral researcher at the Department of clinical molecular biology at the University of Oslo and Akershus University Hospital. Patients with Werner syndrome experience typical age-related diseases and life-threatening complications as early as in their 30s-40s, accompanied by significant changes in cellular metabolism, which means that the cells no longer behave normally.

“Our research has found that one reason for this is that they have lower levels of NAD⁺ in their mitochondria, the body’s cellular powerhouse,” Lautrup shares.

Dr. Lautrup and her colleagues have analysed cells from patients with Werner syndrome in the lab. Their research reveals, for the first time, that these individuals have decreased NAD⁺ levels in their mitochondria compared to healthy individuals. This supports their previous findings on dysregulated NAD⁺ metabolism and mitochondrial function in premature aging.

The promise of NAD⁺, a vital molecule in life

The researchers investigated whether supplementing NAD⁺ could restore normal cellular function and achieved remarkable results. “We found that supplying NAD⁺ can stimulate stem cell growth and inhibit the premature ageing process in stem and skin cells from patients,” Lautrup elaborates. This suggests that NAD⁺ supplementation could be a potential treatment for Werner syndrome patients. But could NAD⁺ also significantly impact normal aging?

So, what exactly is NAD⁺, and why is it essential for our bodies? NAD⁺ is a molecule found in all living cells, which plays a vital role in numerous cellular functions. “We need NAD⁺ to produce energy in our cells. It contributes to cellular health and metabolism by eliminating damaged mitochondria and plays several other critical roles in our cells,” explains Lautrup, adding, “Without NAD⁺, we literally cannot live.”

Thus, despite its small size, NAD⁺ has a monumental effect on the body, acting as an invisible force driving key metabolic processes.

Using Werner Syndrome to understand aging

As natural aging occurs, our NAD⁺ levels substantially decline. Previously, Lautrup and her team observed that patients with Werner syndrome also have significantly lower NAD⁺ levels in their blood. This condition accelerates the aging process, making it a useful model for researchers to gain insights into ageing itself.

Zombie cells: neither dead nor alive

A crucial function of our bodies is cell division, which we need to grow and repair damaged tissue. As we age, this ability diminishes, resulting in a state called senescence. Werner syndrome is caused by mutations in a gene essential for DNA maintenance and repair, and therefore cell division.

“One major hallmark of Werner syndrome is lack of proliferation and premature senescence. This means that cells without the WERNER protein divide poorly. Even though patients are relatively young, their cells stop dividing,” Lautrup explains.

Therefore, Werner syndrome patients show loss of stem cell proliferative capacity, which has detrimental consequences to the patients. “One could explain senescence cells as a type of zombie cells. They are neither dead nor alive, unable to perform their normal functions.”

Researchers suspect that the low level of NAD⁺ in these patients contributes to the early onset of this zombie state.

Reversing aging with NAD⁺

In their studies, the researchers examined both stem cells and skin cells from Werner syndrome patients in the lab, comparing them with cells from healthy controls. “We wondered whether NAD⁺ could reinstall proliferation in patient-derived cells,” Lautrup says.

Within just 24 hours of receiving a precursor molecule that converts to NAD⁺, multiple proliferation-related pathways were upregulated and senescence related pathways were downregulated.

“We found that NAD⁺ treatment can clearly reverse these features of the disease. The cells looked more like healthy cells,” Lautrup states. “NAD⁺ reduced the number of zombie cells and slowed down the ongoing senescence in the patients’ cells.”

A glimmer of hope from fruit flies

Previously, Lautrup and her colleagues conducted experiments with roundworms and fruit flies (drosophila melanogaster) modelling Werner syndrome.

They administered a molecule that converts into NAD⁺ within the cells. The results showed that NAD⁺ treatment successfully stimulated stem cell proliferation in the fruit flies, leading to improved mitochondrial function. Even with Werner syndrome, these organisms lived longer than expected.

“This finding in fruit flies made us wonder if NAD⁺ could restore cell division in the cells of actual patients,” she adds.

Paving the way for new treatments

Lautrup’s research has triggered clinical studies currently underway in Japan, focusing on Werner syndrome and NAD⁺.

“We eagerly await the results,” she shares. “We hope that this study, combined with our previous work on Werner syndrome and NAD⁺, will pave the way for new treatments not only for Werner syndrome but potentially for other aging-related diseases.”

Can we slow down the aging process?

If researchers can restore cellular NAD⁺ levels, the goal is to slow the ageing process. “We use Werner syndrome as a model for normal ageing. We’re continually hopeful that our research will provide insights for studies on typical ageing; however, we still do not know if NAD⁺ can help slow down natural ageing in humans,” Lautrup concludes.

As this research progresses, the scientific community remains hopeful that understanding the role of NAD⁺ and addressing the phenomenon of zombie cells may open new avenues for promoting longevity and better health in aging populations.

The paper builds on a collaborative project between both University of Oslo, Chinese University of Hong Kong, Shiba University in Japan, Bergen University and more supported among others by NordForsk (a Japan-Norway-Sweden collaboration).