Naked mole-rats, those peculiar-looking creatures that live in underground colonies, have fascinated scientists for years. Although appearing perpetually old, these small, wrinkled rodents defy the aging process, living for over 40 years without showing any signs of aging. In contrast, on average a mouse typically enjoys only two years of life. How do naked mole-rats stay youthful and healthy for so long? In this article, we delve into the unique nature of these creatures, exploring the latest research that may unlock the secrets behind their extraordinary longevity and resilience.

One key factor contributing to the naked mole-rat’s remarkable longevity is its ability to repair age-associated damage that accumulates over time. They excel in repairing the damage caused by oxygen free radicals and DNA errors, two major culprits behind aging in most organisms. Even more astonishing is that, despite possessing genes that make them theoretically vulnerable to cancer, naked mole-rats rarely develop this disease. Collaborative research from the University of Rochester, Harvard Medical School, and UCLA is interrogating the role of hyaluronic acid as a molecule responsible for the naked mole-rat’s protracted lifespan and near invulnerability to cancer.

The Hyaluronic Acid Connection

Hyaluronic acid (HA) is a popular ingredient in cosmetics and skincare products due to its exceptional moisturizing properties. A naturally occurring substance in the human body, HA has the ability to hold a significant amount of water, contributing to skin hydration and suppleness. In cosmetics, it is often used in the form of smaller molecules, allowing it to penetrate the skin’s surface and provide deep hydration. While HA applied topically offers noticeable benefits in terms of skin hydration and a more youthful appearance, the recent research on high-molecular-mass hyaluronic acid (HMM-HA) in naked mole-rats hints at the potential for even more profound anti-aging effects when used in this larger molecular form.

While there are several theories about the mechanisms driving naked mole-rat longevity, one theory has gained significant attention recently, thanks to a study published in the journal Nature (Zhang Z, Tian X, Lu JY, et al. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature, 2023: 621:196–205  https://doi.org/10.1038/s41586-023-06463-0). This theory revolves around the abundance of HMM-HA in the naked mole-rat’s body. HMM-HA is found in the chemical-rich matrix between cells throughout the naked mole-rat’s body.

Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester and a prominent researcher in the longevity field, led a groundbreaking study in which she introduced the naked mole-rat gene responsible for producing HMM-HA into mice. The results were promising.

Benefits of HMM-HA

Introducing the naked mole-rat gene into mice resulted in several remarkable benefits. First and foremost, the altered mice had a significantly lower incidence of cancer compared to the control group. While 70% of the control mice eventually developed cancer, only 57% of the HMM-HA-expressing mice faced this outcome. The most significant improvement was observed in the oldest subset of mice, where the difference was 83% and 47%, respectively.

Moreover, the Has2 mice, as they were called (containing the naked mole-rat gene), experienced a substantial increase in lifespan. Has2 males lived more than 16% longer, females a less robust 9%. The most significant impact was on their healthspan, as they scored better in frailty measurements, mobility, coordination, bone density, and various other indicators of health.

The HMM-HA molecule was found to deliver these benefits by reducing senescence, likely resulting from the observed reduction of inflammation through the modulation of multiple pathways. These changes are thought to improve the quality of immune cells, which act as immunoregulatory agents, fortify defense against oxidative stress, and enhance the integrity of the gut barrier, a tissue normally degraded as part of the aging process.

Apart from changes to genes regulating inflammation and senescence, the forced expression of this molecule also upregulated a variety of genes associated with enhanced longevity, specifically those involved in mitochondrial function.

Future Prospects

This study represents the first instance of a gene transferred from one species to another demonstrably extending lifespan, offering tangible evidence of the remarkable interplay between genetic elements and lifespan regulation.

The introduction of the naked mole-rat gene responsible for HMM-HA into mice resulted in a significant increase in their longevity. This unprecedented achievement not only opens new avenues for understanding the intricate mechanisms of aging but also underscores the potential for cross-species genetic transfers to positively influence lifespan and healthspan in ways previously unexplored.

While these findings are exciting, it is essential to approach the idea of transferring genes from one species to another, especially humans, with caution. Such a process is fraught with inherent risks that necessitate careful consideration and extensive research, the primary concern being the potential for unpredictable and unintended consequences. Genes and their functions are highly complex, and introducing foreign genetic material into a human genome could lead to unexpected mutations, disruptions in essential biological processes, and the development of unforeseen health issues. Furthermore, there is a risk of triggering immune responses or adverse reactions, potentially resulting in allergic reactions or autoimmune disorders. However, the insights gained into the naked mole-rat’s longevity and the role of HMM-HA are valuable.

Understanding the mechanisms through which HMM-HA imparts its benefits could lead to further development of pharmaceuticals that harness the potential of HMM-HA to address aging-related issues in humans. Investigating the secrets of the long-lived naked mole-rat could open doors to other pro-longevity therapies, offering new hope for a healthier and longer life. Although the fountain of youth may still be a myth, the humble naked mole-rat is providing tantalizing clues about the potential for improving our health and lifespan.