Scientists Moved A Longevity Gene From One Species To Another. Could Humans Benefit Too?

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Longevity research loves naked mole-rats. Why? Because these small mammals have exceptionally long lifespans relative to their size. An average naked mole-rat would fit in the palm of your hand, yet are capable of living up to 40 years. Not only that, but naked mole-rats display negligible senescence – rather than collecting age-related diseases and becoming increasingly frail in late life, most naked mole-rats remain relatively healthy right up until they die.

If we could learn and harness the secrets of naked mole-rats and other similar animals, humans might be able to live significantly longer and also remain free of age-related diseases for a much greater proportion of our lives. One component of naked mole-rats’ exceptional longevity is their resistance to cancer, a trait that could be down at least in part to a molecule called hyaluronic acid.

Naked mole rat
*https://www.buckinstitute.org/blog/naked-mole-rats-live-slow-die-old/*

What is Hyaluronic Acid?

Hyaluronic acid is a component of the extracellular matrix, the scaffold of proteins that exists in between cells and gives tissue its structure and mechanical properties. Hyaluronic acid affects cancer in different ways depending on its weight – high molecular mass hyaluronic acid (HMM-HA) seems to protect against cancer by reducing inflammation and impeding cell division and migration. Naked mole-rats have about ten times more HMM-HA than mice and humans. What would happen if we gave this ‘heavy’ hyaluronic acid to another species? Researchers set out to answer that question.

The Study

Researchers at the University of Rochester made a genetic mouse model bearing the naked mole rat version of the hyaluronan synthase 2 gene. This gene encodes the protein responsible for synthesising HMM-HA. Because introducing this gene could interfere with the embryonic development of the mice, researchers used a technique called conditional expression. This meant that the gene would not be active at birth, but they could ‘turn it on’ by giving the mice an injection of tamoxifen.

They then compared longevity in these mice with a control group that was treated with an ‘empty’ gene editing treatment. Both the treatment group and the control group contained 80-90 mice, which is quite a large sample size.

The Findings

Mice in the treatment group experienced pretty impressive benefits relative to the control group. In old age, only 40% of treated mice had signs of cancer compared to 80% of the control mice. HMM-HA seemed to protect against cancer whether naturally occurring or artificially induced – when researchers applied a toxin to the skin to induce skin cancer, mice in the treatment group were significantly less likely to be affected.

Treated mice also experienced some general benefits. They performed better on grip strength tests, had healthier bones, less inflammation, were measured to be biologically younger, and lived slightly but significantly longer than controls.

Left: percentage of surviving mice over time in the treatment group (red) vs control group (black).
Right: Estimated biological age relative to chronological age in the two groups. An AgeAccel of -0.2 means biological age is measured to be 0.2 years younger than expected.
Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice

All this was in spite of the fact that mice have much higher levels of hyaluronidase (the enzyme that breaks down HMM-HA) when compared to naked mole rats. The treatment also didn’t succeed in raising levels of HMM-HA to the same extent in all tissues. For example, skeletal muscle HMM-HA was raised eight-fold but the heart was unaffected. This suggests that there may be even greater benefits to be gained from increasing HMM-HA levels in more tissues.

The Implications

Hyaluronic acid is already used in the treatment of arthritis and is also found in many skincare products. However, no such treatment is going to get close to what was done here. In this study, cells throughout the mices’ bodies were producing their own HMM-HA, which is what made the wide-ranging benefits possible. This might be doable in humans using genetic techniques like mRNA or gene therapies, but it will be a long time before we get to that stage. Another approach that might be closer on the horizon would be to develop drugs that slow down the degradation of HMM-HA.

Long-term applications aside, this study demonstrates the value of studying unusually long-lived organisms to gather intel on how we might approach tackling ageing in our own species.