Longevity Briefs: Klotho Protein Extends Mouse Lifespan, But There Are Problems

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Klotho refers to a group of signalling proteins that play an important role in many biological processes, such as the proper functioning of the blood vessels, nervous system and kidneys. Many researchers are also interested in klotho for its apparent anti-ageing properties. Numerous studies in animals suggest that genetically boosting klotho levels can extend lifespan and reduce age-related deterioration and disease. Furthermore, klotho levels and mutations in the klotho gene are associated with age-related disease risk in humans.

There are multiple different forms of klotho with varying properties. In this study, researchers investigate the effects of a particular klotho protein called the secreted KL (s-KL) isoform in mice. The researchers chose this version because it appears to be safer than the alternate isoform, p-KL, which can disrupt mineral metabolism.

The discovery:

The researchers made an adeno-associated virus (AAV) containing genetic code for the s-KL isoform. AAVs carry their genetic code to cells, which then use their genetic machinery to read that code and produce the desired protein. The researchers then took 96 mice and split them into three groups. One group received and injection of the AAV at 6 months of age, another group received the same treatment at 12 months, while the control group received an empty AAV at 6 months.

Starting with the good news, treated mice benefited from improved physical performance, tissue regeneration and lifespan. The bad news is that many of these benefits favoured or were exclusive to either male or female mice. Only the male mice experienced statistically significant improvements in average and maximum lifespans, and only in the group treated at 12 months of age. Over 50% of the male mice in the 12 month treatment group outlived the longest living mouse in the control group. Male mice also had significantly better grip strength and less muscle scarring when tested at 24 months when compared to the female mice, who benefited less. All treated mice also had better muscle regenerative capacity and appeared to have healthier, more rapidly dividing brain cells, though no cognitive tests were done. Only the female mice experienced statistically significant improvements in bone structure and were better able to balance on a rotating rod, a general test of endurance, grip and motor coordination.

The female mice also suffered much worse side effects than the male mice, including skin ulcers and rectal bleeding. This was despite the fact that s-KL levels were increased much more in the males.

The implications:

This study adds to the existing evidence that klotho can extend lifespan in animals and prevent age-related deterioration of various tissues. It also improves our knowledge of a specific klotho protein, s-KL, and what happens when it is expressed throughout life from a relatively early stage before age-related disease has set in. However, it also showcases some of the problems we are likely to face trying to translate anti-ageing therapies to humans. Male and female biology is different, and humanity also contains a lot of genetic diversity that could influence the effectiveness of future anti-ageing therapies. Mouse studies from the Interventions Testing Program, the gold standard research program for determining if a drug extends lifespan, shows that anti-ageing drugs tend to be more effective in males, though this may be partly because males have shorter lifespans to begin with.