Longevity Briefs: Boosting A Single Protein Reduces Frailty In Aged Mice

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:

Chronic inflammation is believed to be an important driver of most age-related diseases. Inflammation is a vital response against pathogens, helping to keep them at bay until the rest of the immune system ‘learns’ how to target those pathogens specifically. But inflammation is a ‘weapon of mass destruction’ – it causes a lot of collateral damage to healthy human cells, and so it is important for inflammation to last only as long as it is needed.

Unfortunately, as we age, the immune system increasingly shifts towards an inflammatory state. Even when no pathogens are present, inflammation ‘simmers’ at a low level. Levels of inflammatory signalling molecules in the blood rise, triggering inflammation in different tissues. Impacted tissues include muscle and bone, both of which see a decline in mass and strength with age, contributing to age-related frailty. In this study, researchers investigate whether tristetraprolin (TTP), a protein that degrades the genetic instructions for inflammatory molecules, can reduce frailty in mice.

The discovery:

TTP is a protein that promotes the degradation of messenger RNA (mRNA) molecules that encode inflammatory signalling molecules. mRNA functions as a temporary blueprint, copied from DNA, that carries instructions to build proteins. Higher levels of TTP mean that mRNA gets degraded faster, meaning that fewer inflammatory proteins are produced. TTP levels have been shown to decline with age in humans, and mouse studies indicated that TTP deficiency in immune cells was enough to skew the immune system towards inflammation. For these reasons, researchers suspected that boosting TTP might be sufficient to correct this course and thereby reduce age-related frailty.

To test this, researchers created a TTP gene variant that would increase the stability of the mRNA encoding TTP, thereby increasing production. Researchers then modified 29 mice to carry this altered gene (TTP∆ARE). When these mice were 22 months old (roughly ‘equivalent’ to a human in their 60s), they were put through various physical tests and compared with 24 unaltered mice that were the same age, as well as 30 unaltered ‘young’ 6 month-old mice.

They found that TTP∆ARE mice had significantly improved gait speed and grip strength, and were able to last longer on a treadmill when compared to control 22 month-old mice. The only exception was in female TTP∆ARE mice specifically, whose grip strength was not significantly better than controls. The female TTP∆ARE mice generally seemed to benefit a little less, as their physical performance was still significantly worse than the young mice in every test, whereas in the male mice, grip strength and treadmill endurance was not significantly worse than in the younger mice.

TTP∆ARE mice were also found to have significantly improved bone mineral density and thickness. This corresponded to reduced activity of M-MDSCs (M-myeloid-derived suppressor cells), which are cells produced in the bone marrow that can stimulate the formation of osteoclasts (cells that break down bone tissue). TTP∆ARE mice also appeared to gain some immune benefits, such as increased counts of certain types of T cell, while some inflammatory signalling molecules were suppressed.

The implications:

This study suggests that increasing tristetraprolin levels alone can significantly enhance bone health and decrease frailty in mice by shifting the immune system away from an inflammatory state. If similar mechanisms are at play in humans, enhancing TTP could potentially be a means of mitigating conditions like osteoporosis and sarcopenia (bone and muscle wasting respectively) which are major causes of frailty and mortality. Rebalancing the immune system in this way could potentially have additional, wide-ranging benefits that weren’t looked at in this study. Chronic inflammation is an important driver of both cardiovascular diseases and neurodegenerative diseases, for example.

Unfortunately, there is currently no known drug capable of increasing TTP levels, which is why researchers had to genetically engineer mice to produce more of it. This raises a potential issue, which is that these mice were producing the altered TTP mRNA throughout their entire lives. For a human therapy to be viable, it would need to work when started in old age. Since inflammatory molecules play a role in embryonic development and early growth, there is also a possibility that TTP influenced the mice’s development in a way that made them less susceptible to frailty later on.