We all age, but we don’t all age the same way. For some people, ageing means an increased risk of developing illnesses such as diabetes, cardiovascular disease, weak bones and cognitive decline.
It would be ideal if we could predict in early adulthood, while a person is still healthy, whether or not they are at risk of becoming ill or needing medical support when they are older. By then taking preventative measures, this would mean fewer people with health issues, fewer people in care, and considerably lower costs for the health system.
Our latest study suggests that predicting long-term health outcomes may be possible. We have found a novel insulin-like hormone in the blood, called insulin-like peptide 3 (INSL3), that may be able to predict long-term health, and whether a person is likely to develop age-related diseases – at least for men.
To conduct our study, we looked at data from one of the largest cohorts of ageing men, the European Male Ageing Study. This had recruited 3,369 men between the ages of 40 and 79 from across Europe, including the UK, and followed them for four-to-five years. It was designed in part to assess whether the incidence of age-related disease in men can be explained by the decline of anabolic hormones such as testosterone, which is important for growth and development in the body.
Using data from the European Male Ageing Study, we looked for significant associations between INSL3 levels in stored blood samples that were taken at the beginning and end of the study, and the incidence of self-reported age-related illness. INSL3 was measured using a new testing method developed in our laboratory. We compared these results with the effects of other hormones such as testosterone, and also adjusted them for age, smoking status, and clinical parameters like obesity.
We were able to show that INSL3 levels can vary markedly from one person to another, and they were strongly associated with the incidence of illnesses such as cardiovascular disease, diabetes, loss of sexual function and bone weakness.
Men who had high INSL3 had lower risk of later becoming ill, while men with low INSL3 had a higher risk of developing age-related disease. Importantly, by looking at blood samples taken at both the beginning and end of the study, we showed that this relationship could be predicted several years in advance.
Although INSL3 is made in men exclusively by the same cells in the testes that make testosterone, the latter is highly variable. Testosterone levels can change markedly from hour to hour and day to day. This high variation makes it difficult to find statistically significant associations with other factors such as disease incidence.
Unlike testosterone, INSL3 levels remain amazingly consistent in a man’s bloodstream over long periods of time. This makes it possible to obtain similar values even when measured weeks, months or years apart. This allowed us to determine that low INSL3 was significantly linked with higher risk of age-related illness.
In fact, previous research from our group has shown that person-to-person variations in INSL3 levels can be seen in apparently healthy men as young as 18. Based on our findings, it seems that INSL3 levels remain similar throughout a man’s life. This means that we may be able to look at a man’s INSL3 levels when they are young and predict how likely they are to develop certain diseases when they get older.
It’s likely that INSL3 has functions in its own right, acting on different organs in the body. This will need to be confirmed by further research. What is clear is that the consistency of INSL3 throughout life makes it a much easier biomarker to observe when predicting age-related disease in men.
What’s behind these variations?
Our group in Nottingham is now focused on finding out what factors influence INSL3 levels in young men, and hence their capacity to make testosterone that could affect their later health.
Preliminary work from animal studies suggests that early-life nutrition may play a role, but many other factors including genetics or exposure to certain environmental factors (such as smoking) may also be involved. We need to confirm the predictive ability of INSL3 by studying men over a much longer period of time.
Of course, this work only relates to ageing men whose testes can function consistently into old age, only gradually declining in terms of sperm and hormone production. A woman’s physiology is much more radically modulated by ovarian function, which changes dramatically after the menopause. Hence we do not yet know of an equivalent to INSL3 for women when it comes to predicting ageing and disease.
Ravinder Anand-Ivell, Associate Professor of Endocrinology and Reproductive Physiology, University of Nottingham and Richard Ivell, Professor of Molecular Biology and Endocrinology, University of Nottingham
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