Signs of ageing: Metabolite linked to rate of ageing

Signs of ageing

Ageing is a complex process that is not fully understood, although it is known to depend on a number of factors. Genetics, lifestyle, diet, and what are loosely termed environmental factors like smoking and exposure to UV rays, pesticides and infectious materials are all known to have an effect on the speed at which we age. The contribution from genetic variations is thought to be about 20-25%, which leaves a large proportion which can be attributed to biochemical and molecular changes within the body.

The health of people in old age has been related to very early developmental factors. For instance, it is well established that people with a low birth weight are more likely to develop age-related diseases later in life but the molecular mechanisms behind this link have not been proven. Several studies have identified specific metabolites whose levels in the body change with age, with up to 160 compounds implicated. It is possible that some of these metabolites could be used to predict how long people will live.

Now, a multinational research team has studied sets of twins with very different birth weights to see how they might affect the metabolic profile of each individual. Senior reporter Ana Valdes from King’s College London explained that using twins rules out any genetic variations, allowing for a clear comparison between paired siblings. They undertook an open metabolomics study of metabolites in the blood, not targeting any particular compounds but looking for those which seemed to correlate with age.

Metabolites linked to ageing

Fasting serum and fasting plasma from a total of 6055 twins registered in the TwinsUK registry of adult twins were analysed by LC/MS/MS in positive- and negative-ion modes and GC/MS/MS. The metabolites were identified by matching their mass spectral features to the spectra of more than 2400 standards held in a library using the retention time, molecular mass, spectral adducts and in-source fragments.

A total of 280 metabolites were identified and their levels were measured using the area-under-the-curve technique so that they could be compared with each other. Using a linear regression analysis with age as the dependent variable, 22 metabolites were found to be strongly associated with age. They included seven amino acids, nine lipids (including steroids and fatty acids), citrate, phosphate, threitol, urate and the xenobiotics erythritol and dimethylurate.

Since some of these 22 had already been correlated with age in earlier studies, the research team took that as proof of principle that the remaining metabolites in the set were genuine age markers. Their concentrations in blood increased with age and when they were added together and associated with age-related traits like lung function, blood pressure and bone mineral density, they appeared to be a measure of biological ageing when the data were adjusted for chronological age.

The special one

One metabolite in particular, C-glycosyltryptophan, caught the eye because it has never been associated with age before. On its own it correlated with age, lung function, bone density, cholesterol levels and blood pressure. The team concentrated on this compound because it could implicate new biological pathways that are involved with ageing.

In the first place, they confirmed its association with chronological age and lung function using data from a group of 887 people who were involved in a German study. They also linked this metabolite directly to birth weight, which is a known indicator of healthy ageing later in life. For 85 genetically identical twins with a weight difference at birth of 750 g, C-glycosyltryptophan accounted for 9.4% of the variance, the twins born lighter having more of the metabolite when they were tested.

The gene that controls the levels of C-glycosyltryptophan was found to be affected by environmental factors or lifestyle, which might alter the metabolism and the risk of age-related diseases. Valdes commented "This shows us that birth weight affects a molecular mechanism that alters this metabolite. This may help us understand how lower nutrition in the womb alters molecular pathways that result in faster ageing and a higher risk of age-related diseases fifty years later."

The work could have far-reaching consequences. As Valdes said "Understanding the molecular pathways involved in the ageing process could ultimately pave the way for future therapies to treat age-related conditions."

However, apart from new treatments, it could lead to a blood test that will predict someone’s lifetime and how fast they will age. "As these 22 metabolites linked to ageing are detectable in the blood, we can now predict actual age from a blood sample pretty accurately and in the future this can be refined to potentially identify future rapid biological ageing in individuals."