Skin autofluorescence and cause-specific mortality in a population-based cohort

The current study is one of the first to report on the association between SAF and cause-specific mortality in the general population. We observed that SAF was associated with a higher all-cause, cardiovascular and cancer-related mortality. Moreover, age-adjusted SAF values were found to be significantly higher for all cause-specific mortality groups, except for people who died of infectious diseases such as Influenza and pneumonia.

A previous study from our group reported an association between SAF and all-cause mortality in the general population¹⁰. Other studies on mortality have been performed in specific groups of patients, and have reported an association between SAF and cardiovascular mortality in patients with chronic kidney disease¹⁸, chronic hemodialysis^11,19,20,21, type 1 and type 2 diabetes¹³, and peripheral artery disease¹². The present study extends our earlier observations because we were able to link overall mortality data with specific causes of death, which are registered at the official death certificates. We confirmed the association of SAF and cardiovascular mortality in the general population. This was not surprising, as previous studies have shown a strong association between SAF and CVD, as well as cardiovascular risk factors. In the present study, we found 40% greater odds of cardiovascular mortality; however, after we adjusted for age, sex, smoking status, and BMI, the association was no longer significant, as all these factors by themselves are associated with higher SAF levels.

Recently, a French study showed that higher SAF predicted the new-onset of cancer in individuals with type 2 diabetes¹⁴. Our current study clearly shows an association between increased SAF and cancer mortality, and as such, these findings confirm the association between SAF and cancer. There is evidence that AGEs may play a role in cancer development and progression²². AGEs have been demonstrated in different types of tumors²³. Also, upregulation of the RAGE receptor is associated with tumor size and malignant potential of ovarian and breast cancer^24,25. However, it should be noted that the association between advanced glycation end-products and cancer could be overestimated due to significant shared risk factors between the pathophysiology of AGE accumulation and cancer. An increase in blood-pressure is associated with increased cancer-related mortality²⁶. Obesity is a proven risk factor for CVD, and is estimated to be related with 1 in 5 types of cancer²⁷. There is overwhelming evidence for smoking – a factor well-known to increase SAF- as a risk factor for heart disease and malignancies, and indeed, in our data the highest SAF values were measured in people who subsequently died from lung cancer. In diabetes, an increased incidence of certain types of cancer is observed compared to individuals without diabetes, with increased levels of insulin and insulin-like growth factor as a promotor of cell proliferation as one of the possible explanations²⁸. Conversely, a healthy lifestyle protects against cardiovascular disease as well as incident cancer²⁹. Coincidentally, all these shared risk factors are also associated with higher SAF⁹, while a healthy lifestyle is associated with a lower SAF³⁰. However even after adjusting for confounders SAF remained significantly associated with cancer-related mortality, unlike cardiovascular mortality. This could be partly explained by lower number of cardiovascular deaths.

A striking finding was that SAF was also elevated in non-cardiovascular and cancer-related mortality. The association between SAF and chronic lower respiratory diseases can be explained by the fact that tobacco use is both an important etiologic factor in respiratory disorders, and is also an important source of AGEs. In previous studies, respiratory disorders have been strongly associated with elevated SAF³¹.

For mortality from accidents, clear conclusions cannot be drawn due to the low number of events. A possible confounder is mortality due to falls in frail elderly, as SAF is associated with frailty³². Additionally, mental disorders are a risk factor for accidental death³³ and SAF has been shown to be associated with affective disorders³⁴.

As the association between SAF and different causes of death can be explained by shared risk factors, the role of SAF in the pathophysiology in non-cardiovascular mortality remains unclear and needs further investigation. According to our data, SAF is elevated in every major group of cause-specific mortality except infectious disorders (influenza and pneumonia). This finding supports the possible utility of SAF as a screening tool, not only for cardiovascular disease and diabetes³⁵, but also for mortality by other causes of death. Measuring SAF may help in selecting populations who benefit from cancer screening, as was also suggested by Foussard et al.

Strength and limitations

A strength of the current study is the unparalleled large number of participants. The Lifelines cohort is representative of the populations of the northern provinces of the Netherlands for sociodemographic parameters³⁶. Also, the reliability of cause of death statistics in the Netherlands is high³⁷.

Limitations include the relatively young age of participants in the Lifelines cohort and relatively short follow-up of approximately 10 years, which resulted in a low number of deaths. This resulted in a lack of power to investigate or reject the association between SAF and cause-specific mortality in a fully-adjusted model. The relatively low age of participants in Lifelines could have influenced the results. In the Netherlands, people are more likely to die of cancer than any other cause, while older people die more frequently due to cardiovascular disease³⁸.