Thymic health consequences in adults | Nature

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Subjects

- Cancer screening

- Cardiovascular diseases

- Lung cancer

- Prognostic markers

Abstract

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults1,2. Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large prospective cohorts of asymptomatic adults: the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581). In both cohorts, thymic health varied markedly across the population. In the National Lung Screening Trial, higher thymic health was consistently associated with lower all-cause mortality, reduced lung cancer incidence and lower cardiovascular mortality over 12 years of follow-up after adjustment for age, sex, smoking and comorbidities. In the independent Framingham Heart Study cohort, higher thymic health was significantly associated with reduced cardiovascular mortality, independent of age, sex and smoking. Thymic health was further linked to systemic inflammation and metabolic dysregulation, and associated with modifiable lifestyle factors including smoking, obesity and physical activity. Together, these findings reposition the thymus as a central regulator of immune-mediated ageing and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy ageing and longevity.

Main

The thymus is a specialized immune organ responsible for maturing T cells, thereby producing a diverse T cell repertoire crucial for mounting an adaptive immune response1,2. The thymus itself decays with age and eventually transforms entirely into adipose tissue through a process known as thymic involution3. While the absence of a functioning thymus in children is associated with profound immunodeficiency4, the consequences of thymic decay in adulthood are more subtle5,6. Indeed, it was long believed that once the thymus generates a sufficiently diverse T cell repertoire in childhood, the T cell repertoire could be peripherally maintained to support an adaptive immune response against a diverse array of pathogens2,7. For this reason, the thymus has long been considered largely nonfunctional in adults.

However, a growing body of evidence challenges this notion2,6,8,9,10,11,12,13,14,15,16,17. In a recent landmark study by Kooshesh et al.8 investigating the impact of thymectomy on long-term health, the authors found that adults who had their thymus removed experienced adverse health consequences across multiple diseases and outcomes, where penetrance can be decades after thymectomy8. While the consequences of thymectomy are impactful, only a small fraction of the population is exposed to this procedure, whereas individual and lifestyle-dependent differences in thymic decay affect everyone.

Although the impact of thymic function is increasingly recognized in ageing and across a wide range of clinical settings, thymic decay across the population has been incompletely explored2,13. However, there is increasing evidence that the rate of thymic involution varies among individuals18,19,20. Indeed, given the role of the thymus in maintaining an adaptive immune response, the individualized rate of thymic decay may be a major driver of age-associated diseases, such as cardiovascular disease and cancer13.

In this study, we investigated the impact of thymic functionality, here called thymic health, in adults. For this purpose, we analysed two prospectively collected cohorts of 27,612 individuals enrolled in the Framingham Heart Study (FHS) and National Lung Screening Trial (NLST). We developed a deep learning system to automatically quantify thymic health on computed tomography (CT) scans. Our results demonstrate that thymic health varies between individuals and is impacted by sex, age and lifestyle habits. Notably, we show that individuals with low thymic health, that is, lost thymic functionality, have a shorter lifespan and an increased risk of cancer and cardiovascular diseases. These findings strongly suggest that thymic health is crucial for long-term health and lifespan.

Quantification of thymic health

For quantification of thymic health, we developed a deep learning system using an independent dataset of 5,674 individuals to determine compositional radiographic characteristics of the thymus as a proxy for its functionality (Fig. 1, Methods and Supplementary Fig. 9). The system takes a CT scan as input and provides the automatic continuous thymic health estimate as output. We applied the system to prospectively collected data from a total of 27,612 individuals from two cohorts, including 2,581 participants in the FHS and 25,03