RERF Report No. 8-13

Paper published in PLOS ONE§“Inverse Associations between Obesity Indicators and Thymic T-cell Production Levels
in Aging Atomic-bomb Survivors”
Kengo Yoshida, Eiji Nakashima, Yoshiko Kubo, Mika Yamaoka, Junko Kajimura, Seishi Kyoizumi,
Tomonori Hayashi, Waka Ohishi, Yoichiro Kusunoki
PLoS ONE 2014 (March); 9(3):e91985(doi: 10.1371/journal.pone.0091985)

Study Findings
T-cell receptor excision circles, or TRECs, are circular molecules of DNA excised fromchromosomes when T cells are produced in the thymus. They indicate new production of T cells, andtheir numbers, which decrease with aging, represent an immunological marker of thymic capacity toproduce naïve T cells. In this study, low TREC numbers were found to be associated with diseases
related to high body mass index (BMI) and obesity, such as diabetes and fatty liver. These results
suggest the possibility that reduction of immunological competence associated with aging may befurther accelerated by obesity.

Figure. Relationship of naïve T-cell production levels to aging and obesity1

RERF Report No. 8-13

Explanation
The production of T cells, which are blood cells with immunological functions, starts in the bonemarrow and then continues in the thymus. In previous immunological studies at the Radiation Effects
Research Foundation (RERF), the number of naïve T cells in peripheral blood was found to decrease
after radiation exposure, leading to a hypothesis describing the mechanism behind this decline as theeffect of radiation exposure on the ability of the thymus to produce naïve T cells.
Based on animal model studies conducted in recent years, obesity has been linked to thefunctional decline of the T-cell immune system associated with aging. However, findings based onstudies of human populations were extremely limited.
We therefore conducted a study of RERF’s Adult Health Study (AHS) participants, whose healthhas been followed for many years, in order to determine the effects of age, radiation dose, and obesity
on indicators of thymic capacity to produce naïve T cells (TREC number).NoteNote) TRECs, excised from chromosomes when T cells are produced in the thymus, are by-productsof this process and characteristic of newly produced naïve T cells. Because they are not replicated bysubsequent cell divisions in blood, TREC number can be used as an indicator of thymic capacity toproduce naïve T cells.

1. Objectives
The objectives of the study were to examine the relationship between radiation exposure andTREC number, an indicator of thymus capacity to produce naïve T cells, and to determine theassociation of TREC number to obesity indicators and diseases associated with obesity, after adjustingfor the effects of age, sex, radiation exposure, alcohol consumption, and smoking.
2. Methods
Among 1,073 A-bomb survivors who participated in the AHS from 2003 to 2009, we measured
TREC number per 10,000 CD4 T cells (helper T cells, which control immune response) and per
10,000 CD8 T cells (killer T cells, which detect and destroy infected or transformed cells) inperipheral blood, utilizing polymerase chain reaction. We used information obtained from the AHS on
BMI as an indicator of obesity, total cholesterol level, HbA1c level (which represents blood glucose
levels over the previous 2–3 months), and CRP level (an indicator of inflammation), as well as
diseases related to obesity (type 2 diabetes, fatty liver, and hypertension), alcohol consumption, andsmoking. We conducted linear regression statistical analysis, with adjustment made for age, sex,radiation dose, amount of alcohol consumed, and number of cigarettes smoked.
3. Results(1) Relationship between TREC number and age
Subject ages ranged from 58 to 109 years. Even in this elderly population, TREC number in CD4
and CD8 T cells decreased with age (p < 0.001 in terms of significance).
(2) Relationship between TREC number and radiation doseRadiation exposure had no effect on TREC number in either CD4 or CD8 T cells. We also
conducted a preliminary analysis by selecting, from among the 1,073 subjects, a high-dose group(radiation dose of at least 1 Gy) and a control group (radiation dose of less than 5 mGy), matched bysuch factors as age and sex, and then comparing the two groups. No difference in TREC number wasobserved in relation to radiation dose.
(3) Association between TREC number and obesity indicators
TREC number in CD4 and CD8 T cells significantly decreased with an increase of HbA1c and
CRP levels (p < 0.05). TREC number also tended to be inversely associated with BMI. Further, TREC
number was small in cases of diabetes and fatty liver (p < 0.05).
In this study, no association between TREC number and radiation exposure was observed, but
TREC number was found to decrease with an increase in the levels of obesity indicators in a human2RERF Report No. 8-13

population. This result provides evidence to suggest that obesity may accelerate immunological aging
in humans. Because obesity is known to increase the risk of several age-related diseases, attenuatedimmune competence due to the reduction in naïve T-cell production may be one of the developmental
mechanisms of diseases associated with obesity.
The Radiation Effects Research Foundation has studied A-bomb survivors and their offspring in Hiroshima
and Nagasaki for more than 60 years. RERF’s research achievements are considered the principal scientific basis
for radiation risk assessment by the United Nations Scientific Committee on the Effects of Atomic Radiation(UNSCEAR) and for recommendations regarding radiation protection standards by the InternationalCommission on Radiological Protection (ICRP). RERF expresses its profound gratitude to the A-bomb survivors
and survivors’ offspring for their cooperation in our studies.
§PLOS ONE is an international peer-reviewed journal published by Public Library of Science, a non-profit
organization. This open-access online journal publishes original papers in various scientific and medical fields.
(Impact factor in 2012: 3.730)

3