Background

Efforts to elucidate genetic and environmental factors contributing to longevity have largely focused on genome analysis or lifestyle tracking, while immunological research has concentrated on understanding immune function decline with aging. In particular, the biological mechanisms by which supercentenarians (individuals aged 110 years or older) live longer without disease despite an increased cancer incidence have long remained elusive. To overcome the limitations of previous analyses that focused solely on immune decline in the elderly, active attempts are being made to analyze immune cells in the blood of supercentenarians at the single-cell level to uncover the link between longevity and cancer suppression.

Key Findings

A research team led by Professor Kosuke Hashimoto at the University of Osaka published a paper in the international journal Cell Reports, revealing the unique secret of the immune system in supercentenarians. The team conducted a detailed analysis using single-cell RNA sequencing technology on mononuclear cells from the blood of 28 supercentenarians and individuals of various age groups. The results showed an abnormally expanded population of CD4-positive cytotoxic T lymphocytes (CD4 CTL) in their blood, which are capable of directly killing cancer cells. Typically, CD4 T cells play a helper role in immune responses, while CD8 T cells are responsible for directly attacking cancer cells. In contrast, within supercentenarians, CD4 CTL exhibited a hybrid nature, expressing surface markers of helper T cells while functioning similarly to CD8 killer T cells in destroying cancer cells. The proportion of these hybrid cells increased significantly with age. The median ratio of CD4 CTL in the 70–99-year-old elderly group was 4%, whereas it rose to 9.6% in the centenarian group (100–109 years old) and surged to 17.6% in the supercentenarian group (110 years or older). This suggests that the immune system of supercentenarians is not merely declining with age but actively proliferating specific cells to counter internal threats. Moreover, these cells maintained high activity without entering an exhausted state, even under chronic stimulation. They continuously secreted perforin and granzyme, substances that attack cancer cells, effectively suppressing tumor growth.

Implications and Future Prospects

This study demonstrates that the human immune system can reconstitute itself to maximize survival capacity even in extreme old age. It suggests a new perspective that aging may not be a collapse of all physiological functions but rather an active remodeling of the immune system aimed at improving survival rates. From a clinical and industrial standpoint, it may provide a starting point for developing cell-based therapies to overcome age-related diseases and cancer. If the receptor structure and genetic characteristics of CD4 CTL in supercentenarians can be mimicked, it could lead to the development of personalized immunotherapies tailored for elderly patients. However, since the study was limited to 28 Japanese individuals, further research is needed to verify whether the same immune mechanisms operate across different ethnicities and environments. Additionally, identifying the genetic and environmental factors that drive the expansion of these unique cells remains a key challenge for future research.