Immunosenescence

Immunosenescence is what happens when the supply of new T cells stops. The thymus involutes from early adulthood, so the naive T-cell pool is progressively replaced by expanded, differentiated CD8 clones that respond poorly to anything new. Rachel Thomas, Weikan Wang and Dong-Ming Su set out the mechanism in Immunity & Ageing, noting that 80 to 95% of peripheral regulatory T cells are generated in the thymus rather than induced peripherally, so thymic atrophy reshapes regulation as well as effector capacity [1]. In the aged atrophied thymus, total thymic Treg numbers did not change but the Treg to conventional T-cell ratio rose against normal thymus controls [1].

The population signal comes from Sweden. Jan Olsson and Anders Wikby followed very old individuals in the OCTO immune study to a fourth assessment 8 years after the 1989 start. Inversion of the CD4/CD8 ratio occurred in 32% of the original sample over the study, and the combination of high CD8 percentage, low CD4 percentage and poor T-cell proliferation was associated with higher 2-year mortality [2]. The alterations tracked with cytomegalovirus antibody status and with expansion of CD8+CD28- and CD57+ subsets, the phenotype of terminally differentiated cells [2].

Inversion is not confined to the very old. Jan Strindhall and colleagues sampled 424 randomly selected 66-year-olds in Jonkoping, then profiled 151 of them in depth, 50 with a CD4/CD8 ratio below 1 and 101 with a ratio above 1.2 [3]. Graham Pawelec later argued the immune risk profile is context-dependent, since the Swedish OCTO/NONA findings in 85-year-olds did not transfer cleanly to Dutch and Belgian cohorts [4].

The interventional evidence is the most interesting part of aging biology. Joan Mannick and colleagues at Novartis gave elderly volunteers the mTOR inhibitor RAD001 and improved influenza vaccine response by about 20% at reasonably tolerated doses, while lowering the percentage of CD4 and CD8 T cells expressing PD-1 [5]. In a phase 2a follow-up, 264 elderly subjects took a low-dose combination of BEZ235 plus RAD001 for 6 weeks; reported infections over the following year fell significantly, P = 0.001, with upregulated antiviral gene expression [6].

The plain takeaway: immunosenescence is measurable in a routine flow cytometry panel, it predicts death in some cohorts and not others, and the only intervention with randomised human evidence is a prescription mTOR inhibitor, not a supplement.