Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells.

The ageing of the global population brings about unprecedented challenges. Chronic age-related diseases in an increasing number of people represent an enormous burden for health and social care. The immune system deteriorates during ageing and contributes to many of these age-associated diseases due to its pivotal role in pathogen clearance, tissue homeostasis and maintenance. Moreover, in order to develop treatments for COVID-19, we urgently need to acquire more knowledge about the aged immune system, as older adults are disproportionally and more severely affected. Changes with age lead to impaired responses to infections, malignancies and vaccination, and are accompanied by chronic, low-degree inflammation, which together is termed immunosenescence. However, the molecular and cellular mechanisms that underlie immunosenescence, termed immune cell senescence, are mostly unknown. Cellular senescence, characterised by an irreversible cell cycle arrest, is thought to be the cause of tissue and organismal ageing. Thus, better understanding of cellular senescence in immune populations at single-cell level may provide us with insight into how immune cell senescence develops over the life time of an individual. In this review, we will briefly introduce the phenotypic characterisation of aged innate and adaptive immune cells, which also contributes to overall immunosenescence, including subsets and function. Next, we will focus on the different hallmarks of cellular senescence and cellular ageing, and the detection techniques most suitable for immune cells. Applying these techniques will deepen our understanding of immune cell senescence and to discover potential druggable pathways, which can be modulated to reverse immune ageing.

Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses.

Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.