Acute priming using elevated fluid viscosity recovers young-like single-cell surveillance behaviors in aged human T cells

Aging is a complex biological process often characterized by increased vulnerability to disease, infection, and death. This increased vulnerability is mechanistically linked to a progressive and functional decline of the immune system. In humans, aged T cells lose their ability to effectively surveil complex microenvironments, thereby decreasing their capacity to clear infections, eradicate diseases, and maintain physiological homeostasis. However, specific mechanisms by which aged T cells lose this capacity to surveil remain unclear. Here, we profile three core characteristics of T cell surveillance at single-cell resolution, specifically migration, deformability, and sensing. While aged human T cells retain their capacity to migrate ex vivo, they exhibit impaired cellular deformability and deficiencies in sensing local biological signals. To modulate this surveillance defect, we perform mechanical reprogramming using elevated fluid viscosity. Results indicate that acute priming of aged T cells with elevated fluid viscosity recovers a transient young-like surveillance phenotype, particularly within CD4+ memory T cell populations. This recovered young-like phenotype is mechanistically linked to elevated SDF-1α receptor expression together with increased membrane tension, cortical F-actin, and Arp3 expression. Altogether, these findings identify a key source of surveillance defects among aged T cells and offer an effective mechano-inducible strategy for modulating single-cell behaviors. Aging is a complex process often characterised by increased vulnerability to disease, and this affects T cell function. Here, the authors characterise migration, deformability, and sensing in aged and young T cells and find impaired cellular sensing in aged T cells. This impairment can be rescued after priming in elevated fluid viscosity. This effect was most prominent in aged memory CD4+ T cells.