Anna Katharina Simon

Vaccine-induced protection relies on the generation and maintenance of stem-like memory B and T cells, a process sustained by two conserved mechanisms: asymmetric cell division (ACD) and autophagy. In T cells, ACD enables them to produce progeny with the same T cell receptor but with divergent metabolic and functional fates upon antigen encounter through the unequal inheritance of cellular cargoes. Autophagy recycles cellular components, provides metabolic substrates essential for sustaining energy demands, and is relevant for the maintenance of T cell memory. Direct evidence of how these processes synergize and affect human immunity is still lacking. Here, we show that mitotic human CD8 ⁺ T cells asymmetrically segregate autophagy-related organelles, including autophagosomes and lysosomes. Furthermore, we show that ACD drives divergent transcriptional and functional fates in daughter cells. Extending these findings to an influenza vaccine trial, we demonstrate that autophagic flux follows the dynamics of clonal expansion and contraction of antigen-specific T cells. Notably, individuals with enhanced ACD capacity, especially with increased LC3B asymmetry, exhibit better vaccine responses, linking early cellular segregation events to long-term immune fitness. Last, transient use of the mechanistic target of rapamycin complex 1 inhibitor rapamycin improved memory survival, which was associated with improved ACD, measured by the asymmetric inheritance of both CD8 and LC3B. Together, these findings highlight that the asymmetric inheritance of the autophagy machinery represents another layer of human adaptive immunity and offers a potential therapeutic target to enhance vaccine outcomes.

Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low‐grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double‐blind, randomised, placebo‐controlled pilot study in 40 adults over 65 years of age following their third SARS‐CoV‐2 vaccine dose to assess the safety of Spermidine and its effects on vaccine‐induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well‐tolerated. Vaccine non‐responsiveness was common, and non‐responders exhibited a distinct immune‐senescence signature marked by elevated p16, mTOR signalling, and γ‐H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike‐specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non‐responders. Single‐cell RNA‐seq after treatment revealed increased expression of TFEB targets and autophagy‐related genes in B cells, in line with elevated autophagic flux. These findings suggest that targeting immune cell senescence with Spermidine may improve vaccine responsiveness in older adults and highlight immune‐senescence markers as potential predictors of vaccine failure in ageing populations.

Skeletal muscle atrophy is a pathological condition characterized by the loss of muscle mass and strength, driven by diverse stimuli including disuse, malnutrition, acute and chronic inflammation, ...

MTOR inhibitors such as rapamycin are among the most robust life‐extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non‐immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole‐organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low‐dose mTOR inhibition. To test this in vivo, we conducted a placebo‐controlled experimental medicine study in older adults administered with low‐dose rapamycin. p21, a marker of DNA damage‐induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8 ⁺ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.

A hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.

Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

MTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, i.e. they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex-vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo , we conducted a placebo-controlled experimental medicine trial in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin’s exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure, and even the hazards of cosmic radiation in space travel.