Polyamine metabolism as a cornerstone of immune health during aging using nutritional interventions

Principal Investigator

Scientific interest within the context of the graduate college:

Healthy aging is increasingly recognized as a dynamically regulated state requiring active molecular maintenance in a concert of organ systems, among which the immune system takes a conducting role. The Else Kröner-Promotionskolleg “Re-Thinking Health” highlights the importance of studying resilience mechanisms that allow the body to adapt to environmental stressors to maintain (immune) homeostasis. Recent work from the PI lab (Alsaleh et al. 2020; 2025; Zhang et al. 2019; Puleston et al. 2014) and the Co-PI (Hofer et al. 2024) has revealed that the polyamine metabolism, traditionally viewed in the context of cellular proliferation, plays a key role in autophagy regulation and immune cell function. Importantly, we have shown that polyamine metabolism is a critical weak point in maintaining autophagy in advanced age (Hofer et al. 2022). Our recent discoveries have demonstrated that feeding-fasting rhythms in humans increase systemic and cellular polyamine levels and that this is crucial for regulating autophagy (Hofer et al. 2024). A central feature of this pathway is the hypusination of the eukaryotic initiation factor 5A (eIF5A), a unique post-translational modification in which the polyamine spermidine is covalently linked to a specific lysine residue, allowing cells to access a special subset of proteins that are crucial for autophagy, mitochondrial function, and immune cell fate. However, the extent to which the nutrition-polyamine axis regulates immune cell functionality in response to exogenous stimuli (e.g., vaccines, infections) has not been investigated. Therefore, this project aims to systematically dissect the role of the polyamine–hypusination axis in human immune cells under nutritional modulation, with a strong focus on clinical relevance and translational applicability.

Project description:

Aging is associated with an increase in chronic inflammation and a decline in immune function, often termed immunosenescence, which leads, inter alia, to poor vaccine responses and higher infection rates. One central metabolic axis involved in immune cell activation and differentiation is polyamine metabolism. Polyamines (putrescine, spermidine, and spermine) support cellular function via translation regulation, chromatin remodeling, and autophagy regulation. While polyamines have shown promise to counteract manifold aspects of aging in murine models, their role in human immune homeostasis, particularly under varying nutritional conditions, remains poorly defined. Previously, the Simon lab has reported that declining polyamine levels lead to autophagy deficiencies, which are partially causal for diminished T and B cell functionality and vaccine responses (Zhang et al. 2019; Alsaleh et al. 2020). Based on this, clinical trials were conceptualized to counteract the aging-polyamine axis via dietary spermidine supplementation (Alsaleh et al. 2025). Further, recent data suggests that short-term fasting activates polyamine synthesis in cells and humans (Hofer et al. 2024) and could thus be employed as an acute intervention to ramp up polyamine levels before, e.g., a vaccine challenge. How this plays out at the granular level of human immune cells has not been addressed thus far. Preliminary data in the Simon lab suggest that acute fasting modulates the downstream effector of polyamines, activated (thus hypusinated) eIF5A, across different immune cell types. This could be one mechanism by which fasting supports autophagy in the human immune system and potentially modulates the immune system’s ability to react to vaccines and infections. Based on this, we will carry out a clinical trial to test the hypothesis that four weeks of fasting could prime the aging immune system to enhance vaccine outcomes. Therefore, this project aims to characterize polyamine metabolism in human immune cells using clinical samples from ongoing dietary intervention trials, with a focus on aging, fasting, and vaccine responses.

Aim 1: We will systematically profile polyamine levels and hypusinated eIF5A across major immune cell subsets (T and B cells, monocytes, and innate lymphoid cells) using a recently established flow cytometry-based assay for hypusinated eIF5A. This will be accompanied by testing polyamine uptake, gene expression analysis, and intracellular metabolite levels, thus giving a holistic overview of the metabolic pathway. This analysis will be performed on fresh PBMCs from healthy donors of different ages to establish a reference atlas of polyamine metabolism across immune populations and to detect baseline inter-individual variability relevant to aging and nutritional state.

Aim 2: Here, we will explore how different immune cell types respond to nutritional cues, focusing on short-term fasting (in humans) and amino acid restriction (in vitro). Using in vitro culture systems and PBMCs from fasted healthy volunteers (collaboration in place), we will assess the dynamics of the polyamine metabolism and hypusination. This will reveal nutrient-responsive immune cell types and provide mechanistic insight into how dietary inputs translate into metabolic changes in the immune system. We will correlate these data with autophagic flux assays and physiological parameters of the volunteers.

Aim 3: We will analyze selected immune cell types from a randomized controlled trial of early Time-Restricted Eating (TRE) followed by influenza vaccination in older individuals (>60 years: a threshold after which vaccine responsiveness significantly drops). Using flow cytometry, metabolomics, and single-cell RNA-seq, we will assess whether the nutritional intervention alters polyamine metabolism and eIF5A hypusination in these target populations, and how these changes correlate with vaccine response and functional immune metrics (e.g., cytokine production, memory formation).

Aim 4: Finally, we will assess the functional consequences of polyamine metabolism and eIF5A hypusination on immune cell performance. Using pharmacologic and genetic tools to block hypusination or polyamine biosynthesis, we will evaluate how these pathways affect immune cell activation, autophagy, and effector function in the context of altered nutrient availability. These mechanistic experiments will be performed in vitro using primary human immune cells.

Together, this project will identify which immune cells depend on polyamine-driven mechanisms for maintaining function during nutritional stress, how these mechanisms change with age, and whether they can be modulated by clinically feasible interventions like TRE.

Methodological scope. This work draws from primary human samples collected in a clinical fasting trial (to be completed early 2026), complemented by mechanistic studies in cell lines and other primary clinical samples. The candidate will apply state-of-the-art molecular biology and immunology techniques, including spectral flow cytometry, metabolomics, single-cell RNA-seq, and autophagy assays. Mechanistic validation will be pursued through in vitro immune assays. Approximately 90% of the work will focus on human translational research.

Outlook. The successful clinician-scientist candidate in this project will generate clinically relevant insights into how polyamine metabolism supports immune resilience and is influenced by varying nutritional conditions. This work will contribute to an emerging paradigm shift in immunology, moving away from merely reacting to diseases toward health preservation through lifestyle-adapted, yet molecularly well-characterized strategies. The knowledge generated will also enhance our understanding of the significant inter-individual differences in systemic and intracellular polyamine metabolism, which could potentially serve as predictive indicators for immune health across aging trajectories.

Application details

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