Aging is a complex process affecting many aspects of mammalian biology, including the immune system. Indeed, age-related alterations of the immune system make the elderly more susceptible to infectious diseases and tumors, resulting in increased morbidity and mortality. In addition, the recent SARS-coV-2 outbreak has reemphasized that the effectiveness of vaccination is significantly reduced in the elderly population, limiting efficient preventive prophylaxis. It is therefore crucial to understand the impact of the aging process on the immune system.
Foxo proteins are critical at the crossroad of different processes, such as metabolism, quiescence, cell survival, oxidative stress resistance, cellular differentiation, autophagy and apoptosis. Previous studies have shown that the Foxo family prevents aging in various phylogenetically unrelated organisms such as Caenorhabditis elegans, Drosophila melanogaster or Hydra vulgaris, in which continuous high activity of Foxo family members extends lifespan and contributes to stem cell proliferation. However, the role of Foxo proteins in mammalian longevity and more specifically in the aging of the immune system has not been explored yet.
The team of Bruno Lucas, in closed collaboration with the core facilities of Institut Cochin, has demonstrated that Foxo1 finely regulates T-cell aging in vivo. Their results show that Foxo1 expression is progressively down-regulated in mouse T cells with age leading to a rewiring of their transcriptional signature. This leads to several defects in the immune compartment with increased exhaustion of aged T cells (characterized by the expression of inhibitory receptors and functional impairment) as well as disruption of naive T-cell homeostasis leading to an increased pool of memory T cells.
Importantly, they also show that the increase of inflammatory cytokine levels with age, a phenomenon known as inflammaging, contributes to Foxo1 down-regulation and aging of T cells. In particular, they identify type 1 interferons as a key molecular cue mediating Foxo1 down-regulation and subsequent T-cell aging.
Both type 1 interferon receptor and transcription factor Foxo1 are expressed by most cell types in mammals. Interestingly, Foxo1 down-regulation with age has been documented in humans, in different organs (brain, muscle, joint cartilage, intervertebral discs and meniscus). In most cases, the extent of its down-regulation has been correlated with pathologies such as neuronal or intervertebral disc degeneration, osteoarthritis or muscle regenerative failure. Thus, the type 1 interferon-Foxo1 axis may be involved in aging in mammals well beyond the immune system.
This work was supported by a grant from the Fondation pour la Recherche Médicale (FRM team number EQU202103012662).
Reference
Aurélie Durand, Nelly Bonilla, Théo Level, Zoé Ginestet, Amélie Lombès, Vincent Guichard, Mathieu Germain, Sébastien Jacques, Franck Letourneur, Marcio Do Cruzeiro, Carmen Marchiol, Gilles Renault, Morgane Le Gall, Céline Charvet, Agnès Le Bon, Bruno Martin, Cédric Auffray and Bruno Lucas. Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice. Nature Communications, 15:1718 (2024). doi.org/10.1038/s41467-024-45984-8
