Inhibition of Thymic Adipogenesis by Caloric Restriction Is Coupled with Reduction in Age-Related Thymic Involution
Open accessAbstract
Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures. Interestingly, CR prevented the age-related increase in epithelial-mesenchymal transition (EMT) regulators, FoxC2, and fibroblast-specific protein-1 (FSP-1), together with reduction in lipid-laden thymic fibroblasts. Additionally, CR specifically blocked the age-related elevation of thymic proadipogenic master regulator, peroxisome proliferator activated receptor γ (PPARγ), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPARγ in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPARγ-driven adipogenesis in OP9-DL1 stromal cells compromised their ability to support T cell development. Conversely, CR-induced reduction in EMT and thymic adipogenesis were coupled with elevated thymic output. Compared with 26-mo-old ad libitum fed mice, the T cells derived from age-matched CR animals displayed greater proliferation and higher IL-2 expression. Furthermore, CR prevented the deterioration of the peripheral TCR repertoire diversity in older animals. Collectively, our findings demonstrate that reducing proadipogenic signaling in thymus via CR may promote thymopoiesis during aging.
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Caloric restriction slows the buildup of senescent T cells in rodents and non-human primates.
“CR has been reported to have multiple beneficial effects on the immune system of both rodents and non-human primates that include a delay in the accumulation of senescent T cells (112) and a stimulation of thymopoiesis (113).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [113]
Caloric restriction stimulates thymopoiesis in rodents and non-human primates.
“CR has been reported to have multiple beneficial effects on the immune system of both rodents and non-human primates that include a delay in the accumulation of senescent T cells (112) and a stimulation of thymopoiesis (113).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [113]
Caloric restriction prevents the age-related rise in thymic PPARγ.
“CR has been reported to block the age-related elevation of the thymic proadipogenic master regulator, PPARγ (113).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [113]
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- Authors
- Yang, H., Youm, Y.-H., & Dixit, V. D.
- Affiliations
- Pennington Biomedical Research Center (US)
- Corresponding author
- Dixit, Vishwa Deep
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-09-01
- Volume
- 183
- Issue
- 5
- Pages
- 3040-3052
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2731487
- OpenAlex
- W1600190664
- Cited by
- 196
- References
- 67
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 14 · 2023: 9 · 2022: 16 · 2021: 12 · 2020: 17 · 2019: 17 · 2018: 13 · 2017: 11 · 2016: 12 · 2015: 15 · 2014: 5 · 2013: 10 · 2012: 12
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK072476)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK072476)
- National Center for Research Resources (P20RR021945)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- caloric restriction, thymic involution, thymic aging, immunosenescence, epithelial-mesenchymal transition, FOXC2, S100A4, PPARγ, xanthine oxidoreductase, thymic stromal cells, thymopoiesis, T cell receptor diversity
- MeSH terms
- Aging, Animals, Animal Feed, Cell Line, Cells, Cultured, Female, Growth Inhibitors, Longevity, Mice, Inbred C57BL, Thymus Gland, Transcription, Genetic, Xanthine Dehydrogenase, Down-Regulation, Stromal Cells, Coculture Techniques, Caloric Restriction, Lymphopoiesis, PPAR gamma, Adipogenesis, Mice
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