Abstract
Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of ‘old’ HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
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Data availability
All data and materials are available from the corresponding author to any researcher for the purpose of reproducing or extending the analyses. Source data are provided with this paper.
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Acknowledgements
We thank G. Coukos (LICR, University of Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois) for critical feedback and F. Derouet (UNIL) for animal care. Flow cytometry analysis and sorting was performed at the Flow Cytometry Facility at UNIL with the help of R. Bedel, F. Sala de Oyanguren, K. Blackney and A. Wilson. We thank Nestlé Health Science for their suggestions about the study. M.G. was partially funded by a collaborative Jebsen Foundation grant (EPFL/UNIL) to N.V. and O.N. The N.V. laboratory is supported by the Swiss Cancer Research Foundation (KFS-4993-02-2020-R) and San Salvatore Foundation. The J.A. laboratory is supported by grants from EPFL, the European Research Council (ERC-AdG-787702), the Swiss National Science Foundation (SNSF) (31003A_179435) and a Global Research Laboratory grant of the National Research Foundation of Korea (2017K1A1A2013124). F.S. is supported by the SNSF (323530_183986). The O.N. laboratory was supported by SNSF grant nos. PP00P3_183725 and CRSII5-186271. P.-C.H. is funded in part by the European Research Council Staring Grant (802773-MitoGuide), an SNSF project grant (no. 31003A_182470), the Cancer Research Institute (Lloyd J. Old STAR Award) and LICR. W.H. is funded in part by a grant from the SNSF (no. 310030_200898). All the funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Contributions
M.G., Y-H.C. and N.V. conceived the ideas, designed the experiments and analyzed the results. M.G., Y-H.C., N.V. and F.S. performed the HSC experiments. M.C., H.C.H. and W.H. performed and interpreted the infection model experiments. P.G. evaluated the impact of UA dietary supplementation on secondary lymphoid tissues and performed and interpreted the cell respiration analyses. J.A. and O.N. conceived the ideas and provided key reagents and samples. S.C. provided the human samples for HSC purification. O.N. and C.B. performed the human HSC experiments. F.F., Y-R.Y., H.G. and P.-C.H. provided the animal model and helped with data interpretation. N.V. wrote the manuscript. All authors edited and reviewed the final manuscript.
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J.A. is a scientific advisor to Amazentis, a company that develops UA as a therapeutic agent. Some elements of this work are part of patent no. 19152437.0 of which N.V. and M.G. are inventors. The remaining authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Old HSCs have higher mitochondria content.
Mitochondrial DNA (mtDNA) quantification by QPCR expressed as fold change compared to young HSCs. Young values are normalized on their mean value (P-value = 0.0571) (n = 4; values are mean ± s.e.m.; two-tailed Mann-Whitney test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001).
Extended Data Fig. 2 Donor chimerism analysis in the bone marrow.
a, Lymphoid vs myeloid compartments of primary transplants in peripheral blood at the indicated timepoints. b, Analysis of donor derived contribution for lymphoid and myeloid lineages in bone marrow at the endpoint of primary transplant (Lymphoid: young ctrl vs old ctrl P-value = 0.0003; old ctrl vs old UA P-value = 0.0011; myeloid: young ctrl vs old ctrl P-value = 0.0002; old ctrl vs old UA P-value = 0.0006;). c, Analysis of donor derived HSCs at the endpoint of primary transplant. d, Analysis of donor derived HSCs at the endpoint of secondary transplant (n = 10; values are mean ± s.e.m.; two-tailed Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001, **** P ≤ 0.0001). e, HSCs isolated from bone marrow of young mice were cultured for three days in the presence of 20μM UA and transplanted in lethally irradiated primary recipient together with bone marrow derived from competitor mice. Blood donor chimerism analyses of primary transplant at indicated timepoints (n = 10; values are mean ± s.e.m.).
Extended Data Fig. 3 UA improves Colony forming capacity (CFU assay) of old human HSCs.
a, 1000 CD34+CD38−CD45RA- cells derived from the bone marrow of anonymous old adults (58-77 years old) were treated for 3 days with 20μM UA, and colony formations was measured at 15 days post seeding and replated for secondary CFUs. b, analysis of primary CFUs (P-value < 0.0001) (n = 14; values are mean ± s.e.m.; two-tailed Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001). c, Assessment of long-term hematopoietic capacity by secondary CFUs analysis (P-value = 0.0042) (n = 8; values are mean ± s.e.m.; two-tailed Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001).
Extended Data Fig. 4 Peripheral blood analyses of UA fed mice.
Peripheral blood cell analyses of old mice fed with ctrl (old ctrl) or UA enriched diet (old UA). Analyses were performed at the indicated time points with blood cell counter and normalized to day 0 (WBC: white blood cell; Lym: Lymphocytes; Gra: Granulocytes; Mon: Monocytes; RBC: red blood cells; HGB: hemoglobin) (n = 8; values are mean ± s.e.m.;).
Extended Data Fig. 5 Hematopoietic stem and progenitor analyses of old mice supplemented with UA.
a, Gating strategy to identify hematopoietic stem and progenitor populations from the BM for endpoint analysis. HSCs: Lineage−cKit+Sca1+ (LKS) CD150+CD48−; Multipotent progenitors (MPPs): LKS CD150−, Common lymphoid progenitor (CLP): CD127+ cKitlow Sca1low; Committed progenitors (cKit+) include common myeloid progenitors (CMPs: Lineage−cKit+Sca1–(KLS–) FcRlowCD34+), granulocyte–macrophage progenitors (GMPs: KLS-FcRlowCD34 + ), and megakaryocyte-erythroid progenitors (MEPs: KLS–FcR–CD34–). b, Analyses of lymphoid vs myeloid compartments of primary transplants at the indicated timepoints (n = 10; values are mean ± s.e.m). c, Donor chimerism analysis of secondary recipient mice in peripheral blood (Total: 4 weeks P-value = 0.0013; 8 weeks P-value < 0.0001; 12 weeks P-value = 0.0003; Lymphoid: 4 weeks P-value < 0.0001; 8 weeks P-value < 0.0001; 12 weeks P-value = 0.0002; Myeloid: 4 weeks P-value = 0.0089; 8 weeks P-value = 0.0049; 12 weeks P-value = 0.0153) (n = 5; values are mean ± s.e.m.; two-tailed Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001).
Extended Data Fig. 6 Expression of inhibitory receptors markers and cytokines by virus-specific CD8 + T cells.
a, Expression of IFNγ (gp33 + : young ctrl vs old UA P-value = 0.0112; np396+: young ctrl vs old UA P-value = 0.0034; old ctrl vs old UA P-value = 0.0160), TNFα (gp33 + :young ctrl vs old ctrl P-value < 0.0001; young ctrl vs old UA P-value = 0.0003; np396+:young ctrl vs old ctrl P-value < 0.0001; young ctrl vs old UA P-value < 0.0001) and IL-2 by CD8+ T cells in response to restimulation with gp33 or np396 peptides. b, Expression of co- inhibitory receptors PD-1 (gp33 + :young ctrl vs old ctrl P-value < 0.0001; young ctrl vs old UA P-value = 0.0125; old ctrl vs old UA P-value = 0.0146 np396+:young ctrl vs old ctrl P-value < 0.0001; young ctrl vs old UA P-value = 0.0025; old ctrl vs old UA P-value = 0.0159)and Lag3 (gp33 + :young ctrl vs old ctrl P-value < 0.0001; young ctrl vs old UA P-value = 0.0007; old ctrl vs old UA P-value = 0.0173; np396+:young ctrl vs old ctrl P-value < 0.0001; young ctrl vs old UA P-value < 0.0001; old ctrl vs old UA P-value = 0.0301) by gp33+ and np396 CD44+ CD8+ T cells (n = 10; values are mean ± s.e.m.; two-way ANOVA; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001, **** P ≤ 0.0001).
Extended Data Fig. 7 Viral response of CD8 + T cells derived from old UA treated HSCs.
a, Quantification of donor derived (CD45.1+) virus specific (gp33+ or np396+) CD8+ T cells (gp33 + :young ctrl vs old ctrl P-value = 0.0407; np396+:young ctrl vs old ctrl P-value = 0.0298). b, Proportion of activated KLRG1+ within donor derived virus specific CD8+ T. (n = 5; values are mean ± s.e.m.; two-way ANOVA; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001, **** P ≤ 0.0001).
Extended Data Fig. 8 UA in vitro treatment modulates T cell function and mitochondrial profiles.
a, Splenocytes derived from old mice were activated at day0 and restimulated at day5 with CD3/CD28 beads cultured with 5 μM UA. b, Analyses of mitochondrial activity (TMRM) and mass (MTG, mitotracker Green) in CD8+ and CD4 + T cells measured as mean fluorescence intensity (MFI). c, Analyses of the proportion of cells INFγ+TNFα+ upon restimulation with CD3/CD28 beads at day 5 (n = 4; values are mean ± s.e.m.; two-tailed paired Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001).
Extended Data Fig. 9 UA modulates mitochondrial recycling in HSCs.
a, Analysis of mitophagy induction in HSCs purified from mito-QC mice measured as MFI ratio between GFP and mCherry signals(P-value = 0.0037). (n = 4; two tailed paired Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001). b, Expression of CD150 measured by mean fluorescence intensity (MFI) in young and old HSCs (P-value = 0.0009)(n = 4; values are mean ± s.e.m.; two-tailed Student’s t test; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001). c, HSCs derived from Mx1-PARK2 mice (CD45.2) were transplanted in lethally irradiated recipient mice (CD45.1/2) together with total bone marrow competitor cells (CD45.1).d, Blood donor chimerism of primary transplant at the indicated timepoint. e, Lymphoid vs myeloid compartments of primary transplants at the indicated timepoints (Ctrl vs PARK2-/- P-value = 0.0002; Ctrl vs PARK2-/- UA P-value = 0.0006) (n = 10; values are mean ± s.e.m.; two-way ANOVA; * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001).
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Girotra, M., Chiang, YH., Charmoy, M. et al. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems. Nat Aging 3, 1057–1066 (2023). https://doi.org/10.1038/s43587-023-00473-3
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DOI: https://doi.org/10.1038/s43587-023-00473-3
