USE OF NMN TO REDUCE IMMUNODEPRESSION AND IMMUNOSENESCENCE

Abstract

The invention pertains to nicotinamide mononucleotide, a pharmaceutically acceptable derivative thereof, a pharmaceutically acceptable precursor thereof, or a pharmaceutically acceptable salt thereof, for use thereof in decreasing immunosenescence and/or for improving immune response to vaccination, and to compositions comprising the same.

Claims

1. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof in the prevention and/or treatment of immunodeficiency, preferably immunosenescence.

2. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 1, wherein the derivative of NMN can be selected from among alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I): ##STR00097## or one the pharmaceutically acceptable stereoisomers, salts, hydrates, solvates or crystals thereof, in which: X is selected from among O, CH.sub.2, S, Se, CHF, CF.sub.2 and C═CH.sub.2; R.sub.1 is selected from among H, azido, cyano, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) thio-alkyl, (C.sub.1-C.sub.8) heteroalkyl, and OR; wherein R is selected from H and (C.sub.1-C.sub.8) alkyl; R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from among H, halogen, azido, cyano, hydroxyl, (C.sub.1-C.sub.12) alkyl, (C.sub.1-C.sub.12) thio-alkyl, (C.sub.1-C.sub.12) heteroalkyl, (C.sub.1-C.sub.12) haloalkyl, and OR; wherein R is selected from among H, (C.sub.1-C.sub.12) alkyl, C(O)(C.sub.1-C.sub.12)alkyl, C(O)NH(C.sub.1-C.sub.12)alkyl, C(O)O(C.sub.1-C.sub.12)alkyl, C(O)aryl, C(O)(C.sub.1-C.sub.12)alkyl aryl, C(O)NH(C.sub.1-C.sub.12)alkyl aryl, C(O)O(C.sub.1-C.sub.12)alkyl aryl, and C(O)CHR.sub.AANH.sub.2; wherein R.sub.AA is a side chain selected from a proteinogenic amino acid; R.sub.6 is selected from among H, azido, cyano, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) thio-alkyl, (C.sub.1-C.sub.8) heteroalkyl, and OR; wherein R is selected from H and (C.sub.1-C.sub.8) alkyl; R.sub.7 is selected from among H, P(O)R9R10, P(S)R9R10 and ##STR00098## wherein n is an integer equal to 1 or 3; in which R.sub.9 and R.sub.10 are each independently selected from among OH, OR.sub.11, NHR.sub.13, NR.sub.13R.sub.14, a (C.sub.1-C.sub.8) alkyl, a (C.sub.2-C.sub.8) alkenyl, a (C.sub.2-C.sub.8)alkynyl, a (C.sub.3-C.sub.10) cycloalkyl, a (C.sub.5-C.sub.12) aryl, (C.sub.1-C.sub.8)alkyl aryl, (C.sub.1-C.sub.8) aryl alkyl, (C.sub.1-C.sub.8) heteroalkyl, (C.sub.1-C.sub.8) heterocycloalkyl, a heteroaryl, and NHCHR.sub.AR.sub.A′C(O)R.sub.12; in which: R.sub.11 is selected from among a group: (C.sub.1-C.sub.10) alkyl, (C.sub.3-C.sub.10) cycloalkyl, (C.sub.5-C.sub.18) aryl, (C.sub.1-C.sub.10) alkylaryl, substituted (C.sub.5-C.sub.12) aryl, (C.sub.1-C.sub.10) heteroalkyl, (C.sub.3-C.sub.10) heterocycloalkyl, (C.sub.1-C.sub.10) haloalkyl, a heteroaryl, —(CH.sub.2).sub.nC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nOC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nOC(O)O(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nSC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2)C(O)O(C.sub.1-C.sub.15)alkyl, and —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15)allyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH).sub.2; R.sub.12 is selected from among H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.4 alkylaryl, and C.sub.5-C.sub.12 heteroaryl; wherein the said aryl or heteroaryl groups are optionally substituted with one or two groups selected from among halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; and R.sub.A and R.sub.A′ are independently selected from among H, a (C.sub.1-C.sub.10) alkyl, (C.sub.2-C.sub.10) alkenyl, (C.sub.2-C.sub.10) alkynyl, (C.sub.3-C.sub.10) cycloalkyl, (C.sub.1-C.sub.10) thio-alkyl, (C.sub.1-C.sub.10) hydroxylalkyl, (C.sub.1-C.sub.10) alkylaryl, and (C.sub.5-C.sub.12) aryl, (C.sub.3-C.sub.10) heterocycloalkyl, a heteroaryl, —(CH.sub.2).sub.3NHC(═NH)NH.sub.2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and a side chain selected from among a proteinogenic amino acid or a non-proteinogenic amino acid; wherein the said aryl groups are optionally substituted with a group selected from among hydroxyl, (C.sub.1-C.sub.10) alkyl, (C.sub.1-C.sub.6) alkoxy, a halogen, a nitro, and a cyano; or R.sub.9 and R.sub.10, together with the phosphorus atoms to which they are attached, form a 6-membered ring in which —R.sub.9-R.sub.10— represents —CH.sub.2—CH.sub.2—CHR—; wherein R is selected from among H, a (C.sub.5-C.sub.6) aryl group, and (C.sub.5-C.sub.6) heteroaryl group, wherein the said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C.sub.1-C.sub.6) alkyl, a (C.sub.1-C.sub.6) alkoxy, and cyano; or R.sub.9 and R.sub.10, together with the phosphorus atoms to which they are attached, form a 6-membered ring in which —R.sub.9-R.sub.10— represents —O—CH.sub.2—CH.sub.2—CHR—O—; wherein R is selected from among H, a (C.sub.5-C.sub.6) aryl group, and (C.sub.5-C.sub.6) heteroaryl group, wherein the said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C.sub.1-C.sub.6) alkyl, a (C.sub.1-C.sub.6) alkoxy, and cyano; R.sub.8 is selected from among H, OR, NHR.sub.13, NR.sub.13R.sub.14, NH—NHR.sub.13, SH, CN, N.sub.3, and halogen; wherein R.sub.13 and R.sub.14 are each independently selected from among H, (C.sub.1-C.sub.8) alkyl and (C.sub.1-C.sub.8) alkyl aryl; Y is selected from among CH, CH.sub.2, C(CH.sub.3).sub.2 and CCH.sub.3; represents a single or a double bond along Y; and represents the alpha or beta anomer depending on the position of R.sub.1 or one of the stereoisomers, one of the salts, one of the hydrates, one of the solvates or one of the crystals thereof or the compound of formula (Ia): ##STR00099## or one of the stereoisomers, one of the salts, one of the hydrates, one of the solvates or one of the crystals thereof, in which X′.sub.1 and X′.sub.2 are independently selected from among O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R′.sub.1 and R′13 are independently selected from among H, azido, cyano, a C1-C8 alkyl, a C1-C8 thio-alkyl, a C1-C8 heteroalkyl, and OR, wherein R is selected from H and a C1-C8 alkyl; R′.sub.2, R′.sub.3, R′.sub.4, R′.sub.5, R′.sub.9, R′.sub.10, R′.sub.11, R′.sub.12 are independently selected from among H, a halogen, an azido, a cyano, a hydroxyl, a C.sub.1-C.sub.12 alkyl, a C.sub.1-C.sub.12 thioalkyl, a C.sub.1-C.sub.12 hetero-alkyl, a C.sub.1-C.sub.12 haloalkyl, and OR; wherein R may be selected from among H, a C.sub.1-C.sub.12 alkyl, a C(O)(C.sub.1-C.sub.12) alkyl, a C(O)NH(C.sub.1-C.sub.12) alkyl, a C(O)O(C.sub.1-C.sub.12) alkyl, a C(O) aryl, a C(O)(C.sub.1-C.sub.12) aryl, a C(O)NH(C.sub.1-C.sub.12) alkyl aryl, a C(O)O(C.sub.1-C.sub.12) alkyl aryl, or a C(O)CHR.sub.AANH2 group; wherein R.sub.AA is a side chain selected from a proteogenic amino acid; R′.sub.6 and R′.sub.8 are independently selected from among H, an azido, a cyano, a C.sub.1-C.sub.8 alkyl and OR, wherein R is selected from H and a C.sub.1-C.sub.8 alkyl; R′.sub.7 and R′.sub.14 are independently selected from among H, OR, NHR, NRR′, NH—NHR, SH, CN, N.sub.3 and a halogen; wherein R and R′ are independently selected from among H and a (C.sub.1-C.sub.8) alkyl aryl; Y′.sub.1 and Y′.sub.2 are independently selected from among CH, CH.sub.2, C(CH.sub.3).sub.2 or CCH.sup.3; M′ is selected from among H or a suitable counter ion; represents a single or double bond depending on Y′.sub.1 and Y′.sub.2; and represents an alpha or beta anomer depending on the position of R′1 and R′13; and combinations thereof.

3. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 1 in combination with at least one other therapeutic agent.

4. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 3, wherein the at least one other therapeutic agent is a vaccine that can be selected from among attenuated live vaccines, inactivated vaccines, multivalent vaccines, or combination vaccines.

5. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 4, wherein the vaccine is selected from among a vaccine against a virus, a bacterium, a parasite, a yeast and/or fungus, or combinations thereof.

6. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 5, wherein said vaccine is selected from among a vaccine against a virus selected from among Influenzavirus, Coronavirus, Respirovirus, Pneutnovirus, Metapneunovirus, Adenovirus, Enterovirus, Rhinovirus, Hepatovirus, Erbovirus, Aphtovirus, Norovirus, Alphavirus, Rubivirus, Flavivirus, Hepacivirus, Pestivirus, Ebola, Morbillivirus, Rubulavirus, Henipavirus, Arenavirus, Orthobunyavirus, Phlebovirus, Rotavirus, Simiplexvirus, Varicellovirus, Papillomavirus, Cytomegalovirus or combinations thereof.

7. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 1, wherein the decrease in immunosenescence can be determined by the reduction of a marker selected from among thymic involution, cytokine levels of immunosenescence, the number of resident senescent T cells in the spleen, the level of circulating IgG immunoglobulin produced by memory B cells, the level of circulating IgA immunoglobulin produced by memory B cells, and combinations thereof.

8. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 1, wherein the decrease in immunosenescence can be determined by the increase of a marker selected from among the production of new naive T cells, the capacity to respond to new antigens, the accumulation of memory T cells, the number of circulating B cells, the level of circulating IgD immunoglobulin produced by naive cells, the level of circulating IgM produced by naive cells, vaccinal immunogenicity and combinations thereof.

9. Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use thereof according to claim 1 in a form adapted for administering thereof via oral, ocular, sublingual, parenteral, transcutaneous, vaginal, peridural, intravesical, rectal or inhalation route, preferably via oral route.

10. A composition comprising nicotinamide mononucleotide, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use thereof according to claim 1.

Description

FIGURES

[0322] FIG. 1 is a graph showing the change in weight gain (FIG. 1A) and water consumption (FIG. 1B) in groups 1 to 4.

[0323] FIG. 2 is a graph showing the change in the weight and size of the thymus in groups 1 to 4.

[0324] FIG. 3 is a graph showing the number of thymocytes in groups 1 to 4.

[0325] FIG. 4A is a graph showing the number of B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0326] FIG. 4B is a graph showing the number of CD38+ B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0327] FIG. 5A is a graph showing the number of CD45+ B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0328] FIG. 5B is a graph showing the number of pre-pro-B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0329] FIG. 5C is a graph showing the number of pro-B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0330] FIG. 5D is a graph showing the number of pre-B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0331] FIG. 5E is a graph showing the number of immature B cells in the bone marrow samples taken from the mice in groups 1 to 4.

[0332] FIG. 6A is a graph showing the number of CD45+ B cells in the spleen samples taken from the mice in groups 1 to 4.

[0333] FIG. 6B is a graph showing the number of activated B cells in the spleen samples taken from the mice in groups 1 to 4.

[0334] FIG. 6C is a graph showing the number of memory B cells in the spleen samples taken from the mice in groups 1 to 4.

[0335] FIG. 6D is a graph showing the number of germinal B cells in the spleen samples taken from the mice in groups 1 to 4.

[0336] FIG. 6E is a graph showing the number of plasma B cells in the spleen samples taken from the mice in groups 1 to 4.

[0337] FIG. 7A is a graph showing the number of CD4+ T cells in the spleen samples taken from the mice in groups 1 to 4.

[0338] FIG. 7B is a graph showing the number of CD4+ memory T cells in the spleen samples taken from the mice in groups 1 to 4.

[0339] FIG. 8A is a graph showing the number of naive CD8+ T cells in the spleen samples taken from the mice in groups 1 to 3.

[0340] FIG. 8B is a graph showing the number of CD8+ effector T cells in the spleen samples taken from the mice in groups 1 to 3.

[0341] FIG. 8C is a graph showing the number of CD8+ effector memory T cells in the spleen samples taken from the mice in groups 1 to 3.

[0342] FIG. 8D is a graph showing the number of CD8+ memory T cells in the spleen samples taken from the mice in groups 1 to 3.

[0343] FIG. 9A is a graph showing the percentage proliferation of CD4+ T cells compared with the non-stimulated cells in groups 1 to 4.

[0344] FIG. 9B is a graph showing the percentage proliferation of CD8+ T cells, compared with the non-stimulated cells in groups 1 to 4.

[0345] FIG. 10A is a graph showing the percentage of CD4+ T cells stimulated and not stimulated by beads coated with anti-CD3/CD28 antibodies, producing interferon gamma (IFNγ) in groups 1 to 4.

[0346] FIG. 10B is a graph showing the percentage of CD4+ T cells stimulated and not stimulated by beads coated with anti-CD3/CD28 antibodies, producing interleukin 10 (I10) in groups 1 to 4.

EXAMPLE

[0347] In the remainder of the present description, the examples are given to illustrate the present invention and are in no way intended to limit the scope thereof.

Example 1—Study of the Effects of Compounds I-A (β-NMN) and I-B (α-NMN) on Immunosenescence

[0348] The administering of β-NMN at 500 mg/kg, of α-NMN at 500 mg/kg and of the vehicle (water) was obtained via oral route (p.o) in the drinking water to young and old mice. The solutions were prepared by dissolving the powder of β-NMN or α-NMN in the vehicle (water).

[0349] The solution was used at ambient temperature for no more than 2 days and was freshly prepared for each new administration. The mice were weighed each week to adapt the dose of the compound to be administered. Throughout the entire phase, a standard food diet and tap water were provided ad libitum.

[0350] The study comprised 4 groups each having 6 mice: [0351] Group 1: young mice (aged 10 weeks)+drinking water (vehicle) [0352] Groupe 2: old mice (aged 15 months)+drinking water (vehicle) [0353] Group 3: old mice (aged 15 months)+compound I-B (alpha-NMN) in the drinking water [0354] Group 4: old mice (aged 15 months)+compound I-A (beta-NMN) in the drinking water

[0355] The water consumption of the mice was assessed per cage every other day. The mice were weighed every week. The mice in Group 3 were sacrificed after 4 weeks for organ collection and characterisation of T cell function. The mice in Group 4 were sacrificed after 6 weeks for organ collection and characterisation of T cell function. On the day of sacrifice, the mice were anaesthetised with Vetoflurane (isoflurane) and blood samples were taken from the retroorbital sinus. The blood was incubated for 30 minutes at ambient temperature and then centrifuged at 1300 g for 10 minutes.

[0356] After sacrificing of the mice, the spleen, thymus, and bone marrow of each animal were removed. The thymus was weighed and measured to evaluate involution thereof. For illustration purposes, photos of the thymus were taken on 5 animals per group. The thymus was divided into two parts: one part was treated with formol for histological examination. The second part was treated for characterisation of the immune cells.

[0357] For characterisation of the cells, the thymus and spleen were crushed through a sieve of 40 cells/μm over a 50 mL tube with a syringe plunger. The bone marrow was rinsed with RPMI culture medium using a needle and syringe. The cell suspension was then centrifuged at 400 g for 5 minutes at 4° C. Lysis of the red blood cells was also performed before the cell count and use thereof for cytometry.

[0358] The isolated cells of the spleen, thymus and bone marrow were marked with antibodies in accordance with the following tables to identify the proportion of effector and memory naive T and B cells.

[0359] The following T cells of the spleen were also examined for characterisation as a function of the combination of proteins on the surface thereof:

TABLE-US-00007 TABLE 3 T cells Combination of surface proteins Naive T cells CD25− CD44lo CD62Lhi CD127+ Effector T cells CD25+ CD44hi CD62Llo CD127− Effector memory T cells CD25− CD44hi CD62Llo CD127+ Central memory T cells CD25− CD44hi CD62Lhi CD127+ Senescent CD8+ T cells CD44hi KLRG1+ CD8+ T Senescent CD4+ T cells CD4+ PD1+ CD153+

[0360] The following B cells of the spleen were also examined for characterisation as a function of the combination of proteins on the surface thereof:

TABLE-US-00008 TABLE 4 B cells Combination of surface proteins Marginal cells in zone B B220+ CD21hi CD23− CD43− Follicular B cells CD19+ B220+ CD23+ CD21− CD43− Activated B cells CD19+ B220+ IgM+ IgD Memory B cells CD19+ B220+ IgM+ IgG+ IgD−

[0361] The following thymocytes were also examined for characterisation as a function of the combination of proteins on the surface thereof:

TABLE-US-00009 TABLE 5 Thymocytes Combination of surface proteins Multipotent thymocytes CD44lo CD25lo CD4− CD8− Double positive thymocytes CD44lo CD25lo CD4+ CD8+ Single positive thymocytes CD44lo CD25lo CD4+ CD8− or CD44lo CD25lo CD4− CD8+

[0362] The following bone marrow cells were also examined for characterisation as a function of the combination of proteins on the surface thereof:

TABLE-US-00010 TABLE 6 Bone marrow cells Combination of surface proteins Pre-pro-B cells CD43+ B220+ IgM− CD19− Pro-B cells CD43+ B220+ IgM− CD19+ Pre-B cells CD43− B220+ IgM− CD19+ Immature B cells CD43− B220+ IgM+ IgD− CD19

[0363] Proliferation assay: At D0+5 weeks, the splenocytes were marked with 2.5 μM CFSE and cultured at a concentration of 0.25×10.sup.6 cells per well in a 96-well plate. The cells were stimulated with 2.5 μg InfluvacTetra® and incubated at 37° C. for 96 hours. The cells were then marked with anti-CD4 and CD8 antibodies and the proliferation of the T CD4+ and CD8+ cells was analysed by flow cytometry.

[0364] Measured parameters: The results of flow cytometry are expressed in number or as a proportion of cells per organ. The weight of the thymus is expressed in grams.

[0365] The consumption of compounds I-A and I-B did not significantly increase the weight of the treated mice compared with the mice of 15 months that were not treated (FIG. 1A) and did not have any effect on water consumption compared with the mice of 11 weeks (FIG. 1B).

[0366] As shown in FIG. 2, the size of the thymus is considerably and significantly reduced in the old mice (Group 2) compared with the young mice (Group 1), which translates as involution of the thymus. Involution of the thymus with age is seen in humans and validates the model. The administering of alpha-NMN did not allow an increase in the volume or size of the thymus compared with the non-treated old mice. On the other hand, administering of β-NMN did allow a significant increase in the size of the thymus compared with the mice in Groups 2 and 3 up to a level close to that of the young mice in Group 1.

[0367] FIG. 3, the total number of thymocytes is reduced in the old mice (Group 2). Solely the treatment with compound 1-A (beta-NMN) allows an increase in the number of CD8+ thymocytes in the old mice.

[0368] FIG. 4, the number of B cells is significantly reduced in the old mice (Group 2) compared with the young mice (Group 1) in the bone marrow. The administering of α-NMN (Group 3) and of β-NMN (Group 4) allows a significant increase in the number of B cells and the restoring of an identical or almost identical level to the level observed in the young mice (FIG. 4A). Regarding the CD38+ cells, the level of these cells is decreased in the old mice (Group 2) compared with the young mice (Group 1). The administering of α-NMN (Group 3) and of β-NMN (Group 4) allows the restoring of the number of CD38+ B cells to the level expressed by the young mice in Group 1 (FIG. 4B).

[0369] As shown in FIGS. 5A to 5E, the level of B cells is significantly decreased in the old mice in Group 2 compared with the young mice in Group 1. The administering of α-NMN and of β-NMN allows a significant increase in the number of CD45+ B cells up to levels even higher than the level expressed by the mice in Group 1 (see FIG. 5A). The administering of α-NMN and of β-NMN also allows an increase in the number of pre-pro B cells (FIG. 5B) but does not show any impact on the number of pro-B cells (FIG. 5C). On the other hand, the administering of α-NMN (Group 3) and of β-NMN (Group 4) allows an increase in the number of pre-B cells (FIG. 5D) and immature B cells (FIG. 5E).

[0370] The B cells present in the spleen of the mice in each of the groups was characterized. As shown in FIG. 6A, the number of CD45+ T cells in the spleen is significantly increased through the administering of β-NMN (Group 4) compared with the other groups of mice. The administering of β-NMN also allows an increase in the number of activated B cells in the spleen in significant manner compared with the other groups (FIG. 6B), as well as memory B cells (FIG. 6C) and germinal B cells (FIG. 6D). The number of plasma cells is not modified among the 4 groups (FIG. 6E).

[0371] The CD4+ T cells present in the spleen of the mice in each of the groups were characterized. As shown in FIG. 7A, the total number of CD4+ T cells in the spleen is significantly increased through the administering of β-NMN (Group 4) compared with the other groups of mice. The administering of β-NMN also allows an increase in the memory T cells that is significant compared with the other groups (FIG. 7B). The administering d′α-NMN and of β-NMN also allows an increase in the number of CD4+ effector T cells compared with Group 3.

[0372] The CD8+ T cells present in the spleen of the mice in Groups 1, 2 and 3 were characterized. As shown in FIG. 8A, the old mice in Group 2 exhibit fewer naive CD8+ T cells than the young mice in Group 1. The administering of α-NMN (Group 3) does not modify the number of naive CD8+ T cells. On the other hand; the administering of α-NMN (Group 3) allows restoring of the levels of effector CD8+ T cells (FIG. 8B), of memory CD8+ T cells (FIG. 8C) and of effector memory CD8+ T cells (FIG. 8D).

[0373] The total splenocytes were stained with Carboxyfluorescein succinimidyl ester (CFSE) and stimulated with beads coated with anti-CD3/CD28 for 96 h. The mean fluorescence intensity of the CFSE was analysed and the ratio before and after stimulation was calculated. As shown in FIGS. 9A and 9B, the proliferation of CD4 and CD8 cells is not impacted by age. However, the treatment with β-NMN allows a significant increase in the proliferation of CD4 and CD8 cells compared with the three other groups of mice.

[0374] The total splenocytes were stimulated with beads coated with anti-CD3/CD28 for 18 h. As shown in FIGS. 10A and 10B, ageing reduced the proportion of cells producing IFNγ and IL10 when simulated with beads coated with anti-CD3/CD28. For IFNγ (FIG. 10A), the response to stimulation was lower in the old mice treated with the vehicle or α-NMN, and lack of response was observed in the β-NMN group.

[0375] To conclude, the administering of compounds I-A et I-B allows a significant decrease in the signs of immunosenescence.