Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects

Abstract

Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD+ levels in aged mice rescues neurovascular function, increases cerebral blood flow, and improves performance on cognitive tasks. To determine the effects of restoring cellular NAD+ levels on neurovascular gene expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. Transcriptome analysis of preparations enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular gene expression signatures in NMN-treated aged mice were compared with those in untreated young and aged control mice. We identified 590 genes differentially expressed in the aged neurovascular unit, 204 of which are restored toward youthful expression levels by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased NAD+ levels promote SIRT1 activation in the neurovascular unit, as demonstrated by analysis of upstream regulators of differentially expressed genes as well as analysis of the expression of known SIRT1-dependent genes. Pathway analysis predicts that neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways. In conclusion, the recently demonstrated protective effects of NMN treatment on neurovascular function can be attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular transcriptome. Our present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Cohen H, Lin SS, Manchester JK, Gordon JI, Sinclair DA (2002) Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J Biol Chem 277:18881–18890

  2. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 444:337–342

  3. Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R (2012) Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 11:443–461

  4. Bernier M, Wahl D, Ali A, Allard J, Faulkner S, Wnorowski A, Sanghvi M, Moaddel R, Alfaras I, Mattison JA, Tarantini S, Tucsek Z, Ungvari Z, Csiszar A, Pearson KJ, de Cabo R (2016) Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet. Aging (Albany NY) 8:899–916

  5. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 30:2114–2120

  6. Bray NL, Pimentel H, Melsted P, Pachter L (2016) Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol 34:525–527

  7. Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J (2012) The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15:838–847

  8. Chen YX, Zhang M, Cai Y, Zhao Q, Dai W (2015) The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE(−)/(−) mice through inhibiting vascular inflammatory response. Biochem Biophys Res Commun 465:732–738

  9. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 305:390–392

  10. Csipo T, Lipecz A, Fulop GA, Hand RA, Ngo BN, Dzialendzik M, Tarantini S, Balasubramanian P, Kiss T, Yabluchanska V, Silva-Palacios F, Courtney DL, Dasari TW, Sorond F, Sonntag WE, Csiszar A, Ungvari Z, Yabluchanskiy A (2019a) Age-related decline in peripheral vascular health predicts cognitive impairment. Geroscience. 41:125–136

  11. Csipo T, Mukli P, Lipecz A, Tarantini S, Bahadli D, Abdulhussein O, Owens C, Kiss T, Balasubramanian P, Nyul-Toth A, Hand RA, Yabluchanska V, Sorond FA, Csiszar A, Ungvari Z, Yabluchanskiy A (2019b) Assessment of age-related decline of neurovascular coupling responses by functional near-infrared spectroscopy (fNIRS) in humans. Geroscience. 41:495–509

  12. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G (2003) Aging-induced proinflammatory shift in cytokine expression profile in rat coronary arteries. FASEB J 17:1183–1185

  13. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G (2004) Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging. Physiol Genomics 17:21–30

  14. Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z (2007) Vasculoprotective effects of anti-TNFalfa treatment in aging. Am J Pathol 170:388–698

  15. Csiszar A, Labinskyy N, Podlutsky A, Kaminski PM, Wolin MS, Zhang C, Mukhopadhyay P, Pacher P, Hu F, de Cabo R, Ballabh P, Ungvari Z (2008a) Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol Heart Circ Physiol 294:H2721–H2735

  16. Csiszar A, Wang M, Lakatta EG, Ungvari ZI (2008b) Inflammation and endothelial dysfunction during aging: role of NF-{kappa}B. J Appl Physiol 105:1333–1341

  17. Csiszar A, Labinskyy N, Jimenez R, Pinto JT, Ballabh P, Losonczy G, Pearson KJ, de Cabo R, Ungvari Z (2009a) Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. Mech Ageing Dev 130:518–527

  18. Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, Pearson KJ, de Cabo R, Pacher P, Zhang C, Ungvari ZI (2009b) Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H13-20. https://doi.org/10.1152/ajpheart.00368.2009

  19. Csiszar A, Sosnowska D, Wang M, Lakatta EG, Sonntag WE, Ungvari Z (2012) Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J Gerontol A Biol Sci Med Sci 67:811–820

  20. Csiszar A, Sosnowska D, Tucsek Z, Gautam T, Toth P, Losonczy G, Colman RJ, Weindruch R, Anderson RM, Sonntag WE, Ungvari Z (2013) Circulating factors induced by caloric restriction in the nonhuman primate Macaca mulatta activate angiogenic processes in endothelial cells. J Gerontol A Biol Sci Med Sci 68:235–249

  21. Csiszar A, Gautam T, Sosnowska D, Tarantini S, Banki E, Tucsek Z, Toth P, Losonczy G, Koller A, Reglodi D, Giles CB, Wren JD, Sonntag WE, Ungvari Z (2014a) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307:H292–H306

  22. Csiszar A, Pinto JT, Gautam T, Kleusch C, Hoffmann B, Tucsek Z, Toth P, Sonntag WE, Ungvari Z (2014b) Resveratrol encapsulated in novel fusogenic liposomes activates Nrf2 and attenuates oxidative stress in cerebromicrovascular endothelial cells from aged rats. J Gerontol A Biol Sci Med Sci. 2015 Mar;70(3):303-13. https://doi.org/10.1093/gerona/glu029

  23. Csiszar A, Tarantini S, Fulop GA, Kiss T, Valcarcel-Ares MN, Galvan V, Ungvari Z, Yabluchanskiy A (2017) Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. GeroScience. 2017 Aug; 39(4): 359–372.

  24. Csiszar A, Tarantini S, Yabluchanskiy A, Balasubramanian P, Kiss T, Farkas E, Baur JA, Ungvari ZI (2019) Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Am J Physiol Heart Circ Physiol. 2019 Jun 1;316(6):H1253-H1266. https://doi.org/10.1152/ajpheart.00039.2019

  25. Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne B, Joshi S, Lu Y, Trevino-Villarreal JH, Kang MJ, Hung TT, Lee B, Williams EO, Igarashi M, Mitchell JR, Wu LE, Turner N, Arany Z, Guarente L, Sinclair DA (2018) Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging. Cell. 173:74–89 e20

  26. de Montgolfier O, Pouliot P, Gillis MA, Ferland G, Lesage F, Thorin-Trescases N, Thorin E (2019) Systolic hypertension-induced neurovascular unit disruption magnifies vascular cognitive impairment in middle-age atherosclerotic LDLr(−/−):hApoB(+/+) mice. Geroscience. 41:511–532

  27. de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR (2016) Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15:522–530

  28. Durinck S, Spellman PT, Birney E, Huber W (2009) Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc 4:1184–1191

  29. Falcon S, Gentleman R (2007) Using GOstats to test gene lists for GO term association. Bioinformatics. 23:257–258

  30. Farias Quipildor GE, Mao K, Hu Z, Novaj A, Cui MH, Gulinello M, Branch CA, Gubbi S, Patel K, Moellering DR, Tarantini S, Kiss T, Yabluchanskiy A, Ungvari Z, Sonntag WE, Huffman DM (2019) Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. Geroscience. 41:185–208

  31. Fulop GA, Ahire C, Csipo T, Tarantini S, Kiss T, Balasubramanian P, Yabluchanskiy A, Farkas E, Toth A, Nyul-Toth A, Toth P, Csiszar A, Ungvari Z (2019) Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice. Geroscience. 41:575–589

  32. Gano LB, Donato AJ, Pasha HM, Hearon CM Jr, Sindler AL, Seals DR (2014) The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am J Physiol Heart Circ Physiol 307:H1754–H1763

  33. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 155:1624–1638

  34. Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science. 339:1216–1219

  35. Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 96:17–42

  36. Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H (2013) Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123:1299–1309

  37. Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464–471

  38. Imperio CG, McFalls AJ, Colechio EM, Masser DR, Vrana KE, Grigson PS, Freeman WM (2016) Assessment of individual differences in the rat nucleus accumbens transcriptome following taste-heroin extended access. Brain Res Bull 123:71–80

  39. Jessen NA, Munk AS, Lundgaard I, Nedergaard M (2015) The glymphatic system: a Beginner’s guide. Neurochem Res 40:2583–2599

  40. Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419–434

  41. Kiss T, Balasubramanian P, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Csipo T, Lipecz A, Reglodi D, Zhang XA, Bari F, Farkas E, Csiszar A, Ungvari Z (2019a) Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for prevention of vascular cognitive impairment. GeroScience. in press

  42. Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, Balasubramanian P, Gautam T, Csipo T, Nyul-Toth A, Lipecz A, Szabo C, Farkas E, Wren JD, Csiszar A, Ungvari Z (2019b) Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects. Geroscience. 2019 Aug;41(4):419–439. https://doi.org/10.1007/s11357-019-00095-x. Accessed 28 Aug 2019

  43. Kramer A, Green J, Pollard J Jr, Tugendreich S (2014) Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 30:523–530

  44. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861

  45. Kwong LK, Sohal RS (2000) Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse. Arch Biochem Biophys 373:16–22

  46. Libert S, Pointer K, Bell EL, Das A, Cohen DE, Asara JM, Kapur K, Bergmann S, Preisig M, Otowa T, Kendler KS, Chen X, Hettema JM, van den Oord EJ, Rubio JP, Guarente L (2011) SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell. 147:1459–1472

  47. Liu L, Su X, Quinn WJ 3rd, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E, Migaud M, Mitchison TJ, Baur JA, Rabinowitz JD (2018) Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab 27:1067–1080 e5

  48. Lopez-Ramirez MA, Male DK, Wang C, Sharrack B, Wu D, Romero IA (2013) Cytokine-induced changes in the gene expression profile of a human cerebral microvascular endothelial cell-line, hCMEC/D3. Fluids Barriers CNS 10:27

  49. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550

  50. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ (2012) Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7:e42357

  51. Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, An SS, Santhanam L, Martin B, Faulkner S, Morrell C, Baur JA, Peshkin L, Sosnowska D, Csiszar A, Herbert RL, Tilmont EM, Ungvari Z, Pearson KJ, Lakatta EG, de Cabo R (2014) Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab 20:183–190

  52. Michan S, Li Y, Chou MM, Parrella E, Ge H, Long JM, Allard JS, Lewis K, Miller M, Xu W, Mervis RF, Chen J, Guerin KI, Smith LE, McBurney MW, Sinclair DA, Baudry M, de Cabo R, Longo VD (2010) SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci 30:9695–9707

  53. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806

  54. Minor RK, Baur JA, Gomes AP, Ward TM, Csiszar A, Mercken EM, Abdelmohsen K, Shin YK, Canto C, Scheibye-Knudsen M, Krawczyk M, Irusta PM, Martin-Montalvo A, Hubbard BP, Zhang Y, Lehrmann E, White AA, Price NL, Swindell WR, Pearson KJ, Becker KG, Bohr VA, Gorospe M, Egan JM, Talan MI, Auwerx J, Westphal CH, Ellis JL, Ungvari Z, Vlasuk GP, Elliott PJ, Sinclair DA, de Cabo R (2011) SRT1720 improves survival and healthspan of obese mice. Sci Rep. 1. https://doi.org/10.1038/srep00070

  55. Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, Minor RK, Vlasuk GP, Ellis JL, Sinclair DA, Dawson J, Allison DB, Zhang Y, Becker KG, Bernier M, de Cabo R (2014) The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep 6:836–843

  56. Mitchell SJ, Bernier M, Aon MA, Cortassa S, Kim EY, Fang EF, Palacios HH, Ali A, Navas-Enamorado I, Di Francesco A, Kaiser TA, Waltz TB, Zhang N, Ellis JL, Elliott PJ, Frederick DW, Bohr VA, Schmidt MS, Brenner C, Sinclair DA, Sauve AA, Baur JA, de Cabo R (2018) Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab 27:667–676 e4

  57. Montagne A, Zhao Z, Zlokovic BV (2017) Alzheimer’s disease: a matter of blood-brain barrier dysfunction? J Exp Med 214:3151–3169

  58. Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair DA, Blackwell TK (2014) Dietary restriction involves NAD(+)-dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 13:1075–1085

  59. Nyul-Toth A, Suciu M, Molnar J, Fazakas C, Hasko J, Herman H, Farkas AE, Kaszaki J, Hermenean A, Wilhelm I, Krizbai IA (2016) Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study. Am J Physiol Heart Circ Physiol 310:H1702–H1714

  60. Oomen CA, Farkas E, Roman V, van der Beek EM, Luiten PG, Meerlo P (2009) Resveratrol preserves cerebrovascular density and cognitive function in aging mice. Front Aging Neurosci 1:4

  61. Pacher P, Mabley JG, Soriano FG, Liaudet L, Komjati K, Szabo C (2002) Endothelial dysfunction in aging animals: the role of poly(ADP-ribose) polymerase activation. Br J Pharmacol 135:1347–1350

  62. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168

  63. Sagare AP, Bell RD, Zlokovic BV (2013) Neurovascular defects and faulty amyloid-beta vascular clearance in Alzheimer's disease. J Alzheimers Dis 33(Suppl 1):S87–S100

  64. Solano Fonseca R, Mahesula S, Apple DM, Raghunathan R, Dugan A, Cardona A, O'Connor J, Kokovay E (2016) Neurogenic niche microglia undergo positional remodeling and progressive activation contributing to age-associated reductions in neurogenesis. Stem Cells Dev 25:542–555

  65. Soneson C, Love MI, Robinson MD (2015) Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res 4:1521

  66. Sorond FA, Whitehead S, Arai K, Arnold D, Carmichael ST, De Carli C, Duering M, Fornage M, Flores-Obando RE, Graff-Radford J, Hamel E, Hess DC, Ihara M, Jensen MK, Markus HS, Montagne A, Rosenberg G, Shih AY, Smith EE, Thiel A, Tse KH, Wilcock D, Barone F (2019) Proceedings from the Albert Charitable Trust Inaugural Workshop on white matter and cognition in aging. Geroscience. 2019 Dec 6. https://doi.org/10.1007/s11357-019-00141-8

  67. Stanimirovic DB, Friedman A (2012) Pathophysiology of the neurovascular unit: disease cause or consequence? J Cereb Blood Flow Metab 32:1207–1221

  68. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550

  69. Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133–150

  70. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019a) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99:21–78

  71. Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, Harrington MG, Pa J, Law M, Wang DJJ, Jacobs RE, Doubal FN, Ramirez J, Black SE, Nedergaard M, Benveniste H, Dichgans M, Iadecola C, Love S, Bath PM, Markus HS, Salman RA, Allan SM, Quinn TJ, Kalaria RN, Werring DJ, Carare RO, Touyz RM, Williams SCR, Moskowitz MA, Katusic ZS, Lutz SE, Lazarov O, Minshall RD, Rehman J, Davis TP, Wellington CL, Gonzalez HM, Yuan C, Lockhart SN, Hughes TM, CLH C, Sachdev P, O’Brien JT, Skoog I, Pantoni L, Gustafson DR, Biessels GJ, Wallin A, Smith EE, Mok V, Wong A, Passmore P, Barkof F, Muller M, MMB B, Roman GC, Hamel E, Seshadri S, Gottesman RF, van Buchem MA, Arvanitakis Z, Schneider JA, Drewes LR, Hachinski V, Finch CE, Toga AW, Wardlaw JM, Zlokovic BV (2019b) Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimers Dement. 15:158–167

  72. Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges EL, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P (2015) Pharmacologically induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35:1871–1881

  73. Tarantini S, Tucsek Z, Valcarcel-Ares M, Toth P, Gautam T, Giles C, Ballabh P, Wei Y, Wren J, Ashpole N, Sonntag W, Ungvari Z, Csiszar A (2016) Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. Age (Dordr) 38:273–289

  74. Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017a) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58

  75. Tarantini S, Yabluchanksiy A, Fulop GA, Hertelendy P, Valcarcel-Ares MN, Kiss T, Bagwell JM, O'Connor D, Farkas E, Sorond F, Csiszar A, Ungvari Z (2017b) Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. Geroscience. 39:601–614

  76. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, Ungvari Z (2017c) Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell 16:469–479

  77. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Fulop GA, Hertelendy P, Gautam T, Farkas E, Perz A, Rabinovitch PS, Sonntag WE, Csiszar A, Ungvari Z (2018) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell. 2018 Apr;17(2). https://doi.org/10.1111/acel.12731

  78. Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Sule Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z (2019a) Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol 24:101192

  79. Tarantini S, Yabluchanskiy A, Csipo T, Fulop G, Kiss T, Balasubramanian P, DelFavero J, Ahire C, Ungvari A, Nyul-Toth A, Farkas E, Benyo Z, Toth A, Csiszar A, Ungvari Z (2019b) Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging. Geroscience. 2019 Oct;41(5):533–542. https://doi.org/10.1007/s11357-019-00101-2

  80. Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari ZI (2014) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidas. Am J Physiol Heart Circ Physiol 306:H299–H308

  81. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015) Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14:400–408

  82. Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312:H1–H20

  83. Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352

  84. Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A (2007a) Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293:H37–H47

  85. Ungvari Z, Orosz Z, Rivera A, Labinskyy N, Xiangmin Z, Olson S, Podlutsky A, Csiszar A (2007b) Resveratrol increases vascular oxidative stress resistance. Am J Physiol 292:H2417–H2424

  86. Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, Zhang C, Pacher P, Csiszar A (2009) Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol 297:H1876–H1881

  87. Ungvari Z, Sonntag WE, de Cabo R, Baur JA, Csiszar A (2011) Mitochondrial protection by resveratrol. Exerc Sport Sci Rev. 2011 Jul;39(3):128–32. https://doi.org/10.1097/JES.0b013e3182141f80.

  88. Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A, Csiszar A, Losonczy G, Valcarcel-Ares MN, Sonntag WE (2013) Aging-induced dysregulation of Dicer1-dependent MicroRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68:877–891

  89. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017) Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol 312:H1128–H1143

  90. Ungvari Z, Tarantini S, Kiss T, Wren JD, Giles CB, Griffin CT, Murfee WL, Pacher P, Csiszar A (2018a) Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol 15:555–565

  91. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018b) Mechanisms of vascular aging. Circ Res 123:849–867

  92. Valcarcel-Ares MN, Tucsek Z, Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, Balasubramanian P, Gautam T, Galvan V, Ballabh P, Richardson A, Freeman WM, Wren JD, Deak F, Ungvari Z, Csiszar A (2018) Obesity in aging exacerbates neuroinflammation, dysregulating synaptic function-related genes and altering eicosanoid synthesis in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline. J Gerontol A Biol Sci Med Sci. 2019 Feb 15;74(3):290–298. https://doi.org/10.1093/gerona/gly127.

  93. Warrington JP, Ashpole N, Csiszar A, Lee YW, Ungvari Z, Sonntag WE (2013) Whole brain radiation-induced vascular cognitive impairment: mechanisms and implications. J Vasc Res 50:445–457

  94. Wei CC, Kong YY, Hua X, Li GQ, Zheng SL, Cheng MH, Wang P, Miao CY (2017) NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia. Br J Pharmacol 174:3823–3836

  95. Wiedenhoeft T, Tarantini S, Nyúl-Tóth A, Yabluchanskiy A, Csipo T, Balasubramanian P, Lipecz A, Kiss T, Csiszar A, Csiszar A, Ungvari Z (2019) Fusogenic liposomes effectively deliver resveratrol to the cerebral microcirculation and improve endothelium-dependent neurovascular coupling responses in aged mice. Geroscience. 2019 Dec;41(6):711–725. https://doi.org/10.1007/s11357-019-00102-1

  96. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 430:686–689

  97. Wren JD, Garner HR (2004) Shared relationship analysis: ranking set cohesion and commonalities within a literature-derived relationship network. Bioinformatics. 20:191–198

  98. Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 130:1095–1107

  99. Yoshino J, Baur JA, Imai SI (2018) NAD(+) intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 27:513–528

  100. Zarzuelo MJ, Lopez-Sepulveda R, Sanchez M, Romero M, Gomez-Guzman M, Ungvary Z, Perez-Vizcaino F, Jimenez R, Duarte J (2013) SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. Biochem Pharmacol 85:1288–1296

  101. Zhang H, Zhang J, Ungvari Z, Zhang C (2009) Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress. Arterioscler Thromb Vasc Biol 29:1164–1171

  102. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947

  103. Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J (2016) NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 352:1436–1443

  104. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 57:178–201

  105. Zlokovic BV (2010) Neurodegeneration and the neurovascular unit. Nat Med 16:1370–1371

  106. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12:723–738

Download references

Funding

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the National Institute of General Medical Sciences Oklahoma Shared Clinical and Translational Resources (OSCTR) (GM104938, to AY and JW) and Molecular Mechanisms and Genetics of Autoimmunity COBRE (P30-GM110766, to LG), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author information

Correspondence to Zoltan Ungvari.

Ethics declarations

All procedures were approved by the Institutional Animal Use and Care Committees of the University of Oklahoma Health Sciences Center. All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978).

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kiss, T., Nyúl-Tóth, Á., Balasubramanian, P. et al. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. GeroScience (2020). https://doi.org/10.1007/s11357-020-00165-5

Download citation

Keywords

  • Aging
  • Geroscience
  • Vascular cognitive impairment
  • Mitochondria dysfunction
  • Transcriptomics