Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience
Alexey Moskalev1,*, Ilia Stambler2,*, Calogero Caruso3,*
1Institute of Biology of FRC of Komi Scientific Center of Ural Branch of Russian Academy of Sciences, Syktyvkar, 167982, Russia. 2Vetek (Seniority), The Movement for Longevity and Quality of Life, Israel. 3Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
The interrelation of the processes of immunity and senescence now receives an unprecedented emphasis during the COVID-19 pandemic, which brings to the fore the critical need to combat immunosenescence and improve the immune function and resilience of older persons. Here we review the historical origins and the current state of the science of innate and adaptive immunity in aging and longevity. From the modern point of view, innate and adaptive immunity are not only affected by aging but also are important parts of its underlying mechanisms. Excessive levels or activity of antimicrobial peptides, C-reactive protein, complement system, TLR/NF-κB, cGAS/STING/IFN 1,3 and AGEs/RAGE pathways, myeloid cells and NLRP3 inflammasome, declined levels of NK cells in innate immunity, thymus involution and decreased amount of naive T-cells in adaptive immunity, are biomarkers of aging and predisposition factors for cellular senescence and aging-related pathologies. Long-living species, human centenarians, and women are characterized by less inflamm-aging and decelerated immunosenescence. Despite recent progress in understanding, the harmonious theory of immunosenescence is still developing. Geroprotectors targeting these mechanisms are just emerging and are comprehensively discussed in this article.
Figure 1. Gut dysbiosis/permeability with aging can induce TLR in microglia and exerts mitochondrial dysfunction.
Figure 2. AGEs/RAGE pathway and age-related diseases.
Figure 3. SASP involvement in aging-related pathologies.
Figure 4. The role of adiposity in inflammation.
Figure 5. Physiological stress factors can induce NF-kB pathway.
Figure 6. Thymus involution and inflamm-aging.
Figure 7. Changes occurring during aging (reproduced with permission from ).
Stambler I (2015). Elie Metchnikoff-The founder of longevity science and a founder of modern medicine: In honor of the 170th anniversary. Adv Gerontol, 5:201-208.
Müller L, Di Benedetto S, Pawelec GThe Immune System and Its Dysregulation with Aging. In: HarrisJR KorolchukVI, editors. Biochemistry and Cell Biology of Ageing: Part II Clinical Science. Singapore: Springer Singapore; 2019, pp. 21-43.
Pawelec G (2017). Does the human immune system ever really become "senescent"? F1000Research, 6:F1000 Faculty Rev-1323.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. (2007). Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev, 128:92-105.
Mahlapuu M, Hakansson J, Ringstad L, Bjorn C (2016). Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front Cell Infect Microbiol, 6:194.
Zhao L, Lu W (2014). Defensins in innate immunity. Curr Opin Hematol, 21:37-42.
Badinloo M, Nguyen E, Suh W, Alzahrani F, Castellanos J, Klichko VI, et al. (2018). Overexpression of antimicrobial peptides contributes to aging through cytotoxic effects in Drosophila tissues. Arch Insect Biochem Physiol, 98:e21464.
Akira S, Uematsu S, Takeuchi O (2006). Pathogen Recognition and Innate Immunity. Cell, 124:783-801.
Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU (2015). Targeting C-Reactive Protein in Inflammatory Disease by Preventing Conformational Changes. Mediat Inflamm, 2015:372432.
Vijay K (2018). Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol, 59:391-412.
Sun L, Wu J, Du F, Chen X, Chen ZJ (2013). Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science, 339:786-791.
Tang Y, Fung E, Xu A, Lan HY (2017). C-reactive protein and ageing. Clin Exp Pharmacol Physiol, 44 Suppl 1:9-14.
Wu J, Sun X (2019). Complement system and age-related macular degeneration: drugs and challenges. Drug Des Devel Ther, 13:2413-2425.
Shim K, Begum R, Yang C, Wang H (2020). Complement activation in obesity, insulin resistance, and type 2 diabetes mellitus. World J Diabetes, 11:1-12.
Kumar V (2019). Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol, 332:16-30.
Rossin D, Barbosa-Pereira L, Iaia N, Testa G, Sottero B, Poli G, et al. (2019). A Dietary Mixture of Oxysterols Induces In Vitro Intestinal Inflammation through TLR2/4 Activation: The Protective Effect of Cocoa Bean Shells. Antioxidants, 8:151.
Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin X-j, et al. (2018). New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature, 560:198-203.
Anderson G, Rodriguez M, Reiter JR (2019). Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells. Int J Mol Sci, 20:5500.
Azam S, Jakaria M, Kim IS, Kim J, Haque ME, Choi DK (2019). Regulation of Toll-Like Receptor (TLR) Signaling Pathway by Polyphenols in the Treatment of Age-Linked Neurodegenerative Diseases: Focus on TLR4 Signaling. Front Immunol, 10:1000.
Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, et al. (2020). Immunology of COVID-19: current state of the science. Immunity, Epub 6 May 2020.
Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, et al. (2020). Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev, 34:428-445.
Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, et al. (2019). LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation. Cell Metab, 29:871-885.e5.
De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, et al. (2019). L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature, 566:73-78.
Lan YY, Heather JM, Eisenhaure T, Garris CS, Lieb D, Raychowdhury R, et al. (2019). Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation. Aging Cell, 18:e12901.
Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A (2014). Role of advanced glycation end products in cellular signaling. Redox Biol, 2:411-429.
Coppe JP, Desprez PY, Krtolica A, Campisi J (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol, 5:99-118.
Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018). Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature, 562:578-582.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530:184-189.
Francisco V, Pino J, Gonzalez-Gay MA, Mera A, Lago F, Gomez R, et al. (2018). Adipokines and inflammation: is it a question of weight? Br J Pharmacol, 175:1569-1579.
Frasca D, Ferracci F, Diaz A, Romero M, Lechner S, Blomberg BB (2016). Obesity decreases B cell responses in young and elderly individuals. Obesity (Silver Spring), 24:615-625.
Forsythe LK, Wallace JM, Livingstone MB (2008). Obesity and inflammation: the effects of weight loss. Nutr Res Rev, 21:117-133.
Tilg H, Moschen AR (2006). Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol, 6:772-783.
Fain JN (2006). Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm, 74:443-477.
Cai D, Liu T (2012). Inflammatory cause of metabolic syndrome via brain stress and NF-kappaB. Aging (Albany NY), 4:98-115.
Yan F, Polk DB (2010). Disruption of NF-kappaB signalling by ancient microbial molecules: novel therapies of the future? Gut, 59:421-426.
Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS (2010). Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A, 107:2669-2674.
Wang W, Zhang J, Wang H, Wang X, Liu S (2019). Vitamin D deficiency enhances insulin resistance by promoting inflammation in type 2 diabetes. Int J Clin Exp Pathol, 12:1859-1867.
Spengler ML, Kuropatwinski KK, Comas M, Gasparian AV, Fedtsova N, Gleiberman AS, et al. (2012). Core circadian protein CLOCK is a positive regulator of NF-kappaB-mediated transcription. Proc Natl Acad Sci U S A, 109:E2457-2465.
Queisser N, Schupp N (2012). Aldosterone, oxidative stress, and NF-kappaB activation in hypertension-related cardiovascular and renal diseases. Free Radic Biol Med, 53:314-327.
Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RA, Thaiss F (2002). Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int, 61:1986-1995.
Kaczmarek E, Hauser CJ, Kwon WY, Rica I, Chen L, Sandler N, et al. (2018). A subset of five human mitochondrial formyl peptides mimics bacterial peptides and functionally deactivates human neutrophils. J Trauma Acute Care Surg, 85:936-943.
Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. (2012). Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 36:401-414.
Danilov A, Shaposhnikov M, Shevchenko O, Zemskaya N, Zhavoronkov A, Moskalev A (2015). Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity. Oncotarget, 6:19428-19444.
Danilov A, Shaposhnikov M, Plyusnina E, Kogan V, Fedichev P, Moskalev A (2013). Selective anticancer agents suppress aging in Drosophila. Oncotarget, 4:1507-1526.
Moskalev A, Shaposhnikov M (2011). Pharmacological inhibition of NF-kappaB prolongs lifespan of Drosophila melanogaster. Aging (Albany NY), 3:391-394.
Karunaweera N, Raju R, Gyengesi E, Munch G (2015). Plant polyphenols as inhibitors of NF-kappaB induced cytokine production-a potential anti-inflammatory treatment for Alzheimer's disease? Front Mol Neurosci, 8:24.
Kim S, Jazwinski SM (2018). The Gut Microbiota and Healthy Aging: A Mini-Review. Gerontology, 64:513-520.
Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. (2016). Gut Microbiota and Extreme Longevity. Curr Biol, 26:1480-1485.
Pawelec G, Gupta S (2019). Editorial: Immunology of Aging. Front Immunol, 10:1614.
Pera A, Caserta S, Albanese F, Blowers P, Morrow G, Terrazzini N, et al. (2018). CD28(null) pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death. Theranostics, 8:4509-4519.
Hermansson RS, Olovsson M, Hoxell E, Lindstrom AK (2018). HPV prevalence and HPV-related dysplasia in elderly women. PLoS One, 13:e0189300.
Cairns DM, Rouleau N, Parker RN, Walsh KG, Gehrke L, Kaplan DL (2020). A 3D human brain-like tissue model of herpes-induced Alzheimer's disease. Sci Adv, 6:eaay8828.
Linard M, Letenneur L, Garrigue I, Doize A, Dartigues JF, Helmer C (2020). Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease. Alzheimers Dement, 16:200-208.
Mancuso R, Sicurella M, Agostini S, Marconi P, Clerici M (2019). Herpes simplex virus type 1 and Alzheimer's disease: link and potential impact on treatment. Expert Rev Anti Infect Ther, 17:715-731.
Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, et al. (2018). Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron, 99:64-82.e7.
Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, et al. (2019). Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front Immunol, 10:2247.
Caruso C, Accardi G, Virruso C, Candore G (2013). Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing, 10:20.
Aiello A, Accardi G, Candore G, Caruso C, Colomba C, Di Bona D, et al. (2019). Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing. Int J Mol Sci, 20:685.
Dixit VD (2010). Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr Opin Immunol, 22:521-528.
Banfai K, Garai K, Ernszt D, Pongracz JE, Kvell K (2019). Transgenic Exosomes for Thymus Regeneration. Front Immunol, 10:862.
Fukushima Y, Minato N, Hattori M (2018). The impact of senescence-associated T cells on immunosenescence and age-related disorders. Inflamm Regen, 38:24.
Minato N, Hattori M, Hamazaki Y (2020). Physiology and pathology of T-cell aging. Int Immunol, 32:223-231.
Schmidt ME, Varga SM (2018). The CD8 T Cell Response to Respiratory Virus Infections. Front Immunol, 9:678.
Vidal SM, Khakoo SI, Biron CA (2011). Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol, 1:497-512.
Effros RB, Dagarag M, Spaulding C, Man J (2005). The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev, 205:147-157.
Song P, An J, Zou M-H (2020). Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases. Cells, 9:671.
Pereira BI, Devine OP, Vukmanovic-Stejic M, Chambers ES, Subramanian P, Patel N, et al. (2019). Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun, 10:2387.
Thomas R, Wang W, Su DM (2020). Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing, 17:2.
Ho YH, Del Toro R, Rivera-Torres J, Rak J, Korn C, Garcia-Garcia A, et al. (2019). Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging. Cell Stem Cell, 25:407-418.e6.
de Haan G, Lazare SS (2018). Aging of hematopoietic stem cells. Blood, 131:479-487.
Ahmed M, Ffrench-Constant C (2016). Extracellular Matrix Regulation of Stem Cell Behavior. Curr Stem Cell Rep, 2:197-206.
Pietras EM (2017). Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood, 130:1693-1698.
Gao X, Xu C, Asada N, Frenette PS (2018). The hematopoietic stem cell niche: from embryo to adult. Development, 145:dev139691.
Varricchi G, Bencivenga L, Poto R, Pecoraro A, Shamji MH, Rengo G (2020). The emerging role of T follicular helper (TFH) cells in aging: Influence on the immune frailty. Ageing Res Rev: 101071.
Hilton HG, Rubinstein ND, Janki P, Ireland AT, Bernstein N, Fong NL, et al. (2019). Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity. PLoS Biol, 17:e3000528.
Seim I, Fang X, Xiong Z, Lobanov AV, Huang Z, Ma S, et al. (2013). Genome analysis reveals insights into physiology and longevity of the Brandt's bat Myotis brandtii. Nat Commun, 4:2212.
Huang Z, Whelan CV, Foley NM, Jebb D, Touzalin F, Petit EJ, et al. (2019). Longitudinal comparative transcriptomics reveals unique mechanisms underlying extended healthspan in bats. Nat Ecol Evol, 3:1110-1120.
Ahn M, Anderson DE, Zhang Q, Tan CW, Lim BL, Luko K, et al. (2019). Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host. Nat Microbiol, 4:789-799.
Keane M, Semeiks J, Webb AE, Li YI, Quesada V, Craig T, et al. (2015). Insights into the evolution of longevity from the bowhead whale genome. Cell Rep, 10:112-122.
Bucci L, Ostan R, Giampieri E, Cevenini E, Pini E, Scurti M, et al. (2014). Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status. Exp Gerontol, 54:14-20.
Santos-Lozano A, Valenzuela PL, Llavero F, Lista S, Carrera-Bastos P, Hampel H, et al. (2020). Successful aging: insights from proteome analyses of healthy centenarians. Aging (Albany NY), 12:3502-3515.
Rubino G, Bulati M, Aiello A, Aprile S, Gambino CM, Gervasi F, et al. (2019). Sicilian centenarian offspring are more resistant to immune ageing. Aging Clin Exp Res, 31:125-133.
Colonna-Romano G, Buffa S, Bulati M, Candore G, Lio D, Pellicano M, et al. (2010). B cells compartment in centenarian offspring and old people. Curr Pharm Des, 16:604-608.
Moskalev A (2020). Is anti-ageing drug discovery becoming a reality? Expert Opin Drug Discov, 15:135-138.
Moskalev A, Chernyagina E, de Magalhaes JP, Barardo D, Thoppil H, Shaposhnikov M, et al. (2015). Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY), 7:616-628.
Barardo D, Thornton D, Thoppil H, Walsh M, Sharifi S, Ferreira S, et al. (2017). The DrugAge database of aging-related drugs. Aging Cell, 16:594-597.
Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut'ko V, et al. (2016). Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell, 15:407-415.
Moskalev A, Chernyagina E, Kudryavtseva A, Shaposhnikov M (2017). Geroprotectors: A Unified Concept and Screening Approaches. Aging Dis, 8:354-363.
Gonzalez-Freire M, Diaz-Ruiz A, Hauser D, Martinez-Romero J, Ferrucci L, Bernier M, et al. (2020). The road ahead for health and lifespan interventions. Ageing Res Rev, 59:101037.
Campbell JP, Turner JE (2018). Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan. Front Immunol, 9:648.
Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, et al. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell, 14:810-823.
Buono R, Longo VD (2019). When Fasting Gets Tough, the Tough Immune Cells Get Going-or Die. Cell, 178:1038-1040.
Pahlavani MA (2004). Influence of caloric restriction on aging immune system. J Nutr Health Aging, 8:38-47.
Mu WC, VanHoosier E, Elks CM, Grant RW (2018). Long-Term Effects of Dietary Protein and Branched-Chain Amino Acids on Metabolism and Inflammation in Mice. Nutrients, 10:918.
Takatsu K (2011). Interleukin-5 and IL-5 receptor in health and diseases. Proc Jpn Acad Ser B Phys Biol Sci, 87:463-485.
Chapman IM (2006). Nutritional disorders in the elderly. Med Clin North Am, 90:887-907.
Miller RA, Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M (2005). Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell, 4:119-125.
Hagglund B, Sandberg G (1993). Effect of L-alanine and some other amino acids on thymocyte proliferation in vivo. Immunobiology, 188:62-69.
Partridge L, Fuentealba M, Kennedy BK (2020). The quest to slow ageing through drug discovery. Nat Rev Drug Discov. Epub 28 May 2020.
Murru A, Manchia M, Hajek T, Nielsen RE, Rybakowski JK, Sani G, et al. (2020). Lithium's antiviral effects: a potential drug for CoViD-19 disease? Int J Bipolar Disord, 8:21.
Zhao Y, Yan K, Wang Y, Cai J, Wei L, Li S, et al. (2020). Lithium chloride confers protection against viral myocarditis via suppression of coxsackievirus B3 virus replication. Microb Pathog, 144:104169.
Maddu N, Raghavendra PB (2015). Review of lithium effects on immune cells. Immunopharmacol Immunotoxicol, 37:111-125.
Desdin-Mico G, Soto-Heredero G, Aranda JF, Oller J, Carrasco E, Gabande-Rodriguez E, et al. (2020). T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science. Epub 21 May 2020.
Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, et al. (2020). Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation. Cell Metab, Epub 12 May 2020.
Zhang X, Fang Z, Zhang C, Xia H, Jie Z, Han X, et al. (2017). Effects of Acarbose on the Gut Microbiota of Prediabetic Patients: A Randomized, Double-blind, Controlled Crossover Trial. Diabetes Ther, 8:293-307.
Mo D, Liu S, Ma H, Tian H, Yu H, Zhang X, et al. (2019). Effects of acarbose and metformin on the inflammatory state in newly diagnosed type 2 diabetes patients: a one-year randomized clinical study. Drug Des Devel Ther, 13:2769-2776.
Malaguarnera L (2019). Influence of Resveratrol on the Immune Response. Nutrients, 11:946.
Zhang H, Simon AK (2020). Polyamines reverse immune senescence via the translational control of autophagy. Autophagy, 16:181-182.
Hale DA, Gottschalk R, Fukuzaki T, Wood ML, Maki T, Monaco AP (1997). Superiority of sirolimus (rapamycin) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow. Transplantation, 63:359-364.
Al-Hammadi S, Almarzooqi S, Albawardi A, Souid AK (2015). Effects of molecularly targeted therapies on murine thymus: highly selective mTOR inhibitors induce reversible thymic involution. Exp Hematol Oncol, 5:22.
Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol, 105:53-69.
Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F (2020). Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov, 6:14.
Szczepanik M (2007). Melatonin and its influence on immune system. J Physiol Pharmacol, 58 Suppl 6:115-124.
Nir Barzilai, James C Appleby, Steven N Austad, Ana Maria Cuervo, Matt Kaeberlein, Christian Gonzalez-Billault, Stephanie Lederman, Ilia Stambler, Felipe Sierra. Geroscience in the Age of COVID-19[J]. Aging and disease, 2020, 11(4): 725-729.