Immunosenescence Abstracts 2


Melatonin and viral infections.
            (Bonilla et al., 2004) Download
The therapeutic effects of melatonin against viral infections, with emphasis on the Venezuelan equine encephalomyelitis (VEE), are reviewed. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also postpones the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed by either isolation or dexamethasone injection. An increase in the host resistance to the virus via a peripheral immunostimulatory activity is considered responsible for these effects. It has also been demonstrated that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. This protective effect seems to be due to the increase in the production of interleukin-1beta (IL-1beta), as 100% of the infected mice treated with melatonin die when IL-1beta is blocked with antimurine IL-1beta antibodies. Although melatonin administration raises serum levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), the mortality observed in neutralization experiments with the corresponding anticytokine antibodies, suggests that neither TNF-alpha nor IFN-gamma are essential for the protective effect of melatonin on murine VEE virus infection. Melatonin treatment also enhances the efficiency of immunization against the VEE virus. Reactive oxygen species have been implicated in the dissemination of this virus, and their deleterious effects may be diminished by melatonin. This indole inhibits nitric oxide synthetase activity and it is a potent scavenger of nitric oxide, which also plays an important role in the spread of the VEE virus. In conclusion, the immunomodulatory, antioxidant, and neuroprotective effects of melatonin suggest that this indole must be considered as an additional therapeutic alternative to fight viral diseases.


Melatonin: buffering the immune system.
            (Carrillo-Vico et al., 2013) Download
Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed.

Role of redox imbalance in the molecular mechanisms responsible for immunosenescence.
            (Daynes et al., 2003) Download
The elderly suffer impairments to their immune system, evidenced by higher susceptibility to infections, cancer, and many diseases believed to be autoimmune in nature. A dysregulated overexpression of many proinflammatory cytokines also occurs with aging, as does the synthesis of enzymes that control expression of inflammatory lipid mediators and reactive oxygen species. An inappropriate activation of redox-controlled transcription factors, like nuclear factor-kappaB, occurs in many tissues from aged donors, and has been linked to excesses in cellular oxidative stress. Recently, the peroxisome proliferator-activated receptor-alpha (PPARalpha) has been evaluated for its effects on inflammatory and adaptive immune processes. PPARalpha provides redox-balancing influences on various lymphoid cell types and their inducible responses. We recently discovered that PPARalpha transiently suppresses the transcription of gamma-interferon (IFNgamma) by inhibiting the induction of T-bet. We now report that PPARalpha expression in CD4+ T cells is affected by the aging process. Lower PPARalpha levels are present in aged CD4+ T cells, and appear responsible for the suppressed interleukin-2 and exaggerated IFNgamma responses by these cells. Restoration of PPARalpha, T-bet, interleukin-2, and IFNgamma responses was found in T cells from aged animals supplemented with vitamin E, suggesting that interventions that focus on restoring redox balance might benefit the ailing aged immune system.


Clinical evaluation of the oral probiotic Streptococcus salivarius K12 in the prevention of recurrent pharyngitis and/or tonsillitis caused by Streptococcus pyogenes in adults.
            (Di Pierro et al., 2013) Download
BACKGROUND:  Streptococcus salivarius K12 has been shown to inhibit the growth of Streptococcus pyogenes due to bacteriocins release. Because of its ability to colonize the oral cavity, we have tested the strain K12 for its efficacy in preventing streptococcal pharyngitis and/or tonsillitis in adults. METHODS:  Forty adults with a diagnosis of recurrent oral streptococcal pharyngitis were enrolled in the study. Twenty of these subjects took for 90 days a tablet containing Streptococcus salivarius K12 (Bactoblis®). The other 20 subjects served as untreated controls. A 6-month follow-up was included to evaluate any persistent protective role. RESULTS:  The 20 adults who completed the 90-day course of Bactoblis® showed a reduction in their episodes of streptococcal pharyngeal infection (about 80%). The 90 days treatment was also associated with an approximately 60% reduction in the incidence of reported pharyngitis in the 6-month period following use of the product. The product was well tolerated by the subjects with no treatment-related side effects or drop-outs reported. CONCLUSION:  Prophylactic administration of Streptococcus salivarius K12 to adults having a history of recurrent oral streptococcal pathology reduced the number of episodes of streptococcal pharyngeal infections and/or tonsillitis.

Use of Streptococcus salivarius K12 in the prevention of streptococcal and viral pharyngotonsillitis in children.
            (Di Pierro et al., 2014) Download
BACKGROUND:  Streptococcus salivarius K12 is an oral probiotic strain releasing two lantibiotics (salivaricin A2 and salivaricin B) that antagonize the growth of S. pyogenes, the most important bacterial cause of pharyngeal infections in humans also affected by episodes of acute otitis media. S. salivarius K12 successfully colonizes the oral cavity, and is endowed with an excellent safety profile. We tested its preventive role in reducing the incidence of both streptococcal and viral pharyngitis and/or tonsillitis in children. MATERIALS AND METHODS:  We enrolled 61 children with a diagnosis of recurrent oral streptococcal disorders. Thirty-one of them were enrolled to be treated daily for 90 days with a slow-release tablet for oral use, containing no less than 1 billion colony-forming units/tablet of S. salivarius K12 (Bactoblis®), and the remaining 30 served as the untreated control group. During treatment, they were all examined for streptococcal infection. Twenty children (ten per group) were also assessed in terms of viral infection. Secondary end points in both groups were the number of days under antibiotic and antipyretic therapy and the number of days off school (children) and off work (parents). RESULTS:  The 30 children who completed the 90-day trial with Bactoblis® showed a significant reduction in their episodes of streptococcal pharyngeal infection (>90%), as calculated by comparing the infection rates of the previous year. No difference was observed in the control group. The treated group showed a significant decrease in the incidence (80%) of oral viral infections. Again, there was no difference in the control group. With regard to secondary end points, the number of days under antibiotic treatment of the treated and control groups were 30 and 900 respectively, days under antipyretic treatment 16 and 228, days of absence from school 16 and 228, and days of absence from work 16 and 228. The product was well tolerated by the subjects, with no side effects, and only one individual reported bad product palatability and dropped out. CONCLUSION:  Prophylactic administration of S. salivarius K12 to children with a history of recurrent oral streptococcal disease resulted in a considerable reduction of episodes of both streptococcal and viral infections and reduced the number of days under antibiotic and/or antipyretic therapy and days of absence from school or work.

Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects.
            (Farges et al., 2012) Download
Prospective studies have indicated an age-related impairment of the immune response. Carotenoids have been hypothesised to enhance immune cell function. The aim of the present study was to describe the age-related effects and the impact of in vivo dietary carotenoid depletion and repletion on specific and non-specific immunity. A total of ninety-eight healthy male subjects (aged 20-75 years) received a carotenoid-depleted diet for 3 weeks and were then supplemented daily for 5 weeks with 30 mg β-carotene, 15 mg lycopene and 9 mg lutein. Blood samples were collected at study entry, after depletion and supplementation, and biomarkers of immune status were determined. We found that serum IgA levels were positively correlated with ageing. Lymphocyte phenotyping indicated an increase with age in the memory T-helper cell subpopulation (CD4⁺CD45RO⁺) concomitantly with a decrease in naive T-helper cells (CD4⁺CD45RA⁺). A significant increase in the natural killer cells subpopulation and a small decrease in B lymphocytes were also observed, especially for the oldest volunteers. From ex vivo cell function exploration, a positive correlation was observed between age and IL-2 production of phytohaemagglutinin-stimulated lymphocytes. Neutrophils' bactericidal activity was significantly impaired with age (from 50 years) and was modulated by carotenoid status. An age effect was found on neutrophils' spontaneous migration but not on directed migration. Immune response in healthy human subjects is mostly affected by age rather than by dietary carotenoid depletion and repletion. Even in carefully selected healthy volunteers, some age-related immune changes occur predominantly from 50 years onwards. This immunosenescence could generate a loss in the immune system adjustment capacity.


Immunosupportive therapies in aging.
            (Fülöp et al., 2007) Download
The primary role of the immune system is to protect the organism against pathogens, but age-associated alterations to immunity increase the susceptibility of the elderly to infectious disease. The exact nature of these changes is still controversial, but the use of screening procedures, such as the SENIEUR protocol to exclude underlying illness, helped to better characterize the changes actually related to physiological aging rather than pathology. It is generally agreed that the most marked changes occur in the cellular immune response reflecting profound alterations in T cells. Much of this is due to thymic involution as well as changes in the proportions of T cell subpopulations resulting from antigen exposure, and altered T cell activation pathways. However, a body of data indicates that innate immune responses, including the critical bridge between innate and adaptive immunity, and antigen presenting capacity are not completely resistant to senescence processes. The consequences of all these alterations are an increased incidence of infections, as well as possibly cancers, autoimmune disorders, and chronic inflammatory diseases. The leading question is what, if anything, can we do to prevent these deleterious changes without dangerously dysregulating the precarious balance of productive immunity versus immunopathology? There are many potential new therapeutic means now available to modulate immunosenescence and many others are expected to be available shortly. One main problem in applying these experimental therapies is ethical: there is a common feeling that as ageing is not a disease; the elderly are not sick and therefore do not require adventurous therapies with unpredictable side-effects in mostly frail individuals. Animal models are not helpful in this context. In this chapter we will first briefly review what we think we know about human immunosenescence and its consequences for the health status of elderly individuals. We will then discuss possible interventions that might one day become applicable in an appropriate ethical environment.

Inflammaging as a prodrome to Alzheimer's disease.
            (Giunta et al., 2008) Download
Recently, the term "inflammaging" was coined by Franceshci and colleagues to characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is characterized by a relative decline in adaptive immunity and T-helper 2 responses and is associated with increased innate immunity by cells of the mononuclear phagocyte lineage. While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype") may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. We and others have found that IFN-gamma and other pro-inflammatory cytokines interact with processing and production of Abeta peptide, the pathological hallmark feature of Alzheimer's disease (AD), suggesting that inflammaging may be a "prodrome" to AD. Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age "well" demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immune response of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD. In this review, we fully characterize the aging immune system. In addition, we explain how three novel treatments, (1) human umbilical cord blood cells (HUCBC), (2) flavanoids, and (3) Abeta vaccination oppose the forces of inflammaging and AD-like pathology in various mouse models.

Herba Cistanche (Rou Cong-Rong): One of the Best Pharmaceutical Gifts of Traditional Chinese Medicine.
            (Li et al., 2016) Download
Cistanche species, known as Rou Cong-Rong in Chinese, are an endangered wild species and are mainly distributed in the arid lands and warm deserts of northwestern China. Within Traditional Chinese Medicine (TCM), Herba Cistanche is applied as a tonic and/or in a formula for chronic renal disease, impotence, female infertility, morbid leucorrhea, profuse metrorrhagia, and senile constipation. The chemical constituents of Herba Cistanche mainly consist of volatile oils, non-volatile phenylethanoid glycosides (PhGs), iridoids, lignans, alditols, oligosaccharides, and polysaccharides. There have been an increasing number of studies focusing on its bio-activities, including antioxidation, neuroprotection, and antiaging. The objective of this review is to introduce this herb to the world. Its taxonomy, distribution, and corresponding biological functions and molecular mechanisms are addressed in this review.

Immunosenescence and age-related viral diseases.
            (Ma and Fang, 2013) Download
Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing. Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly. Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process. Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity. However, it is unclear which of these defects are critical for impaired immune defense against infection. This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing.

The immune system in extreme longevity.
            (Sansoni et al., 2008) Download
Recent observations indicate that immunosenescence is not accompanied by an unavoidable and progressive deterioration of the immune function, but is rather the result of a remodeling where some functions are reduced, others remain unchanged or even increased. In addition, it appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison to the more recent and sophisticated adaptive compartment that exhibit more profound modifications. The T-cell branch displays an age-dependent decline of the absolute number of total T-cells (CD3+), involving both CD4+ and CD8+ subsets, accompanied by an increase of NK cells with well-preserved cytotoxic function and by a reduction of B-cells. One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T-cells (CD95-), which is particularly profound at the level of the CD8+ subpopulation of the oldest old subjects. The progressive exhaustion of this important T-cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral, neoplastic, bacterial ones), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells that are replaced by large clonal expansions of CD28- T-cells. The origin of CD28- cells has not been completely clarified yet, but it is assumed that they represent cells in the phase of replicative senescence characterized by shortening telomers and reduced proliferative capacity. A major characteristic of the immune system during aging is the up-regulation of the inflammatory responses which appears to be detrimental for longevity. In this regard, we have recently observed a progressive age-dependent increase of type 1(IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4, IL-6, IL-10) positive CD8+ T-cells; in particular, type 1 cytokine-positive cells significantly increased, with age, in all CD8+ subsets particularly among effector/cytotoxic and memory cells. A major force able to drive a chronic pro-inflammatory state during aging may be represented by persistent viral infections by EBV and CMV. Therefore, we have determined the frequency and the absolute number of viral antigen-specific CD8+ T-cells in subjects older than 85 years, who were serologically positive for CMV or EBV. In the majority of these subjects we detected the presence of T lymphocytes positive for epitopes of CMV or EBV. In all subjects the absolute number of CMV-positive CD8+ cells outnumbered that of EBV-positive ones. In addition, the majority of CMV+ T cells were included within the CD28- subpopulation, while EBV+ T cells belonged mainly to the CD28+ subset. These data indicate that the chronic antigenic stimulation induced by persistent viral infections during aging bring about important modifications among CD8+ subsets, which are particularly evident in the presence of CMV persistence. The age-dependent expansions of CD8+CD28- T-cells, mostly positive for pro-inflammatory cytokines and including the majority of CMV-epitope-specific cells, underlines the importance of chronic antigenic stimulation in the pathogenesis of the main immunological alterations of aging and may favour the appearance of several pathologies (arteriosclerosis, dementia, osteoporosis, cancer) all of which share an inflammatory pathogenesis.

Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways.
            (Taub et al., 2010) Download
One of the major fundamental causes for the aging of the immune system is the structural and functional involution of the thymus, and the associated decline in de novo naïve T-lymphocyte output. This loss of naïve T-cell production weakens the ability of the adaptive immune system to respond to new antigenic stimuli and eventually leads to a peripheral T-cell bias to the memory phenotype. While the precise mechanisms responsible for age-associated thymic involution remain unknown, a variety of theories have been forwarded including the loss of expression of various growth factors and hormones that influence the lymphoid compartment and promote thymic function. Extensive studies examining two hormones, namely growth hormone (GH) and ghrelin (GRL), have demonstrated their contributions to thymus biology. In the current review, we discuss the literature supporting a role for these hormones in thymic physiology and age-associated thymic involution and their potential use in the restoration of thymic function in aged and immunocompromised individuals.

Effects of health food containing Cistanche deserticola extract on QOL and safety in elderly: an open pilot study of 12-week oral treatment
            (Yonei et al., 2011) Download
Objective: The purpose of the present study was to elucidate the effects and safety of Cistanche deserticola Y. C. Ma extract (CDX), which was given to elderly persons as a 12-week oral administration via CDX containing health food. Methods: A non-controlled open study was conducted with 25 elderly persons, without severe illness. Participants were given test product containing 100 mg of CDX as well as vitamin E, vitamin B6, ubiquinone, zinc and fukoidan, by oral administration for 12 weeks, with examination conducted before and after the study. Results: Subjective symptoms of “tired eyes” and “feeling tired all the time” were significantly improved after 12 weeks. With regard to anthropometric measurements, pulse rate was significantly reduced (–8.0%, p = 0.002). Biochemical examinations showed significant changes in white blood cell count (–14.1%, p < 0.001), platelet count (–4.3%, p = 0.040), albumin (–3.7%, p < 0.001), albumin/globulin ratio (–3.7%, p = 0.016), and fasting blood sugar (–10.2%, p = .039). Immune function was significantly improved with elevation of percentage of CD4 positive cells (6.1%, p = 0.003), CD4/CD8 ratio (20.2%, p = 0.002) and natural killer (NK) cell activity (11.7%, p = 0.024) accompanied by a decrease in percentage of CD8 positive cells (–7.7%, p = 0.022). Arteriosclerosis examinations by fingertip acceleration pulse wave analysis showed significant improvement in vascular age (–4.2%, p = 0.016) and significant decrease in cardio ankle vascular index (CAVI) (right: –10.9%, p < 0.001, left: –12.6%, p <0.001). Conclusion: The test product appears to promote quality of life by decreasing fatigue, activating immune function and favorably affecting the vascular system in the elderly. No severe adverse effects were observed during the study.

Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence.
            (Zanni et al., 2003) Download
The ageing process is characterized by a progressive exhaustion of the naïve T cell reservoir that is accompanied by a compensatory expansion of effector/cytotoxic CD8+CD28- T cells. However, the origin and function of this subpopulation is not completely clarified. In this study, we examined the intracellular cytokine profile in purified CD8+ T cells obtained from 29 healthy subjects of different ages. Type 1 (IFN-gamma IL-2 and TNF-alpha) and type 2 (IL-4, IL-6 and IL-10) cytokines were determined in three CD8+ T subsets, i.e. CD95-CD28+ (naïve), CD95+CD28- (effector/cytotoxic), and CD95+CD28+ (memory). As a general trend, we observed, in aged subjects, an increase of type 1 and type 2 intracellular cytokines within the three CD8+ subsets. In particular, we showed that type 1 cytokine-positive cells significantly increased, with age, among all the CD8+ subsets, while a marked increase of type 2 producing cells was observed only in memory CD8+ T cells. These profound changes are compatible with inflame-aging, an hypothesis which suggest that immunosenescence is mainly driven by a chronic antigenic load which not only induces an enormous expansion of CD28- T cells, but also increases their functional activity, exemplified by an high frequency of cells positive for pro-inflammatory cytokines.



Bonilla, E, et al. (2004), ‘Melatonin and viral infections.’, J Pineal Res, 36 (2), 73-79. PubMed: 14962057
Carrillo-Vico, A, et al. (2013), ‘Melatonin: buffering the immune system.’, Int J Mol Sci, 14 (4), 8638-83. PubMed: 23609496
Daynes, RA, EY Enioutina, and DC Jones (2003), ‘Role of redox imbalance in the molecular mechanisms responsible for immunosenescence.’, Antioxid Redox Signal, 5 537-48. PubMed: 14580308
Di Pierro, F, et al. (2013), ‘Clinical evaluation of the oral probiotic Streptococcus salivarius K12 in the prevention of recurrent pharyngitis and/or tonsillitis caused by Streptococcus pyogenes in adults.’, Expert Opin Biol Ther, 13 (3), 339-43. PubMed: 23286823
Di Pierro, F, et al. (2014), ‘Use of Streptococcus salivarius K12 in the prevention of streptococcal and viral pharyngotonsillitis in children.’, Drug Healthc Patient Saf, 6 15-20. PubMed: 24600248
Farges, MC, et al. (2012), ‘Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects.’, Br J Nutr, 108 (11), 2054-65. PubMed: 22397808
Fülöp, T, et al. (2007), ‘Immunosupportive therapies in aging.’, Clin Interv Aging, 2 (1), 33-54. PubMed: 18044074
Giunta, B, et al. (2008), ‘Inflammaging as a prodrome to Alzheimer’s disease.’, J Neuroinflammation, 5 51. PubMed: 19014446
Li, Z, et al. (2016), ‘Herba Cistanche (Rou Cong-Rong): One of the Best Pharmaceutical Gifts of Traditional Chinese Medicine.’, Front Pharmacol, 7 41. PubMed: 26973528
Ma, Y and M Fang (2013), ‘Immunosenescence and age-related viral diseases.’, Sci China Life Sci, 56 (5), 399-405. PubMed: 23633071
Sansoni, P, et al. (2008), ‘The immune system in extreme longevity.’, Exp Gerontol, 43 (2), 61-65. PubMed: 17870272
Taub, DD, WJ Murphy, and DL Longo (2010), ‘Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways.’, Curr Opin Pharmacol, 10 (4), 408-24. PubMed: 20595009
Yonei, Y, et al. (2011), ‘Effects of health food containing Cistanche deserticola extract on QOL and safety in elderly: an open pilot study of 12-week oral treatment’, Anti-Aging Medicine, 8 (2), 7-14. PubMed:
Zanni, F, et al. (2003), ‘Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence.’, Exp Gerontol, 38 (9), 981-87. PubMed: 12954485