Crystal Tze Ying Tan

Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore longitudinal aging studies.

Chronic systematic inflammation and reduced immune system fitness are considered potential contributing factors to the development of age-related frailty, but the underlying mechanisms are poorly defined. This exploratory study aimed to identify frailty-related inflammatory markers and immunological phenotypes in a cohort of community-dwelling adults aged ≥ 55 years. Frailty was assessed using two models, a Frailty Index and a categorical phenotype, and correlated with levels of circulating immune biomarkers and markers of senescence in immune cell subsets. We identified eight serological biomarkers that were associated with frailty, including sgp130, IL-2Rα, I-309, MCP-1, BCA-1, RANTES, leptin, and IL-6R. Frailty Index was inversely predicted by the frequency of CD3+, CD45RA+, and central memory CD4 cells, and positively predicted by the loss of CD28 expression, especially in CD8+ T cells, while frailty status was predicted by the frequency of terminal effector CD8+ T cells. In γ/δ T cells, frailty was negatively associated with CD27, and positively associated with IFNγ+TNFα- secretion by γ/δ2+ cells and IFNγ-TNFα+ secretion by γ/δ2- cells. Increased numbers of exhausted and CD38+ B cells, as well as CD14+CD16+ inflammatory monocytes, were also identified as frailty-associated phenotypes. This pilot study supports an association between inflammation, cellular immunity, and the process of frailty. These findings have significance for the early identification of frailty using circulating biomarkers prior to clinical manifestations of severe functional decline in the elderly.

Downregulation of inhibitory SRC Homology 2 Domain-containing Phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly

BackgroundImmune responses are generally impaired in aged mammals. T cells have been extensively studied in this context due to the initial discovery of their reduced proliferative capacity with aging. The decreased responses involve altered signaling events associated with the early steps of T cell activation. The underlying causes of these changes are not fully understood but point to alterations in assembly of the machinery for T cell activation. Here, we have tested the hypothesis that the T cell pool in elderly subjects displayed reduced functional capacities due to altered negative feedback mechanisms that participate in the regulation of the early steps of T cell activation. Such conditions tip the immune balance in favor of altered T cell activation and a related decreased response in aging.ResultsWe present evidence that the tyrosine phosphatase SHP-1, a key regulator of T cell signal transduction machinery is, at least in part, responsible for the impaired T cell activation in aging. We used tyrosine-specific mAbs and Western blot analysis to show that a deregulation of the Csk/PAG loop in activated T cells from elderly individuals favored the inactive form of tyrosine-phosphorylated Lck (Y505). Confocal microscopy analysis revealed that the dynamic movements of these regulatory proteins in lipid raft microdomains was altered in T cells of aged individuals. Enzymic assays showed that SHP-1 activity was upregulated in T cells of aged donors, in contrast to young subjects. Pharmacological inhibition of SHP-1 resulted in recovery of TCR/CD28-dependent lymphocyte proliferation and IL-2 production of aged individuals to levels approaching those of young donors. Significant differences in the active (Y394) and inactive (Y505) phosphorylation sites of Lck in response to T cell activation were observed in elderly donors as compared to young subjects, independently of CD45 isoform expression.ConclusionsOur data suggest that the role of SHP-1 in T cell activation extends to its increased effect in negative feedback in aging. Modulation of SHP-1 activity could be a target to restore altered T cell functions in aging. These observations could have far reaching consequences for improvement of immunosenescence and its clinical consequences such as infections, altered response to vaccination.

CMV induces expansion of highly polyfunctional CD4+ T cell subset coexpressing CD57 and CD154

CD4+ T cells are essential for human CMV infection control. CMV‐specific CD4+ T cells possess antiviral functions and participate in anti‐CMV humoral/cellular responses. In the elderly, CMV infection impairs immunity to other viruses and has been traditionally associated with T cell senescence; however, recent results suggest that, in younger people, CMV confers immune protection against other pathogens (heterologous immunity). To shed light on this controversy, we analyzed latent CMV infection effects on the quality of young individuals’ immune response, specifically, the presence of polyfunctional T cells through an extensive phenotypic and functional characterization of the CD4+ T cell subset. CD154 expression, degranulation (CD107a), and cytokine production (IFN‐γ, TNF‐α, and IL‐2) as well as T cell phenotype markers (CD57, CD28, and CD27) were analyzed. We demonstrate that CD4+ T cells that coexpress CD57 and CD154, which are exclusively present in CMV‐positive individuals, are the most polyfunctional CD4+ subset, whereas CD4+CD27+CD28− T cells associate with lower polyfunctionality. Conversely, the frequency of CD4+CD28+ T cells correlates with higher polyfunctionality of CD4+CD57− T cells from CMV‐seronegative individuals and CD4+CD57+CD154+ T cells from CMV‐seropositive individuals. Thus, polyfunctionality is a property of central memory CD4+ T cells in CMV‐seronegative individuals, whereas after CMV infection, polyfunctional T cells become highly differentiated, which allows efficient eradication of infections. We extend previous observations of the impact of CMV on CD8+ T cell functionality to the CD4+ T cell compartment, revealing CD57 as a polyfunctionality marker of T cells which expands after CMV infection. CD57+ T cells have been associated with inflammatory conditions, but their potential role in the response against infectious disease and vaccination should now be investigated.

Markers of T-cell senescence and physical frailty: insights from Singapore Longitudinal Ageing Studies

Background:Elderly individuals have an eroded immune system but whether immune senescence is implicated with the development of frailty is unknown. The underlying immune mechanisms and the link between markers of senescence and physical frailty is not well established.Methods:We explored the association of specific T-cell subset markers of immune differentiation and senescence on CD4+ and CD8+ cells (CD28−, CD27− and CD57+) and the immune risk profile (inverted CD4/CD8 ratio <1) with physical frailty among 421 participants who were frail (N=32), prefrail (N=187) and robust (N=202) in the Singapore Longitudinal Ageing Study cohort.Results:In ordinal logistic regression models relating tertile category rank scores of immune biomarker with frailty status (robust, prefrail and frail), CD8+CD28−CD27+ (odds ratio (OR)=1.35, P=0.013), CD4+CD28−CD27+ (OR=1.29, P=0.025), CD8+CD28− (OR=1.31, P=0.022), and CD4/CD8 ratio (OR=1.27, P=0.026) were positively associated with frailty, controlling for age, sex and multimorbidity. CD4/CD8 ratio less than one was not associated with frailty (OR=0.84, P=0.64). In stepwise multinomial logistic regression controlling for age, sex and comorbidity, only CD8+CD28−CD27+ was the independent predictor of prefrailty: highest tertile of the immune marker significantly predicted prefrailty (versus low tertile, OR=1.72, P=0.037) and frailty (OR=2.56, P=0.06).Conclusion:The study supports the hypothetical role of immune senescence in physical frailty, particularly in regard to the observed loss of CD28 expression from both CD8+ cells and CD4+ cells, but not for CD27 or CD4/CD8 ratio as a marker of senescence. The potential of CD8+CD28−CD27+ as a biological marker of frailty should be further investigated in prospective studies.

The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence

Human primary monocytes comprise a heterogeneous population that can be classified into three subsets based on CD14 and CD16 expression: classical (CD14high/CD16−), intermediate (CD14high/CD16+), and non-classical (CD14low/CD16+). The non-classical monocytes are the most pro-inflammatory in response to TLR stimulation in vitro, yet they express a remarkably high basal level of miR-146a, a microRNA known to negatively regulate the TLR pathway. This concurrence of a pro-inflammatory status and a high miR-146a level has been associated with cellular senescence in other cell types. Hence, we assessed the three monocyte subsets for evidence of senescence, including proliferative status, telomere length, cellular ROS levels, and mitochondrial membrane potential. Indeed, the non-classical subset exhibited the clearest hallmarks of senescence, followed by the intermediate and then the classical subset. In addition, the non-classical subset secreted pro-inflammatory cytokines basally in vitro. The highly pro-inflammatory nature of the non-classical monocytes could be a manifestation of the senescence-associated secretory phenotype (SASP), likely induced by a high basal NF-κB activity and IL-1α production. Finally, we observed an accumulation of the non-classical monocytes, in conjunction with higher levels of plasma TNF-α and IL-8, in the elderly. These factors may contribute to inflamm-aging and age-related inflammatory conditions, such as atherosclerosis and osteoarthritis. With our new understanding that the non-classical monocyte subset is a senescent population, we can now re-examine the role of this subset in disease conditions where this subset expands.

THE EFFECTS OF HORTICULTURAL THERAPY ON THE PSYCHOLOGICAL WELL-BEING AND ASSOCIATED BIOMARKERS OF ELDERLY IN SINGAPORE

improved balance, there were striking increases in community structure of somatomotor brain regions in PWD (Fig.2). Self-reported QOL improved in 3 of the 5 PWD in the intervention group and declined in 4 of 5 PWD in the control group, although this did not reach statistical significance (b1⁄41.39, 95% CI [-2.3 to 5.0]). Positive results were noted for CG in balance, PHLMS awareness SF-36 general health, SF-36 emotional well-being, and mood, although none of these reached statistical significant. Improved consistency was noted in somatomotor brain networks of CG. Conclusions:Neuropsychiatric symptoms and increased fall risk often accompany cognitive decline in dementia. Results from this pilot study suggest that an improvisational movement class that combines an engaging social environment with movement can improve balance, alter brain networks, and affect quality of life in PWD and their caregivers.

Effects of Horticultural Therapy on Asian Older Adults: A Randomized Controlled Trial

The effect of horticultural therapy (HT) on immune and endocrine biomarkers remains largely unknown. We designed a waitlist-control randomized controlled trial to investigate the effectiveness of HT in improving mental well-being and modulating biomarker levels. A total of 59 older adults was recruited, with 29 randomly assigned to the HT intervention and 30 to the waitlist control group. The participants attended weekly intervention sessions for the first 3 months and monthly sessions for the subsequent 3 months. Biological and psychosocial data were collected. Biomarkers included IL-1β, IL-6, sgp-130, CXCL12/SDF-1α, CCL-5/RANTES, BDNF (brain-derived neurotrophic factor), hs-CRP, cortisol and DHEA (dehydroepiandrosterone). Psychosocial measures examined cognitive functions, depression, anxiety, psychological well-being, social connectedness and satisfaction with life. A significant reduction in plasma IL-6 level (p = 0.02) was observed in the HT intervention group. For the waitlist control group, significant reductions in plasma CXCL12 (SDF-1α) (p = 0.003), CXCL5 (RANTES) (p = 0.05) and BDNF (p = 0.003) were observed. A significant improvement in social connectedness was also observed in the HT group (p = 0.01). Conclusion: HT, in reducing plasma IL-6, may prevent inflammatory disorders and through maintaining plasma CXCL12 (SDF-1α), may maintain hematopoietic support to the brain. HT may be applied in communal gardening to enhance the well-being of older adults.

Influenza Vaccine-Induced Antibody Responses Are Not Impaired by Frailty in the Community-Dwelling Elderly With Natural Influenza Exposure

Background: Elderly adults over 65 years of age are recommended to receive seasonal influenza vaccination as they are at a higher risk of infection and its complications than the younger community. The elderly are often stratified according to frailty status where frail individuals are more susceptible to adverse health outcomes than their non-frail counterparts, however, it is not known whether immunity induced by influenza vaccination is impaired in the frail elderly. Study Design: Two hundred and five elderly subjects of Chinese ethnicity in Singapore (mean age 73.3 ± 5.3 years, 128 females and 77 males) were administered the recommended trivalent inactivated 2013–14 seasonal influenza vaccine (Vaxigrip™) containing A/H1N1, A/H3N2, and B strains. The elderly subjects were stratified into three groups according to Frieds frailty criteria (59 frail, 85 pre-frail, 61 robust) and were also ranked by Rockwoods frailty index (RFI). Statistical associations were evaluated between frailty status and pre- and post-vaccination antibody titres in sera measured by Hemagglutination inhibition (HAI) and microneutralization (MN) assays. Immunological responses across frailty strata were also studied in terms of leukocyte cellular distribution, cytokine levels and gene expression. Results: Post-vaccination, 83.4% of the subjects seroconverted for A/H1N1, 80.5% for A/H3N2, and 81% for the B strain. The seroconversion rates were comparable across frailty groups (A/H1N1, ANOVA, p = 0.7910; A/H3N2, ANOVA, p = 0.8356, B, ANOVA, p = 0.9741). Geometric mean titres of HAI and MN as well as seroprotection rates were also similar in all three frailty groups and uncorrelated with RFI (Spearman, r = 0.023, p = 0.738). No statistically significant differences were observed between the frailty groups in vaccine-induced modulation of leukocyte populations, cytokine responses, and gene expression profiles of peripheral blood mononuclear cells (PBMCs). Whereas, post- and pre-vaccination HAI titres were positively correlated after adjusting for age and gender (A/H1N1, R2 = 0.216, p = 9.1e−11; A/H3N2, R2 = 0.166, p = 3.4e−8; B, R2 = 0.104, p = 3.1e−5). With most subjects lacking previous history of influenza vaccination, the pre-vaccination titres were likely due to natural exposure and seen to match the pattern of influenza subtype prevalence in the time period of vaccination. Conclusion: The majority of the elderly subjects seroconverted for seasonal influenza upon vaccination, and importantly, influenza vaccination-induced humoral immune responses and seroprotection were similar across the frailty strata, indicating that frail individuals may also benefit from influenza vaccination. Pre-existing antibodies due to natural exposure appeared to positively influence vaccine-induced antibody responses.