Immunity & Ageing最新文献

Epidemiological investigations consistently demonstrate an overrepresentation of the elderly in COVID-19 hospitalizations and fatalities, making the advanced age as a major predictor of disease severity. Despite this, a comprehensive understanding of the cellular and molecular mechanisms explaining how old age represents a major risk factor remain elusive. To investigate this, we compared SARS-CoV-2 infection outcomes in young adults (2 months) and geriatric (15-22 months) mice. Both groups of K18-ACE2 mice were intranasally infected with 500 TCID₅₀ of SARS-CoV-2 Delta variant with analyses performed on days 3, 5, and 7 post-infection (DPI). Analyses included pulmonary cytokines, lung RNA-seq, viral loads, lipidomic profiles, and histological assessments, with a concurrent evaluation of the percentage of mice reaching humane endpoints. The findings unveiled notable differences, with aged mice exhibiting impaired viral clearance, reduced survival, and failure to recover weight loss due to infection. RNA-seq data suggested greater lung damage and reduced respiratory function in infected aged mice. Additionally, elderly-infected mice exhibited a deficient antiviral response characterized by reduced Th1-associated mediators (IFNγ, CCL2, CCL3, CXCL9) and diminished number of macrophages, NK cells, and T cells. Furthermore, mass-spectrometry analysis of the lung lipidome indicated altered expression of several lipids with immunomodulatory and pro-resolution effects in aged mice such as Resolvin, HOTrEs, and NeuroP, but also DiHOMEs-related ARDS. These findings indicate that aging affects antiviral immunity, leading to prolonged infection, greater lung damage, and poorer clinical outcomes. This underscores the potential efficacy of immunomodulatory treatments for elderly subjects experiencing symptoms of severe COVID-19.

Background: Immunosenescence, the gradual deterioration of the immune system, is critical for aging-related diseases. However, the lack of detailed population-level immune data has limited our understanding, underscoring the need for innovative analytical approaches. The Health and Retirement Study (HRS) in the United States provides a unique opportunity to examine T and B lymphocyte subsets using compositional data analysis and dimension reduction techniques.

Methods: We constructed a hierarchical tree structure to map relationships among T and B subset cells in HRS. Network analysis examined conditional dependence across 16 immune subset cells, while stepwise redundancy analysis (SRDA) identified a subset of pairwise logratio measures that capture main variance in immune composition. We conducted two sets of supervised learning analyses: first, linear penalized log-contrast models to examine the associations between subset cells and three health outcomes (chronic disease index, self-reported health, and frailty level); second, linear regressions to examine the associations between the top selected logratios and health outcomes.

Findings: Our study included 6,250 participants from the HRS with a median age of 68. Network analysis showed some dependence among 16 immune subset cells, including associations between central memory CD4 + T cells and both other CD4 + T cells and other lymphocytes, as well as between central memory CD8 + T cells and other CD8 + T cells. SRDA identified nine key log-ratio measures, explaining over 90% of the variance in immune composition. Linear penalized log-contrast models showed that a lower proportion of naïve CD4 + T cells and higher proportions of other CD4 + and central memory CD8 + T cells were significantly associated with greater chronic disease burden, poorer self-reported health, and higher frailty levels. Linear regression models using log-ratios reinforced these patterns, showing that a higher ratio of other lymphocytes over naïve CD4 + T cells and terminally differentiated effector memory CD4 + T cells over other CD8 + T cells were associated with greater chronic disease burden, poorer self-reported health, and higher frailty levels. In contrast, a higher ratio of other lymphocytes over central memory CD4 + T cells was associated with better health outcomes.

Interpretation: Our findings highlight the value of a systems-based approach and compositional analysis in understanding immunosenescence and its impact on health. The identified subset cells and logratio measures provide meaningful insights into immune aging and warrant further investigation to explore their long-term relationships with health outcomes.

Background: The T cell compartment undergoes significant age-related changes, contributing to the decline of the adaptive immune system and increasing the risk of suboptimal antibody responses to vaccines in older adults. To better understand the association between T cell phenotypes and vaccine responsiveness, we conducted an in-depth analysis of CD4+, CD8+, and γδ + T cells on VITAL cohort participants who are low or high responders to multiple vaccines (influenza, pneumococcal, and SARS-CoV-2).

Results: Using spectral cytometry and FlowSOM, we identified detailed phenotypes of naïve, regulatory, and terminally differentiated T cells. We observed that the percentages of CD31 + naïve CD4+, CD31 + naïve CD8+, and CD38 + naïve CD8 + T cells were significantly lower in low vaccine responders. Notably, CD31 + naïve T cell subsets showed a stronger correlation with immune entropy, a measure of cumulative immune system perturbations, than with age itself.

Conclusions: These findings suggest that subsets of naïve cells could be associated with weak vaccine responsiveness and immunosenescence. Furthermore, these naive T cell signatures could help predict weak vaccine responses, potentially informing targeted vaccination strategies in older adults.

Clinical trial number: EudraCT: 2019-000836-24.

Background: Maintenance of the retina, part of the central nervous system, and other structures in the eye is critical for vision preservation. Aging increases the prevalence of vision impairment, including glaucoma, macular degeneration, and diabetic retinopathy. The retina is primarily maintained by glial cells; however, recent literature suggests that lymphocytes may play a role in the homeostasis of central nervous system tissues. Natural antibodies are produced by B cells without infection or immunization and maintain tissue homeostasis. Here, we explored the potential role of natural immunoglobulin M (IgM) produced by B lymphocytes in maintaining retinal health during aging in mice.

Results: Our results indicate that the vitreous humor of both mice and humans contains IgM and IgG, suggesting that these immunoglobulins may play a role in ocular function. Furthermore, we observed that aged mice lacking secreted IgM (µs-/-) exhibited pronounced retinal degeneration, accompanied by reactive gliosis, and a proinflammatory cytokine environment. This contrasts with the aged wild-type counterparts, which retain their ability to secrete IgM and maintain a better retinal structure and anti-inflammatory environment. In addition to these findings, the absence of secreted IgM was associated with significant alterations in the retinal pigment epithelium, including disruptions to its morphology and signs of increased stress. This was further observed in changes to the blood-retinal-barrier, which is critical for regulation of retinal homeostasis.

Conclusions: These data suggest a previously unrecognized association between a lack of secreted IgM and alterations in the retinal microenvironment, leading to enhanced retinal degeneration during aging. Although the precise mechanism remains unclear, these findings highlight the potential importance of secreted IgM in processes that support retinal health over time. By increasing our understanding of ocular aging, these results show that there is a broader role for the immune system in retinal function and integrity in advanced age, opening new areas for the exploration of immune-related interventions in age-associated retinal conditions.

The importance of vitamin D for a well-functioning immune system is becoming increasingly evident. Nevertheless, the other fat-soluble vitamins A, E and K also seem to play a central role regarding the adequate function of immune cells and to counteract excessive immune reactions and inflammatory processes. However, recognizing hidden hunger, particularly micronutrient deficiencies in vulnerable groups like the elderly, is crucial because older adults often lack sufficient micronutrients for various reasons. This review summarizes the latest findings on the immune modulating functions of fat-soluble vitamins in a physiological and pathophysiological context, provides a graphical comparison of the Recommended Daily Allowances between Deutschland, Austria, Confoederatio Helvetica (D-A-CH; eng. GSA, Germany, Switzerland, Austria), Deutsche Gesellschaft für Ernährung (DGE; eng. German Nutrition Society) and National Institutes of Health (NIH) across all age groups and, in particular, addresses the question regarding the benefits of supplementation of the respective micronutrients for the aging population of industrialized nations to strengthen the immune system. The following review highlights the importance of fat-soluble vitamins A, D, E and K which play critical roles in maintaining immune system function and, in some cases, in preventing excessive immune activation. Therefore, a better understanding of the relevance of adequate blood levels and consequently potential supplementation strategies may contribute to the prevention and management of infectious diseases as well as better overall health of the elderly.

Background: Advanced aging invariably triggers an overabundance of apoptosis, stemming from diminished autophagy or a disarray in cellular autophagic processes. This, in turn, leads to an accelerated breakdown of muscle proteins, which exacerbates the ongoing deterioration of skeletal muscle and intensifies the severity of senile sarcopenia. This study aimed to investigate the role and mechanism of miRNA-regulated autophagy in senile sarcopenia.

Methods: The miRNAs associated with sarcopenia were screened, and the target genes of significant miRNAs were predicted. The effects of significantly differentially expressed miRNA-144-5p on cell aging and autophagy were validated in vivo and in vitro.

Results: The inhibition of miR-144-5p enhanced the multiplication of mouse myoblasts, increased the expression of MHC and autophagic markers LC3II/LC3I and Beclin-1, facilitated the formation of autophagosomes in mouse myoblasts, and reduced the number of aging cells and the expression of senescence-related proteins acetylated p53, p53, and p21 expression in mouse myoblasts. miR-144-5p affects myoblast senescence, myogenic differentiation, and autophagy by regulating the downstream target gene, Atg2A. Inhibiting miR-144-5p markedly increased the grip strength of the posterior limb in old mice, and the CSA of old mice and young mice was also markedly increased.

Conclusion: All experiments have demonstrated that miRNA-144-5p has a significant impact on the regulation of autophagy and the development of senile sarcopenia.

Background: The relationship between psoriasis and aging remains unclear. Biological age is considered as a tool for strong association with aging, but there is a lack of reports on the relationship between biological age and psoriasis. Therefore, this study aimed to explore the relationship between biological age and psoriasis.

Methods: Patients with psoriasis and non-psoriasis were recruited from National Health and Nutrition Examination Survey (NHANES) (12,973 cases), Medical Information Mart for Intensive Care (MIMIC-IV) (558 cases) and The First Clinical Medical College of Zhejiang Chinese Medical University (206 cases). Biological age was calculated using Klemera-Doubal method age (KDM-age) and phenotypic age (PhenoAge). Linear regression and logistic regression were used to explore the association between psoriasis and biological age advance. Cox regression was used to investigate the association between biological age advance and mortality. Finally, biological age advance was used to predict the death of psoriasis patients.

Results: In NHANES, linear regression showed that psoriasis led to a 0.54 advance in PhenoAge (Adjust Beta: 0.54, 95CI: 0.12-0.97, p = 0.018). The KDM-age advance due to psoriasis was not statistically significant (p = 0.754). Using data from China, we came to the new conclusion that for every unit rise in Psoriasis Area and Severity Index, PhenoAge advance rose by 0.12 (Beta: 0.12, 95CI: 0.01-0.22, p = 0.031). Using NHANES data, cox regression shows for every unit rise in PhenoAge advance patients had an 8% rise in mortality (Adjust hazard ratio: 1.08, 95CI: 1.04-1.12, p < 0.001). Using MIMIC-IV, logistic regression showed a 13% increase in mortality within 28 days of admission for every 1 unit rise in PhenoAge advance (odds ratio: 1.13, 95CI: 1.09-1.18, P < 0.001). Finally, we used PhenoAge advance to predict death, with an AUC of 0.71 in the NHANES, an ACU of 0.79 for predicting death within 1 years in the general ward of MIMIC-IV. In the ICU of MIMIC-IV, the AUC for predicting death within 28 days was 0.71.

Conclusion: Psoriasis leads to accelerated biological aging in patients, which is associated with the severity of psoriasis and more comorbidities. In addition, PhenoAge has the potential to monitor the health status of patients with psoriasis.

Phytochemicals help mitigate skin aging by scavenging free radicals, modulating key enzymatic pathways, and promoting the skin's structural integrity. Carotenoids, vitamins, essential fatty acids, and phenolic compounds work by acting as antioxidants, inhibiting enzymes like hyaluronidase, collagenase, and elastase, which degrade skin structure, and reducing levels of inflammatory markers (IL-6, IL-8, etc.) and matrix metalloproteinases (MMP-1, MMP-2) linked to aging. Recent research highlights that plant-based phytochemicals can improve skin elasticity, reduce hyperpigmentation, prevent the breakdown of important skin proteins, and support wound healing, making them valuable components for skin care and treatments. This review explores the multifaceted roles of phytochemicals in maintaining and improving skin health, highlighting their mechanisms of action and potential in skin anti-aging innovations.

Background: The characteristics of ulcerative colitis (UC) in the elderly are quite different from the young population. Mitochondrial injury is a key mechanism regulating both aging and inflammation. This study aims to reveal the role of mitochondrial damage in the pathogenesis of adult- and elderly-onset UC.

Methods: RNA-sequencing of colonic mucosa from adult- and elderly-onset UC patients was performed. Mitochondria-related differentially expressive genes (mDEGs) and immune cell infiltration analysis were identified and performed in colonic tissues from UC patients. Mice aged 6-8 weeks and 20-24 months were administered 2% dextran sodium sulphate (DSS) for 7 days to induce colitis. Mitochondrial morphological changes and ATP levels were evaluated in the colons of mice. Mechanistically, we explored the association of key mDEG with reactive oxygen species (ROS), oxygen consumption rates, NLRP3/IL-1β pathway in HCT116 cell line.

Results: Thirty mDEGs were identified between adult- and elderly-onset UC, which were related primarily to mitochondrial respiratory function and also had significant correlation with different infiltrates of immune cells. Compared with young colitis mice, DSS-induced colitis in the aged mice exhibited more severe inflammation, damaged mitochondrial structure and lower ATP levels in colonic tissues. ALDH1L1 was identified as a hub DEG through protein-protein interaction networks of RNA-seq, which was downregulated in UC patients or colitis mice versus healthy controls. In tumor necrosis factor-alpha-stimulated HCT116 cells, mitochondrial ROS, NLRP3 and IL-1β expression increased less and mitochondrial respiration had an upregulated trend after knocking down ALDH1L1.

Conclusion: There are significant differences in mitochondrial structure, ATP production and mitochondria-related gene expression between adult- and elderly-onset UC, which have a potential link with cytokine pathways and immune microenvironment. The more prominent mitochondrial injury may be a key factor for more severe inflammatory response and poorer outcome in elderly-onset UC.

Background: Older people living with HIV-1 (PLWH) experience a dual burden from the combined effects of aging and HIV-1 infection, resulting in significant immune dysfunction. Despite receiving HAART, immune reconstitution is not fully optimized. The objective of this study was to investigate the impact of aging and HAART on T cell subsets and function in PLWH across different age groups, thereby providing novel insights into the prognosis of older PLWH.

Method: This study was conducted at Yunnan AIDS Care Center, China, to explore the immunological responses of old PLWH to HAART and compared with the middle-age and the younger. Blood samples were collected from 146 PLWH to analyze T cell subsets and their functions, with a particular emphasis on markers related to T cell differentiation, activation, exhaustion, inflammation, and cellular function, using multicolor flow cytometry analysis.

Results: Older age may have a greater effect on long-term CD4⁺T cell recovery. Compared with young and middle-aged PLWH, older PLWH presented distinct alterations in their immune profile, including a decline in the Naïve CD4⁺T and CD8⁺T cell subsets, an expansion of effector memory cells, and other potential immune risk phenotypes, such as activation, exhaustion, and up-regulation of aging markers. In addition, we observed a significant association between the CD4 + EM3 subset and the CD8 + EM2 subset with HIV-1 progression, independent of age, suggesting their potential as reliable markers for assessing immune reconstitution in all PLWH.

Conclusion: Our study extends previous findings showing that older participants exhibit a wide range of late differentiation, senescence, or exhaustion phenotypes in cells, including all the CD4⁺T and CD8⁺T subsets, consistent with an immunosenescent phenotype. This may accelerate poor immune recovery in older PLWH. Identifying new strategies to improve the immune risk phenotypes of older PLWH may help improve their immune reconstitution outcomes. The CD4 + EM3 subset and the CD8 + EM2 subset should be studied as additional markers of late presentation.