The disease burden of Atopic Dermatitis in the elderly is increasing in tandem with global population aging, and epidemiological studies have revealed a significantly elevated risk of cognitive impairment and Alzheimer’s disease associated with this condition,, posing a serious threat to their quality of life. However, the specific mechanisms by which skin inflammation mediates central nervous system (CNS) neurodegeneration across organs remain unclear. Cellular senescence and immunosenescence may form a positive feedback loop through Senescence-Associated Secretory Phenotype (SASP): senescent cells release SASP that induce chronic low-grade inflammation, while chronic inflammation in turn accelerates cellular senescence and immunosenescence, creating a vicious immune-aging cycle. From the perspective of the Immune-Aging Axis, this study demonstrates that skin-derived SASP drive the comorbidity mechanism of Atopic Dermatitis and Alzheimer’s disease in the elderly through bidirectional skin-brain feedback loops—including disruption of the blood-brain barrier, induction CNS inflammation, and epigenetic remodeling, with the aim of providing theoretical strategies for targeted combined interventions against SASP. 1. Innovative Integration of Theoretical Frameworks: This study innovatively applies the concept of the “Immuno-Aging Axis” to elucidate the context of comorbidity between Atopic Dermatitis and Alzheimer’s disease. 2. In-Depth Mechanistic Elucidation: By synthesizing existing literature, this review explores how SASP may mediate bidirectional interactions between the skin and CNS, providing a molecular bridge for interventions targeting this comorbidity. 3. Translational Clinical Value: This study provides a theoretical basis for targeting SASP to treat the comorbidity of Atopic Dermatitis and Alzheimer’s disease and advances the development of precision treatment strategies for elderly patients with comorbidities.
Loss of kidney function is associated with premature immunological aging involving loss of naïve T cells and expansion of pro-inflammatory memory T cells. The changes in the adaptive T cell system contribute to the uremia-related complications of increases susceptibility for infection, poor vaccination response and increased cardiovascular disease burden. Recently, it has become evident that the functional status of the thymus, called thymic health, may have a central role in key aspects of immunological aging such as loss of naïve T cells, expansion of oligoclonal memory T cells and a decrease in the T cell receptor diversity. The negative impact of poor thymic health on mortality, cardiovascular disease, and cancer incidence appears substantial. Although thymic function/health declines with increasing age, thymic function may still be present in the elderly, but variation is large and is, for instance, dependent on metabolic health, exercise, smoking and kidney function. Loss of kidney function leads to increased inflammation and oxidative stress which negatively impact thymic health that in turn can negatively affect decline of kidney function. The possible mechanisms involved in the latter feedback loop are decreased clearance of senescent kidney cells and an increase in symptomatic atherosclerotic disease. As such, the effects of progressing of chronic kidney disease on thymic function may explain the findings of premature immunological aging and offer new insights on the importance of this relationship and mechanisms involved.
The rapidly growing population of older people living with HIV-1 (PLWH) continues to experience persistent immune dysfunction despite viral suppression, yet the underlying mechanisms remain unclear. To investigate the molecular basis of the unique immunological defects in these elderly PLWH, we performed time-course transcriptomic analysis of CD3/CD28-stimulated CD4⁺ T cells from 58 participants (stratified by age and HIV status), validated through flow cytometry, qPCR, and cytokine profiling in 120 subjects. Gene modulated Jurkat cell models and pharmacological inhibition experiments were employed to dissect mechanistic pathways. Our results demonstrate that activated CD4⁺ T cells from older PLWH exhibited broad suppression of TNF, NF-κB and IL-17 signaling pathways, with 40 critical genes showing co-regulation by aging and HIV-1. Among them, the expression of stimulator of interferon genes (STING) was significantly elevated in older PLWH, correlating with CD4⁺ T cell depletion. Mechanistically, STING hyperactivation induced src homology 2 containing protein tyrosine phosphatase 1/2 (SHP-1/2) phosphorylation, which suppressed Janus kinase 1 (JAK1)-mediated phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1), thereby reducing IFN-γ production. STING inhibition with H151 restored IFN-γ secretion (3.1-fold increase) while reducing T cell activation markers (CD25⁺Ki67⁺ cells). Moreover, STING hyperactivation induced classical T cell exhaustion, characterized by TIM-3 upregulation, TOX-centered transcriptional programming, and loss of polyfunctional cytokine output; these changes were reversed by STING inhibition. This study identifies STING-mediated JAK-STAT suppression as a novel mechanism of immune dysfunction in aging PLWH, proposing targeted STING inhibition as a potential therapeutic strategy to improve immune recovery in this vulnerable population (Graphical abstract).
Vaccine responses are impaired in aged mice and older people. A key first step in mounting successful responses to vaccines is for antigens to access the draining lymph node from the site of injection. Here we tested the hypothesis that nanoparticle drainage to the lymph node is impaired in older mice after intramuscular injection. We observed fewer 20 nm nanoparticles in the draining lymph node in aged mice after intramuscular injection. However, there was no significant difference in the abundance of larger 1000 nm particles in the lymph nodes of aged mice, which are typically transported to the lymph node by antigen presenting cells. This impaired nanoparticle access was associated with changes in lymph node stromal cells, and a reduction in lymphatic endothelial cells in aged mice. These data suggest that access of smaller antigens to the lymph node may be impaired in ageing and may have implications for the initiation of T and B cell responses after vaccination.
Centenarians represent a model of exceptional longevity and immune resilience. In young adults, acute exercise typically induces rapid immune cell redistribution and provides a useful paradigm to assess immune adaptability. However, immune cell responses to acute exercise in centenarians remain unknown. To characterise acute exercise-induced changes in circulating immune cell populations and phenotypes in centenarians using high-dimensional spectral flow cytometry. Seven centenarians (100–104 years; six women) participated in a randomised crossover study including an acute exercise session ( 20 min of combined walking, mobility and resistance exercise) and a time-matched seated control condition. Peripheral blood mononuclear cells collected before and after each condition were analysed using spectral flow cytometry and high-dimensional approaches. In this exploratory study, acute exercise was associated with nominally significant condition-by-time interactions in selected immune cell subpopulations, including natural killer (NK) cell subsets and classical monocytes (all nominal p < 0.05). Yet, these findings should be interpreted cautiously given the exploratory nature of the study and the large number of immune outcomes analysed. Furthermore, these effects were modest, occurred alongside baseline differences between study visits, and primarily reflected divergent temporal patterns between conditions rather than pronounced exercise-induced redistribution. No nominally significant changes were observed in phenotypic marker expression or metacluster relative abundance. In centenarians, acute exercise does not induce widespread redistribution or phenotypic changes in circulating immune cells but elicits modest, selective responses, indicating that selected components of immune adaptability may remain detectable even in extreme ageing. These findings support the notion that immune resilience in extreme ageing may be characterised by maintenance of immune homeostasis under physiological stress rather than by pronounced immune reactivity.
