Aging Medicine最新文献

Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored. Identifying the effect of fasting and CR on the immune system and how it modulates different parameters of immunosenescence could be important in designing pharmacological or nutritional interventions that slow or revert immunosenescence and strengthen the immune system of elderly individuals. Furthermore, clinical intervention can also be planned, by incorporating fasting or CR with medication, chemotherapy, and vaccination regimes. This review discusses age-associated changes in the immune system and how these changes are modified by fasting and CR which add information on interventions that promote healthy aging and longevity in the growing aging population.

Frailty is a multidimensional syndrome associated with a decline in reserve capacity across multiple organ systems involving physical, psychological, and social aspects. Weakness is the earliest indicator of the frailty process. Multi-morbidity is the state of presence of two or more chronic diseases. Frailty and chronic diseases are interlinked as frail individuals are more prone to develop chronic diseases and multi-morbid individuals may present with frailty. They share common risk factors, pathogenesis, progression, and outcomes. Significant risk factors include obesity, smoking, aging, sedentary, and stressful lifestyle. Pathophysiological mechanisms involve high levels of circulating inflammatory cytokines as seen in individuals with frailty and chronic diseases such as hypertension, cardiovascular diseases, type 2 diabetes mellitus, chronic kidney disease, and anemia. Hence, frailty and chronic diseases go hand in hand and it is of utmost importance to identify them and intervene during early stages. Screening frailty and treating multi-morbidity incorporate both pharmacological and majorly non- pharmacological measures, such as physical activities, nutrition, pro-active care, minimizing polypharmacy and addressing reversible medical conditions. The purpose of this mini-review is to highlight the interrelation of frailty and chronic diseases through the discussion of their predictors and outcomes and how timely interventions are essential to prevent the progression of one to the other.

Arterial stiffening is a critical risk factor contributing to the exponential rise in age-associated cardiovascular disease incidence. This process involves age-induced arterial proinflammation, collagen deposition, and calcification, which collectively contribute to arterial stiffening. The primary driver of proinflammatory processes leading to collagen deposition in the arterial wall is the transforming growth factor-beta1 (TGF-β1) signaling. Activation of this signaling is pivotal in driving vascular extracellular remodeling, eventually leading to arterial fibrosis and calcification. Interestingly, the glycosylated protein vasorin (VASN) physically interacts with TGF-β1, and functionally restraining its proinflammatory fibrotic signaling in arterial walls and vascular smooth muscle cells (VSMCs). Notably, as age advances, matrix metalloproteinase type II (MMP-2) is activated, which effectively cleaves VASN protein in both arterial walls and VSMCs. This age-associated/MMP-2-mediated decrease in VASN levels exacerbates TGF-β1 activation, amplifying arterial fibrosis and calcification in the arterial wall. Importantly, TGF-β1 is a downstream molecule of the angiotensin II (Ang II) signaling pathway in the arterial wall and VSMCs, which is modulated by VASN. Indeed, chronic administration of Ang II to young rats significantly activates MMP-2 and diminishes the VASN expression to levels comparable to untreated older control rats. This review highlights and discusses the role played by VASN in mitigating fibrosis and calcification by alleviating TGF-β1 activation and signaling in arterial walls and VSMCs. Understanding these molecular physical and functional interactions may pave the way for establishing VASN-based therapeutic strategies to counteract adverse age-associated cardiovascular remodeling, eventually reducing the risk of cardiovascular diseases.

Catheter ablation has been validated as an effective intervention for atrial fibrillation (AF) patients, significantly reducing recurrence rates, improving prognoses, and enhancing life quality.^1-3 However, conventional methods employing radiofrequency or cryothermal energy suffer from a lack of tissue specificity, potentially leading to complications such as pulmonary vein stenosis, atrioesophageal fistula, and hemidiaphragmatic paralysis.^{2, 3} Pulsed field ablation (PFA) has recently emerged as a promising alternative, utilizing the microsecond-scale, high-voltage electrical fields to induce irreversible electroporation and cell membrane destabilization, culminating in cellular necrosis.^{4, 5} Its superior tissue selectivity minimizes damage to non-target tissues during ablation, positioning PFA as an ideal modality for cardiac ablation.

Preclinical experiments utilizing animal models have underscored the potential of PFA for achieving durable pulmonary vein isolation (PVI),^{6, 7} highlighting the method's capability to form comprehensive transmural lesions devoid of adverse effects like pulmonary vein ostia stenosis or esophageal damage.^{8, 9} Notably, PFA's application has shown efficacy in permanently neutralizing the atrial ganglion plexus without compromising atrial myocardium integrity or triggering inflammatory responses and fibrosis.^7-9

In 2018, Reddy and colleagues¹⁰ pioneered the application of PFA for the clinical management of paroxysmal AF Their groundbreaking work revealed that an average of 3.26 ablations was sufficient to achieve complete PVI with an operation duration of approximately 67 ± 10.5 min. The procedure was characterized by minimal chest and diaphragmatic sensations, yet remarkably, it resulted in no complications. Follow-up studies involving 81 patients undergoing mono-phase and bi-phase PFA demonstrated 100% acute isolation of pulmonary veins, with the procedure taking an average of 92.2 ± 27.4 min and the ablation itself 13.1 ± 7.6 min.¹¹ Given the pivotal role of pulmonary vein reconnection in ablation recurrence, the stability of PVI post-procedure emerges as crucial. Notably, advancements in PFA waveform technology have significantly increased PVI durability from 18% to a full 100% at the 3-month benchmark. Aside from a single incident of cardiac tamponade related to the operation, no severe complications were reported within the first 120 days post-ablation. At the one-year follow-up mark, the rate of sinus rhythm maintenance impressively stood at 87.4%. These findings collectively affirm the efficacy of PFA in achieving swift and durable PVI, primarily through selective myocardial tissue targeting, while maintaining a commendable safety profile.

Nevertheless, the inherent challenge of high recurrence rates i