npj aging最新文献

Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu) in 26 men, ProtAgeGap decreased by the equivalent of 10 months. While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk. Clinical trial number: clinicaltrials.gov: NCT01803568 registered 2013-02-26.

Myeloid-derived suppressor cells (MDSCs) are recognized as a key mediator of immunosuppression in aging, which induce immunosenescence and increase elderly people's susceptibility to infections, cancers, autoimmune diseases, and degenerative diseases. However, the commonly used MDSC markers overlap with those defining healthy and normal neutrophils or monocytes, which makes it challenging to distinguish MDSCs from their myeloid counterparts, and hampers deeper understanding of the pathophysiological functions of MDSCs. In this study, we compared MDSCs from aged mice to young controls using single-cell RNA sequencing. We established MDSC-specific gene signature, which revealed the general characteristics of MDSCs during aging, and thus facilitating distinguishing them from normal myeloid cells. Experimental study revealed that CD300c may serve as a specific marker for improved detection and enrichment of MDSCs in aging. CD11b⁺Gr1⁺CD300c⁺ cells demonstrated a robust ability of T cell suppression. The universality and applicability of MDSC-specific gene signature have also been demonstrated in human myeloid cells. We also found that MDSCs from aged individuals shared the similar developmental trajectory with their myeloid counterparts, and may develop from mature myeloid cells, both in mice and human beings, which has been reported by a limited number of studies. Overall, our work extends the understanding of MDSCs in aging process.

Biomarkers of aging have the potential to transform geroscience clinical trials because of their broad applications in stratifying participants, prioritizing interventions, and monitoring responses to geroprotectors. As longevity biotechnology companies (LBCs) continue to plan and launch innovative clinical trials, standard practices in collecting data and applying biomarkers of aging will allow the field to support parallel and ongoing validation and benchmarking efforts for aging biomarkers. Moreover, defining best practices will ensure future reuse of valuable clinical data through pre-competitive alignment on shared tools. Here, we propose recommendations for such collections. We believe that wide adoption of these recommendations will allow LBCs to produce and leverage the highest quality data from their clinical trials, while also benefiting the geroscience field more broadly with minimal additional effort.

Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is associated with changes in microglia function. While age remains the biggest risk factor, the underlying molecular cause of PD onset and its concurrent neuroinflammation are not well understood. Many identified PD risk genes have been directly linked to dopamine neuron impairment, while others are linked to immune cell function. In this study, we found that the PD risk gene FAM49B is critically expressed in microglia of the human SNpc and is downregulated with age and PD. We utilized human and murine microglia cells to demonstrate the role of FAM49B in regulating fundamental microglial functions such as cytoskeletal maintenance, migration, surface adherence, energy homeostasis, autophagy, and, importantly, inflammatory response. Downregulation of microglial FAM49B, as observed in the SNpc of aging individuals, led to significant alterations in these cellular functions, which are associated with increased microglial activation. Thus, our study highlights novel cell-type-specific roles of FAM49B and provides a potential mechanism for susceptibility to neuroinflammation, and reactive gliosis observed in both PD and normal aging.

Aging clocks use machine learning to estimate biological age as a proxy for general health state. Here, we critically examine their practical value, highlighting fundamental challenges: abstract definitions, inconsistent clinical validation, and ignored prediction uncertainty. By comparing aging clocks with expert risk scores, direct outcome predictors, and emerging large health models, we question their benefits and encourage researchers to explicitly justify clock advantage over established alternatives, ensuring truly actionable insights.

Biological clocks aim to estimate the physiological state of an organism, or of specific organs or systems, from the perspective of aging. The inferred individual age acceleration is presumably linked to increased mortality and morbidity risks. Here, we introduce a cognitive aging clock based on a battery of five tests (sensomotor arithmetic, sensomotor mirror letter, 1-back, campimetry and the Stroop), capturing sensory and verbal perception, working memory, and decision-making in the context of cognitive conflict. The developed LightGBM machine learning model has the cognitive age MAE of 7.6 years. SHAP analysis yields the overall and individualized interpretations of accelerated aging. In particular, we demonstrate the dominant contribution of Stroop and campimetry test variables to cognitive age. The cognitive age is accelerated in the patients with dementia, whereas moderate cognitive impairment also shows the acceleration trend, but lacks statistical significance. MoCA test score is negatively associated with cognitive age deviation.

Older adults frequently use medications deemed high-risk, despite clinical recommendations supporting their discontinuation. We conducted a retrospective cohort study using administrative claims data from a large national U.S. health insurer (2017-2023) to assess high-risk medication discontinuation among adults aged ≥65 years and their association with sociodemographic factors. Among 729,705 long-term users of high-risk medications (mean age 74 [SD: 7], 59% female), only 22.8% discontinued for ≥90 consecutive days without subsequent refills (mean follow-up: 626 days). Discontinuation was more likely among Black adults (HR = 1.07, 95% CI: 1.03-1.11), particularly between 2020-2021, while men (HR = 0.89, 95% CI: 0.87-0.91) and those aged ≥75 years (HR = 0.86, 95% CI: 0.84-0.91) were less likely to discontinue compared to women and younger older adults, respectively. Notably, the combined effect of male gender and older age was associated with increased discontinuation (HR = 1.04, 95% CI: 1.02-1.06), whereas other sociodemographic combinations showed no meaningful interaction. When stratified by medication class, significant variation persisted for central nervous system, gastrointestinal, and pain medications but not for endocrine or cardiovascular medications. These findings highlight persistently low discontinuation rates and suggest the need for targeted interventions to reduce inappropriate medication use in older adults.

Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant forms of primary liver cancer, with limited therapeutic options and a poor prognosis. Cellular senescence contributes to the progression of chronic liver disease while creating a microenvironment that supports tumor growth. This study aims to identify dual-purpose therapeutic targets for HCC treatment and cellular senescence intervention, potentially leading to more effective therapeutic strategies. Utilizing the AI-driven target discovery platform PandaOmics, we prioritized 27 high-confidence, and 8 novel HCC targets potentially associated with cellular senescence. Experimental validations confirmed that the knockdown of pre-mRNA-processing factor 19 (PRPF19) or mitogen-activated protein kinase 9 (MAPK9) in HCC cells significantly reduced cell proliferation. Additionally, suppression of PRPF19 or MAPK9 in hepatic stellate cells treated with doxorubicin resulted in a significant decrease in cellular senescence. These findings underscore the pivotal roles of PRPF19 and MAPK9 in both HCC cell proliferation and cellular senescence, suggesting them as promising novel dual-purpose therapeutic targets for HCC treatment and mitigation of senescence-associated pathologies.

Accelerated biological aging (BA) is linked to adverse cardiovascular events, but its role in heart failure with preserved ejection fraction (HFpEF) remains unclear. We analyzed 1,727 HFpEF patients from RED-CARPET Study (ChiCTR2000039901), assessing BA using Klemera-Doubal and PhenoAge methods. During a median 4.9-year follow-up, 321 all-cause and 180 cardiovascular deaths occurred. After full adjustment, per 1-SD increase in BA acceleration showed significantly higher risk of all-cause mortality (KDMAge HR 1.55, 95% CI 1.40-1.72; PhenoAge HR 1.24, 95% CI 1.11-1.40) and cardiovascular mortality (KDMAge HR 1.47, 95% CI 1.28-1.69; PhenoAge HR 1.21, 95% CI 1.04-1.41). BA acceleration was also significantly related to increased left ventricular mass index (LVMI), relative wall thickness, and E/e' ratio. Mediation analysis revealed that both LVMI and the E/e' ratio partially mediated the relationship between BA acceleration and mortality. These findings suggest BA acceleration may serve as a key prognostic marker in patients with HFpEF.

The central nervous system, comprised of the brain, spinal cord, and nerves, includes the autonomic nervous system (ANS) that regulates involuntary functions. Within the ANS, the sympathetic and the parasympathetic nervous systems (SNS and PNS, respectively) control the same bodily functions, but in opposing directions. For example, the sympathetic nervous system elicits our "fight or flight" response, while the parasympathetic system supports "rest and repair" mechanisms in the broadest possible sense. With age, changes occur in how information is transmitted, in energetic requirements and expenditures, and in the ability to respond to change. These alterations with age result in the "hallmarks of aging", specifically including genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and chronic inflammation. Understanding these age-dependent changes is essential for promoting healthy aging and longevity. We propose that, at the core of aging, there is an imbalance between the SNS and PNS, which provides opportunities for therapeutic intervention.