Frontiers in aging最新文献

The dauer larva is a specialized stage of worm development optimized for survival under harsh conditions that have been used as a model for stress resistance, metabolic adaptations, and longevity. Recent findings suggest that the dauer larva of Caenorhabditis elegans may utilize external ethanol as an energy source to extend their lifespan. It was shown that while ethanol may serve as an effectively infinite source of energy, some toxic compounds accumulating as byproducts of its metabolism may lead to the damage of mitochondria and thus limit the lifespan of larvae. A minimal mathematical model was proposed to explain the connection between the lifespan of a dauer larva and its ethanol metabolism. To explore theoretically if it is possible to extend even further the lifespan of dauer larvae, we incorporated two natural mechanisms describing the recovery of damaged mitochondria and elimination of toxic compounds, which were previously omitted in the model. Numerical simulations of the revised model suggested that while the ethanol concentration is constant, the lifespan still stays limited. However, if ethanol is supplied periodically, with a suitable frequency and amplitude, the dauer could survive as long as we observe the system. Analytical methods further help to explain how feeding frequency and amplitude affect lifespan extension. Based on the comparison of the model with experimental data for fixed ethanol concentration, we proposed the range of feeding protocols that could lead to even longer dauer survival and it can be tested experimentally.

Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.

Globally, our population is ageing at an unprecedented rate and by 2030, which marks the end of the United Nations (UN) Decade of Healthy Ageing, the number of people aged 60 years and older will be 34% higher than today, reaching 1.4 billion. Vaccination is one of the most effective public health interventions of modern times and a key action in fostering healthy ageing throughout the life-course. To promote wellbeing at all ages, global agendas including the WHO Immunization Agenda 2030, the UN Decade of Healthy Ageing and the World Health Organization (WHO) Global Report on Ageism outline strategic actions and guidance to help implement policies and programs. Yet, the linkages between healthy ageing, functional ability and adult vaccination are not substantively recognized or integrated as cross-cutting themes, which impacts operationalization into national immunization plans. When aligned and connected strategically, these agendas have potential to substantially contribute to policy change to prioritize life-course immunization and support the preservation of function at all stages of life. This article describes the intersecting goals and visions of these strategic agendas and identifies specific elements of overlap, which when connected, could strengthen the development of comprehensive and effective national immunization policies.

In this review, we explore the application of novel biomaterial-based therapies specifically targeted towards craniofacial bone defects. The repair and regeneration of critical sized bone defects in the craniofacial region requires the use of bioactive materials to stabilize and expedite the healing process. However, the existing clinical approaches face challenges in effectively treating complex craniofacial bone defects, including issues such as oxidative stress, inflammation, and soft tissue loss. Given that a significant portion of individuals affected by traumatic bone defects in the craniofacial area belong to the aging population, there is an urgent need for innovative biomaterials to address the declining rate of new bone formation associated with age-related changes in the skeletal system. This article emphasizes the importance of semiconductor industry-derived materials as a potential solution to combat oxidative stress and address the challenges associated with aging bone. Furthermore, we discuss various material and autologous treatment approaches, as well as in vitro and in vivo models used to investigate new therapeutic strategies in the context of craniofacial bone repair. By focusing on these aspects, we aim to shed light on the potential of advanced biomaterials to overcome the limitations of current treatments and pave the way for more effective and efficient therapeutic interventions for craniofacial bone defects.

The impact of shoulder pain on health-related quality of life and physical function among community-dwelling older adults (>60 years) not seeking medical care is not well understood. Forty-four community-dwelling older adult volunteers with low comorbidity were stratified into two groups by the presence (n = 18) or absence (n = 26) of shoulder pain. Participants completed the 36-Item Short Form and American Shoulder and Elbow Surgeon surveys and received shoulder range of motion and magnetic resonance imaging testing. Participants with shoulder pain perceived more difficulty accomplishing usual tasks secondary to their physical and emotion health and displayed inferior shoulder function, relative to participants without shoulder pain. This study suggests that shoulder pain reduces quality of life and physical function in the population of community-dwelling older adults not seeking medical evaluation for their symptoms.

Aging is defined as the functional decline of tissues and organisms, leading to many human conditions, such as cancer, neurodegenerative diseases, and hair loss. Although stem cell exhaustion is widely recognized as a hallmark of aging, our understanding of cell state changes-specifically, the dynamics of the transcriptome and open chromatin landscape, and their relationship with aging-remains incomplete. Here we present a longitudinal, single-cell atlas of the transcriptome and open chromatin landscape for epithelia cells of the skin across various hair cycle stages and ages in mice. Our findings reveal fluctuating hair follicle stem cell (HF-SC) states, some of which are associated with the progression of the hair cycle during aging. Conversely, inner bulge niche cells display a more linear progression, seemingly less affected by the hair cycle. Further analysis of the open chromatin landscape, determined by single-cell Assay for Transposase-Accessible Chromatin (ATAC) sequencing, demonstrates that reduced open chromatin regions in HF-SCs are associated with differentiation, whereas gained open chromatin regions in HF-SCs are linked to the transcriptional control of quiescence. These findings enhance our understanding of the transcriptional dynamics in HF-SC aging and lay the molecular groundwork for investigating and potentially reversing the aging process in future experimental studies.

Introduction: Klotho is a protein associated with protection from aging-related diseases and health conditions. Obesity is associated with lower Klotho concentrations. Thus, this secondary analysis of adults with obesity examined 1) the change in serum Klotho concentration in response to a behavioral weight loss intervention by the magnitude of weight loss achieved; and 2) the association among serum Klotho concentration and weight, body composition, and cardiorespiratory fitness. Methods: Participants were randomized to either diet alone (DIET), diet plus 150 min of physical activity per week (DIET + PA150), or diet plus 250 min of physical activity per week (DIET + PA250). Participants [n = 152; age: 45.0 ± 7.9 years; body mass index (BMI): 32.4 ± 3.8 kg/m²] included in this secondary analysis provided blood samples at baseline, 6-, and 12 months, and were classified by weight loss response (Responder: achieved ≥10% weight loss at 6 or 12 months; Non-responder: achieved <5% weight loss at both 6 and 12 months). Serum Klotho was measured using a solid-phase sandwich enzyme-linked immunosorbent assay (ELISA). Analyses of covariance (ANCOVA's) were used to examine changes in weight, body composition, cardiorespiratory fitness, and Klotho concentration by weight loss response across the 12-month weight loss intervention. Results: Responders had a greater reduction in measures of weight and body composition, and a greater increase in cardiorespiratory fitness, compared to Non-Responders (p < 0.05). Change in Klotho concentration differed between Responders and Non-Responders (p < 0.05), with the increase in Klotho concentration from baseline to 6 months for Responders being statistically significant. The 6-month change in Klotho concentration was inversely associated with the 6-month change in weight (r _s = -0.195), BMI (r _s = -0.196), fat mass (r _s = -0.184), and waist circumference (r _s = -0.218) (p-values <0.05). Discussion: Findings provide evidence within the context of a behavioral intervention, with and without exercise, that change in Klotho concentration is significantly different between adults with weight loss ≥10% compared to <5% across 12 months. These findings suggest that weight loss and reduction in fat mass may be favorably associated with the change in Klotho concentration. This may reduce the risk of negative health consequences associated with accelerated aging in middle-aged adults.

Introduction: Implicated in both aging and Alzheimer's disease (AD), mammalian target of rapamycin (mTOR) is overactive in AD brain and lymphocytes. Stimulated by growth factors such as insulin, mTOR monitors cell health and nutrient needs. A small molecule oral drug candidate for AD, simufilam targets an altered conformation of the scaffolding protein filamin A (FLNA) found in AD brain and lymphocytes that induces aberrant FLNA interactions leading to AD neuropathology. Simufilam restores FLNA's normal shape to disrupt its AD-associated protein interactions. Methods: We measured mTOR and its response to insulin in lymphocytes of AD patients before and after oral simufilam compared to healthy control lymphocytes. Results: mTOR was overactive and its response to insulin reduced in lymphocytes from AD versus healthy control subjects, illustrating another aspect of insulin resistance in AD. After oral simufilam, lymphocytes showed normalized basal mTOR activity and improved insulin-evoked mTOR activation in mTOR complex 1, complex 2, and upstream and downstream signaling components (Akt, p70S6K and phosphorylated Rictor). Suggesting mechanism, we showed that FLNA interacts with the insulin receptor until dissociation by insulin, but this linkage was elevated and its dissociation impaired in AD lymphocytes. Simufilam improved the insulin-mediated dissociation. Additionally, FLNA's interaction with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), a negative regulator of mTOR, was reduced in AD lymphocytes and improved by simufilam. Discussion: Reducing mTOR's basal overactivity and its resistance to insulin represents another mechanism of simufilam to counteract aging and AD pathology. Simufilam is currently in Phase 3 clinical trials for AD dementia.

Introduction: This study investigated how psychological resilience influenced greater technology use among older adults, and whether they moderated the impact of social isolation on loneliness during the COVID-19 pandemic. We also explored whether technology mediates the impact of psychological resilience on loneliness. To explain the relationship between variables, the research drew upon the socio-emotional selective theory, which posits the notion that older adults are more focused on current and emotionally important relationships and goals concerning emotional regulation goals such as psychological well-being. Methods: Using a cross-sectional observational design, data were collected from 92 residents aged 65 to 89 in England from March 2020 to June 2021. Participants completed the Connor-Davidson Resilience Scale, Technology Experience Questionnaire, UCLA Loneliness Scale, and Lubben Social Network Index. Pearson correlation, mediation and moderation analyses were conducted to investigate the hypotheses. Results: Most participants experienced moderate to severe levels of loneliness, displaying higher levels than pre-pandemic. Psychological resilience predicted greater technology use, and lower levels of loneliness. Technology was found to mediate the relationship between psychological resilience and loneliness. Neither technology use, nor psychological resilience was found to moderate the impact of social isolation on loneliness. Discussion: Findings suggested that strategies directed towards screening older adults for psychological resilience levels and low technology experience may help identify those most at risk for adapting poorly when exposed to stressors in situations like the Covid-19 pandemic. Early interventions can be initiated to increase psychological resilience and technology use, including empirical interventions, that may help decrease loneliness, especially in times of elevated risks for loneliness.

Age is the greatest risk factor for adverse outcomes following influenza (flu) infection. The increased burden of senescent cells with age has been identified as a root cause in many diseases of aging and targeting these cells with drugs termed senolytics has shown promise in alleviating many age-related declines across organ systems. However, there is little known whether targeting these cells will improve age-related deficits in the immune system. Here, we utilized a well characterized senolytic treatment with a combination of dasatinib and quercetin (D + Q) to clear aged (18-20 months) mice of senescent cells prior to a flu infection. We comprehensively profiled immune responses during the primary infection as well as development of immune memory and protection following pathogen reencounter. Senolytic treatment did not improve any aspects of the immune response that were assayed for including: weight loss, viral load, CD8 T-cell infiltration, antibody production, memory T cell development, or recall ability. These results indicate that D + Q may not be an appropriate senolytic to improve aged immune responses to flu infection.