GeroScience最新文献

The aim of this study is to evaluate the association of systemic inflammation measured by plasma biomarkers with the change in cognitive function among participants from the Multidomain Alzheimer Preventive Trial (MAPT) exposed to the multidomain intervention (MI). Secondary analysis of the MAPT longitudinal data. MAPT is a randomized, placebo-controlled trial with 3 interventional groups (omega-3 only, MI only, omega-3 plus MI) and a control group. We tested the association of the change in cognitive function with inflammatory biomarkers (tumoral necrosis factor receptor-1 (TNFR1), monocyte chemoattractant protein-1 (MCP1), Growth Differentiation Factor-15 (GDF15), Interleukin-6 (IL6) and C reactive protein (CRP)) using mixed-effects models. A subgroup analysis was performed in those exposed to the MI. The response to the MI was defined as the change in the composite cognitive score over the 2-year clinical follow-up period. by modeling the response to the intervention and identifying “good responders”, i.e., those in the 5th quintile of response at the end of the intervention period (2 years after the measurement of inflammatory markers). We included 1,527 participants (mean age 75.3, SD = 4.4; 64% female). Higher levels of GDF15 and TNFR1 were associated with a worse trajectory in the cognitive composite score in adjusted models. "Good responders" had an estimated mean change in the composite score of 0.051 (SD 0.062) over two years of intervention, compared to -0.136 (SD = 0.111) for the "not-good responders". Higher IL6 levels were associated with a decreased likelihood of being a "good responder" (OR = 0.22, p = 0.018, 95% CI 0.06; 0.78), with similar results for CRP (OR = 0.48, p = 0.009, 95% CI 0.28; 0.84). Higher inflammation was associated with a worse cognitive trajectory among nondemented participants and a lower likelihood of being classified as a "good responder" in those receiving a MI. Further confirmation of these findings could lead to the use of systemic inflammation as inclusion or stratification criteria in prevention trials.

Cellular senescence contributes to inflammation and organ dysfunction during aging. While this process is generally characterized by irreversible cell cycle arrest, its morphological features and functional impacts vary in different cells from various organs. In this study, we examined the expression of multiple senescent markers in the lungs of young and aged humans and mice, as well as in mouse lung endothelial cells cultured with a senescence inducer, suberoylanilide hydroxamic acid (SAHA), or doxorubicin (DOXO). We detected increased levels of p21, γH2AX, and SA-β-Gal and decreased Ki-67 and Lamin B1 in aged lungs and senescent lung endothelial cells. Importantly, the expression of senescent markers was associated with an inflammatory response in aged mouse lungs characterized by neutrophil infiltration, increased expression of intercellular adhesion molecule 1 (ICAM-1), and decreased protein levels of VE-cadherin and ZO-1. As the latter two are critical constituents of endothelial cell–cell junctions, we hypothesized that their decreased expression could lead to compromised junction barrier integrity. Indeed, senescent endothelial cells (ECs) exhibited impaired barrier properties, as measured by increased permeability to solutes of small size (3-kD) and albumin (70-kD). When co-cultured with neutrophils, senescent ECs and their supernatant promoted neutrophil chemotaxis and trans-endothelial migration. Taken together, our results suggest that lung EC senescence weakens cell–cell junctions, impairs barrier function, and promotes neutrophil adhesion and migration, which may contribute to the development of inflammation and related pathologies in the lungs during aging.

D-β-hydroxybutyrate, BHB, has been previously proposed as an anti-senescent agent in vitro and in vivo in several tissues including vascular smooth muscle. Moreover, BHB derivatives as ketone esters alleviate heart failure. Here, we provide evidence of the potential therapeutic effect of BHB on Hutchinson-Gilford progeria syndrome (HGPS), a rare condition characterized by premature aging and heart failure, caused by the presence of progerin, the aberrant protein derived from LMNA/C gene c.1824C > T mutation. We have assessed several hallmarks of HGPS-senescent phenotype in vitro, such as progerin levels, nuclear morphometric aberrations, nucleolar expansion, cellular senescent morphology, SA-βGal-positive cells, H3K9me3 heterochromatin, γH2AX foci, Lamin B1, p21^Waf1/Cip1 and p16^CDKN2A abundance, and autophagy. Strikingly, BHB improved nuclear and nucleolar morphometrics, diminished the senescence-phenotype, and unstuck autophagy in HGPS as observed by an enhanced degradation of the cargo protein receptor SQSTM1/p62, suggesting the stimulation of the autophagic flux. Additionally, we observed a decrease in progerin abundance, the cause of senescence in HGPS. Furthermore, compound C, an inhibitor of AMPK, and SBI-0206965, an inhibitor of ULK1/2 and AMPK, which prevent autophagy activation, reversed BHB-induced progerin decline as well as its anti-senescent effect in an AMPK-mTORC1 dependent manner. Altogether, these results suggest that the anti-senescence effect of BHB involves progerin clearance by autophagy activation supporting the potential of BHB for HGPS therapeutics and further preclinical trials.

Graphical Abstract

Individuals who suffer a major burn injury are at higher risk of developing a range of age-associated diseases prematurely leading to an increase in mortality in adult and juvenile burn injury survivors. One possible explanation is that injury is accelerating the biological ageing process. To test this hypothesis, we analysed DNA methylation in peripheral blood mononuclear cells from adult burn-injured patients (> 5%TBSA) upon admission to hospital and 6 months later, to calculate an epigenetic clock value which can be used to determine biological age. Fifty-three burn-injured participants (mean age 45.43 years, 49 male, mean TBSA 37.65%) were recruited at admission and 34 again 6 months post injury (mean age 40.4 years, 34 male, mean TBSA 30.91%). Twenty-nine healthy controls (mean age 43.69 years, 24 male) were also recruited. Epigenetic age acceleration at admission by PhenoAge was + 7.2 years (P = 8.31e-5) but by month 6 was not significantly different from healthy controls. PCGrimAge acceleration was + 9.23 years at admission (P = 5.79e-11) and remained 4.18 years higher than in controls by month 6 (P = 2.64e-6). At admission, the burn-injured participants had a Dunedin PACE of ageing score 31.65% higher than the control group (P = 2.14e-12), the equivalent of + 115 days per year of biological ageing. Six months post injury the Dunedin PACE of ageing remained significantly higher (+ 11.36%, 41 days/year) than in the control group (P = 3.99e-5). No differences were seen using the Horvath and Hannum clocks. Enrichment analysis revealed that key pathways enriched with burn injury related to immune function, activation, and inflammation. The results reveal that epigenetic age, specifically the PACE of ageing and PCGrimAge, was accelerated in burn-injured adults at admission, with some return towards control values by 6 months. That these two clocks are built upon morbidity outcomes suggests that the injury is invoking a biological response that increases the risk of disease. Burn injury in adults induces epigenetic changes suggestive of an acceleration of the ageing process, which may contribute to the increased morbidity and mortality in these patients.

Flaxseed, a rich source of omega-3 polyunsaturated fatty acid alpha-linolenic acid (ALA), lignans, and soluble fiber, has attracted attention for its potential to improve multiple cardiometabolic risk factors. While its benefits are well-recognized, comprehensive evaluations of its direct impact on clinical outcomes, such as the prevention or progression of cardiometabolic diseases, remain limited. Additionally, its potential to support healthy aging and longevity through fundamental biological mechanisms has not been fully elucidated. This review synthesizes existing research on flaxseed supplementation, highlighting its effects on cardiometabolic risk factors and outcomes, the underlying biological mechanisms, and its broader implications for health promotion and aging. Findings demonstrate that flaxseed supplementation significantly improves several cardiometabolic risk factors, including body weight, body mass index, lipid levels, blood pressure, glycemic measures, markers of inflammation (e.g., C-reactive protein and interleukin-6), oxidative stress, and liver enzymes. Blood pressure reductions range from approximately 2 to 15 mmHg for systolic blood pressure and 1 to 7 mmHg for diastolic blood pressure, with the magnitude influenced by dose, duration, and baseline risk profiles. While direct evidence linking flaxseed to the prevention of hypertension, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, chronic kidney disease, and cardiovascular disease is limited, its bioactive components—ALA, lignans, and fiber—are strongly associated with reduced risks of these conditions. The benefits of flaxseed are mediated through multiple pathways, including anti-inflammatory and antioxidant effects, improved lipid levels, improved glucose metabolism and insulin sensitivity, modulation of gut microbiota, and enhanced vascular health. Beyond cardiometabolic outcomes, flaxseed may influence key biological processes relevant to aging, underscoring its potential to promote healthy aging and longevity. Optimal cardiometabolic benefits appear to be achieved with ground whole flaxseed at doses of ≥ 30 g/day for at least 12 weeks, particularly among individuals at high cardiometabolic risk. Future research should focus on elucidating flaxseed’s mechanisms of action, clarifying its role in disease prevention, and refining dietary recommendations to harness its potential for cardiometabolic health and aging interventions.

Disability and multimorbidity increase with aging and constitute a challenge for the health system. However, different individuals display different aging trajectories, and understanding the underlying relationships between lifespan and disease is fundamental for identifying the different patterns in human lifespan. A previous study explored associations between lifespan and age of onset of diseases of different organ systems, prevalence of escapers, and percentage of life free of disease (health span), comparing them between genders in Catalonian population. In this retrospective study, we analyzed a cohort of 41,063 old individuals (20,722 men, with a mean lifespan of 79 years [50–109], and 20,341 women, with a mean lifespan of 84 years [50–109]) deceased between 2014 and 2019 in Gipuzkoa (Basque Country, Spain) taken from the Basque Health Service electronic health records data lake and analyzed and contrasted the above cited characteristics. Longevity, defined by age above the mean lifespan of the population, showed a protective effect against developing diseases, with higher lifespans delaying the onset of all diseases both at single and multisystemic levels. Furthermore, individuals with the lowest and highest lifespans were the ones presenting the healthier profiles, with fewer systems altered. There were specific differences according to sex, with women exhibiting decreased mortality risk despite having greater multimorbidity and men having less multimorbidity. In addition, men reached the highest lifespans with a smaller number of comorbidities. These results define the aging trajectories of the Basque population, extend the characterization of the human aging, and provide insight into sex-specific differences in multimorbidity and survival risk.

During their daily lives humans are often confronted with sustained cognitive activities (SCA) leading to state fatigue, a psychobiological state characterized by a decrease in cognitive and/or motor performance and/or an increase in perception of fatigue. It was recently shown that performing SCA can impair overground dual-task gait performance in older adults, but it is currently unknown whether there is a task- and/or age-specific modulation in gait performance during treadmill walking. Therefore, the effect of a SCA on single- and dual-task treadmill walking performance was investigated in young and old adults. Using a crossover design, spatio-temporal gait parameters of 24 young and 23 older healthy participants were measured using motion capturing during single- and dual-task (including three cognitive interference tasks: word list generation, arithmetic, and Stroop-task) treadmill walking before and after SCA (30 min Stroop-task) and a control task (reading). Moreover, cognitive fatigue, wakefulness, mood, and arousal were assessed. Although the SCA induced age-specific perceptual responses, no difference was found for cognitive performance during the Stroop-task. The cognitive interference task performance (word list generation, arithmetic, and Stroop-task) during walking on the treadmill did not decrease after the SCA. Single- and dual-task gait performance (e. g., step width and step length) specifically changed after the SCA and after the reading control task in both groups. Data indicate that perceived cognitive fatigue has an impact on single- and dual-task treadmill walking performance, with task- and age-specific differences. Although no general age-specific changes in single- and dual task gait performance following SCA were identified, perceived cognitive fatigue should be considered as an intrinsic risk factor for falls.

Aging is influenced by a complex interplay of multifarious factors, including an individual’s genetics, environment, and lifestyle. Notably, high altitude may impact aging and age-related diseases through exposures such as hypoxia and ultraviolet (UV) radiation. To investigate this, we mined risk exposure data (summary exposure value), disease burden data (disability-adjusted life years (DALYs)), and death rates and life expectancy from the Global Health Data Exchange (GHDx) and National Data Management Center for Health of Ethiopia for each subnational region of Ethiopia, a country with considerable differences in the living altitude. We conducted a cross-sectional clinical trial involving 227 highland and 202 lowland dwellers from the Tigray region in Northern Ethiopia to gain a general insight into the biological aging at high altitudes. Notably, we observed significantly lower risk exposure rates and a reduced disease burden as well as increased life expectancy by lower mortality rates in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells (PBMCs) in blood smears with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude in agreement with the idea that oxidative stress may drive aging.

Analysis of preclinical lifespan studies often assume that outcome data from co-housed animals are independent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result, the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20,000 observations. We show that the independence assumption underlying common analytic techniques does not hold in these data, particularly for traits associated with frailty. We describe and demonstrate various analytical tools available to accommodate this study design and highlight a limitation of standard variance components models (i.e., linear mixed models) which are the usual statistical tools for handling correlated errors. Through simulations, we examine the statistical biases resulting from intra-cage correlations with similar magnitudes as observed in these case studies and discuss implications for power and reproducibility.

As the elderly population expands, enhancing emergency department (ED) care by assessing frailty becomes increasingly vital. To address this, we developed a novel electronic Frailty Index (eFI) from ED health records, specifically designed to assess frailty and predict hospitalization, in-hospital mortality, ICU admissions, and 30-day ED readmissions. This retrospective, single-center study included patients 65 years old or older who presented to the ED of IRCCS Humanitas Research Hospital in Milan, Italy, between January 2015 and December 2019. Frailty was assessed using a novel electronic Frailty Index (eFI), based on the cumulative deficit model, incorporating 45 health deficits to quantify frailty. Patients were divided into four quartiles based on eFI scores to explore the association between frailty levels and adverse outcomes, including hospitalization, in-hospital mortality, ICU admission, and 30-day ED readmission. The study included 21,537 patients (mean age 77.4, 50.7% males). The median eFI score was 0.16. Hospitalization rates rose significantly with frailty, from 20% in the least frail quartile to 43% in the most frail. Similarly, in-hospital mortality and ICU admissions increased markedly with higher eFI scores, with mortality rates climbing from 0.44 to 5.0% across quartiles. The 30-day ED readmission rates significantly rose from 9.9 to 19.8%. For every 0.01 increase in eFI score, the odds of hospitalization, in-hospital mortality, ICU admission, and 30-day ED readmission significantly increased (P < 0.0001). Specifically, the adjusted odds ratios (OR) for hospitalization, in-hospital mortality, ICU admission, and ED readmission rose to 3.55, 14.15, 4.70, and 2.22, respectively (P < 0.0001), in the most frail compared to the least frail quartile. The integration of the eFI into ED settings can enable more precise risk stratification and resource allocation, significantly improving patient management and healthcare delivery for older persons in these urgent care contexts.