The journals of gerontology. Series A, Biological sciences and medical sciences最新文献

Common features of the aging heart are dysregulated metabolism, inflammation, and fibrosis. Elevated oxidative stress is another hallmark of cardiac aging that can exacerbate each of these conditions. We hypothesize that by increasing natural antioxidant levels (glutathione), we will improve cardiac function. Twenty-one-month-old mice were fed glycine and N-acetyl cysteine (GlyNAC; glutathione precursors)-supplemented or control diets for 12 weeks. Heart function was monitored longitudinally, and the exercise performance was determined at the end of the study. We found that the GlyNAC diet was beneficial for old male but not old female mice, leading to an increase of Ndufb8 expression (a subunit of the mitochondrial respiratory chain complex), and higher enzymatic activity for CPT1b and CrAT, 2 carnitine acyltransferases that are critical to cardiomyocyte metabolism. Although no quantifiable change of collagen turnover was detected, hearts from GlyNAC-fed old males exhibited a slight but significant enrichment in Fmod, a protein that can inhibit collagen fibril formation, possibly reducing extracellular matrix stiffness and thus improving diastolic function. Cardiac diastolic function was modestly improved in males but not females, and surprisingly GlyNAC-fed female mice showed a decline in exercise performance. In summary, our work supports the concept that aged male and female hearts are phenotypically different. These basic differences may affect the response to pharmacological and diet interventions, including antioxidants.

Background: The apolipoprotein E (APOE) ε4 allele, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) are well-established risk factors for dementia. Relationships between APOE and incidence of T2DM and CVD are not fully understood but may shed light on the mechanisms underlying dementia pathogenesis.

Methods: Postmenopausal women (N = 6 795) from the Women's Health Initiative hormone therapy clinical trial with APOE genotyping and no prior diagnosis of T2DM or CVD were included. We examined associations of APOE status (APOE2+ [ε2/ε2, ε2/ε3], APOE3 [ε3/ε3], and APOE4+ [ε4/ε4, ε3/ε4] carriers) with incidence of T2DM, coronary heart disease, stroke, and total CVD events using Cox regression. CVD outcomes were examined in baseline non-statin users and adjusted for statin initiation over follow-up to account for possible confounding by statins.

Results: Among all participants (mean age 66.7 ± 6.5 years, 100% non-Hispanic White), 451 (6.6%) were using statins at baseline. Over the follow-up (mean 14.9 and 16.0 years for T2DM and CVD, respectively), 1 564 participants developed T2DM and 1 578 developed CVD. T2DM incidence did not differ significantly by APOE status (ps ≥ .09). Among non-statin users, APOE4+ had higher incidence of total CVD (hazard ratio [95% confidence interval] = 1.18 [1.02-1.38], p = .03) compared with APOE3 carriers, but risks for coronary heart disease (1.09 [0.87-1.36], p = .47) and stroke (1.14 [0.91-1.44], p = .27) were not significantly elevated when examined individually. CVD outcomes did not differ between APOE2+ and APOE3 carriers (ps ≥ 0.11).

Conclusions: T2DM risk did not differ by APOE status among postmenopausal women, but APOE4+ carriers not using statins had an increased risk of total CVD events.

As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

Background: Subjective wellbeing (SWB) is a crucial measure of life quality in older adults. Understanding its relationship with frailty may inform strategies to promote healthy aging.

Methods: We analyzed data for older adults aged ≥ 60 years old from Waves 3 and 4 of the China Health and Retirement Longitudinal Study. SWB was measured based on participants' self-reported overall satisfaction with life. A frailty index was developed using the deficit accumulation approach. We conducted a cross-sectional Poisson regression to investigate the relationship between SWB and counts of frailty deficits. Additionally, we conducted a longitudinal analysis to determine the three-year relative risk of clinically significant frailty progression or mortality for different levels of SWB. The analyses were adjusted for individual weights, including adjustments for household nonresponse.

Results: The cross-sectional analysis included 9,702 individuals. After adjusting for covariates, lower baseline life satisfaction was associated with higher counts of frailty deficits (mean deficit counts ratio [95% confidence interval]: 1.66 [1.54, 1.78] for "not satisfied" and 1.06 [1.02, 1.10] for "somewhat satisfied" relative to the reference "very satisfied"). The longitudinal analysis included 8,599 individuals. Participants who were "not satisfied" with life at baseline were at a greater risk of frailty progression compared with those who were "very satisfied" (risk ratio: 1.16 [1.00, 1.35]).

Conclusion: Our study finds that a lower level of SWB is associated with more severe frailty. It is also associated with frailty progression or death. These results emphasize that both psychological wellbeing and physical health are essential components of healthy aging.

Background: Racial/ethnic minoritized groups in the U.S. have higher prevalence of cardiometabolic multimorbidity and experience higher risk of dementia. This study evaluates the relationship between cardiometabolic multimorbidity and dementia onset according to racial/ethnic group in a nationally representative cohort of U.S. middle-aged and older adults.

Methods: Data from the Health & Retirement Study (1998-2018, N=7,960, mean baseline age 59.4 years) and discrete-time survival models were used to estimate differences in the risk of dementia onset, defined by Langa-Weir classification. Models included race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic), chronic disease/multimorbidity categories (no disease, one disease, cardiovascular multimorbidity, metabolic multimorbidity, cardiometabolic multimorbidity, other multimorbidity), age, sex, education, wealth, body-mass index, and proxy status.

Results: Over a mean follow-up of 14.6 years, 7.7% of the participants (n=614) developed dementia. In the fully adjusted model, participants with cardiometabolic multimorbidity had the highest risk of dementia onset (HR:3.27, 95%CI: 2.06,5.21), followed by metabolic (HR:1.83, 95%CI: 1.14,2.94) and cardiovascular (HR:1.81, 95%CI: 1.24,2.64) multimorbidity, relative to participants with no disease. The risk of dementia was significantly greater among Black (HR: 6.40, 95% CI: 3.84,10.67) and Hispanic participants (HR: 4.90, 95% CI: 2.85,8.43) with cardiometabolic multimorbidity, compared to White adults with no disease.

Conclusions: Individuals from racial/ethnic minoritized groups have a higher risk of dementia. The risk of dementia onset was significantly greater for Black and Hispanic participants experiencing cardiometabolic multimorbidity, highlighting the value of intervening on cardiometabolic conditions among middle-age and older adults, in particular those from racial/ethnic minoritized backgrounds to reduce the risk of developing dementia.

The African turquoise killifish Nothobranchius furzeri represents an emerging short-lived model for aging research. Captive strains of this species are characterized by large differences in lifespan. To identify the gene expression correlates of this lifespan differences, we analyzed a public transcriptomic dataset consisting of four different tissues in addition to embryos. We focused on the GRZ and the MZM0410 captive strains, which show a near twofold difference in lifespan, but similar growth and maturation and validated the results in a newly-generated dataset from a third longer-lived strain. The two strains show distinct transcriptome expression patterns already as embryos and the genotype has a larger effect than age on gene expression, both in terms of number of differentially expressed genes and magnitude of regulation. Network analysis detected RNA processing and histone modifications as the most prominent categories upregulated in GRZ that also showed idiosyncratic expression patterns such as high expression of DND is somatic tissues. The short-lived GRZ strain shows transcriptional aging signatures already at sexual maturity (anticipated aging) in all four tissues suggesting that short lifespan is the results of events that occur early in life rather than the progressive accumulation of strain-dependent differences. The GRZ strain is the most commonly used N. furzeri strain in intervention studies and our results warrant replication of at least key intervention studies in longer-lived strains.

Background: The association between subclinical cardiovascular disease (CVD) and cognitive decline in hypertensive adults and the underlying brain pathologies remain unclear. It is also undetermined whether intensifying blood pressure (BP) treatment slows down cognitive decline associated with subclinical CVD.

Methods: We conducted a post hoc analysis of the Systolic Blood Pressure Intervention Trial. Subclinical CVD at baseline was identified by elevated levels of high-sensitivity cardiac troponin T (hs-cTnT≥14 ng/L) and N-terminal pro-B-type natriuretic peptide (NT-proBNP≥125 pg/mL). Global cognitive function and domain-specific measures (memory, processing speed, language, and executive function) were assessed at baseline and follow-up (years 2, 4, and 6) in 2733 participants. White matter lesions, cerebral blood flow, and brain tissue volume were assessed by MRI at baseline and years 4 in a subset of 639 participants.

Results: Both elevated hs-cTnT and NT-proBNP levels at baseline were associated with accelerated cognitive decline across all domains after adjusting for potential confounding factors. The group with elevated levels of both cardiac biomarkers showed the fastest decline, with a larger annual decline rate of 0.033 (95% CI: 0.024-0.041) in the z-score of global cognitive function compared to the group with normal levels. Elevated levels of both biomarkers were also associated with a faster progression in white matter lesions, but not with changes in total brain tissue volume or cerebral blood flow. Intensive BP treatment did not attenuate these associations compared to standard treatment.

Conclusions: Subclinical CVD may contribute to faster white matter lesion progression and accelerated cognitive decline in patients with hypertension, regardless of intensive BP treatment.

Cellular senescence is a pivotal contributor to aging and age-related diseases. The targeted elimination of senescent cells, known as senolysis, has emerged as a promising therapeutic strategy for mitigating these conditions. Glutaminase 1 (GLS1), a key enzyme in the glutaminolysis pathway, has been implicated in various cellular senescence processes. However, its specific role in senescent renal tubular epithelial cells (TECs) remains unclear. This study investigates the role and underlying mechanisms of GLS1 in senescent TECs. Using D-galactose (D-gal)-induced senescence of HK-2 cells, we found that GLS1 inhibition eliminated senescent TECs by promoting excessive mitochondrial permeability transition pore (mPTP) opening. Mechanistically, the excessive mPTP opening is associated with upregulation of mitofusin 1 (MFN1). Inhibition of GLS1 in D-gal-treated HK-2 cells induced a shift in mitochondrial dynamics from fission to fusion, accompanied by a significant increase in MFN1 expression. Knocking down MFN1 reduced the mPTP opening and the expression of mPTP-related genes (PPIF, VDAC and BAX) in cells co-treated with D-gal and the GLS1 inhibitor BPTES. Moreover, treatment of aged mice with BPTES specifically eliminated senescent TECs and ameliorated age-associated kidney disease. These findings reveal that GLS1 inhibition eliminate senescent TECs by promoting excessive mPTP opening, suggesting that targeting GLS1 may be a novel senolytic strategy for alleviating aging-related kidney diseases.

Excess adipose tissue may promote chronic systemic inflammation and oxidative stress, causing endothelial damage. Early evidence indicates that obesity may be associated with poorer cerebral perfusion. The purpose of this study was to examine the relationship between body composition and cerebral hemodynamics. A total of 248 middle-aged adults (50-58 years old; 55% women) underwent a ramp test on a cycle-ergometer until volitional exhaustion. Gas exchange was assessed on a breath-by-breath basis. Mean middle cerebral artery velocity (MCAv) was measured using transcranial Doppler, and pulsatility index (PI) was calculated. Body composition was assessed by dual X-ray absorptiometry. Statistical analyses were performed using a compositional data approach including a 3-compartment model for body composition (trunk fat mass, extremities fat mass, and fat-free mass). The unadjusted models for the whole sample showed that trunk fat mass relative to other compartments was negatively associated with MCAvrest, MCAvmax, and gain, and positively associated with PImax; extremities fat mass relative to other compartments was positively associated with MCAvrest and MCAvmax, and negatively associated with PImax; and fat-free mass relative to other compartments was positively associated with PImax. These associations were sex-dependent, remaining in the women's subgroup. However, after adjusting for confounders, these associations became nonsignificant, except for PImax in the whole sample and women's subgroup. These findings suggest a possible association between cerebral hemodynamics and body composition in middle-aged adults, highlighting sex-specific differences. Moreover, our results indicate that higher trunk fat mass relative to other compartments may negatively affect cerebral hemodynamics, reducing MCAv and increasing PImax.