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The Lancet. Healthy Longevity Jul 2024
Topics: Humans; Exercise; Age Factors; Aging; Aged
PubMed: 38945124
DOI: 10.1016/S2666-7568(24)00115-6 -
European Journal of Cell Biology Jun 2024The knowledge about cellular senescence expands dynamically, providing more and more conclusive evidence of its triggers, mechanisms, and consequences.... (Review)
Review
The knowledge about cellular senescence expands dynamically, providing more and more conclusive evidence of its triggers, mechanisms, and consequences. Senescence-associated secretory phenotype (SASP), one of the most important functional traits of senescent cells, is responsible for a large extent of their context-dependent activity. Both SASP's components and signaling pathways are well-defined. A literature review shows, however, that a relatively underinvestigated aspect of senescent cell autocrine and paracrine activity is the change in the production of proteins responsible for the reception and transmission of SASP signals, i.e., receptors and binding proteins. For this reason, we present in this article the current state of knowledge regarding senescence-associated changes in cellular receptors and insulin-like growth factor binding proteins. We also discuss the role of these alterations in senescence induction and maintenance, pro-cancerogenic effects of senescent cells, and aging-related structural and functional malfunctions.
PubMed: 38945074
DOI: 10.1016/j.ejcb.2024.151438 -
Hormones and Behavior Jun 2024In a subset of females, postmenopausal status has been linked to accelerated aging and neurological decline. A complex interplay between reproductive-related factors,...
In a subset of females, postmenopausal status has been linked to accelerated aging and neurological decline. A complex interplay between reproductive-related factors, mental disorders, and genetics may influence brain function and accelerate the rate of aging in the postmenopausal phase. Using multiple regressions corrected for age, in this preregistered study we investigated the associations between menopause-related factors (i.e., menopausal status, menopause type, age at menopause, and reproductive span) and proxies of cellular aging (leukocyte telomere length, LTL) and brain aging (white and gray matter brain age gap, BAG) in 13,780 females from the UK Biobank (age range 39-82). We then determined how these proxies of aging were associated with each other, and evaluated the effects of menopause-related factors, history of depression (= lifetime broad depression), and APOE ε4 genotype on BAG and LTL, examining both additive and interactive relationships. We found that postmenopausal status and older age at natural menopause were linked to longer LTL and lower BAG. Surgical menopause and longer natural reproductive span were also associated with longer LTL. BAG and LTL were not significantly associated with each other. The greatest variance in each proxy of biological aging was most consistently explained by models with the addition of both lifetime broad depression and APOE ε4 genotype. Overall, this study demonstrates a complex interplay between menopause-related factors, lifetime broad depression, APOE ε4 genotype, and proxies of biological aging. However, results are potentially influenced by a disproportionate number of healthier participants among postmenopausal females. Future longitudinal studies incorporating heterogeneous samples are an essential step towards advancing female health.
PubMed: 38944998
DOI: 10.1016/j.yhbeh.2024.105596 -
Geriatric Nursing (New York, N.Y.) Jun 2024This paper explores the ageing population in Italy, where older adults account for more than 14 million individuals (in January 2023) and constitute 24.1 % of the total...
This paper explores the ageing population in Italy, where older adults account for more than 14 million individuals (in January 2023) and constitute 24.1 % of the total population. Frailty, a condition encompassing biological, psychological, social, and economic challenges, is recognised as a significant public health issue. The study introduces the Short Functional Geriatric Evaluation (SFGE) as a large-scale screening tool for frailty in community-dwelling older individuals. A Confirmatory Factor Analysis (CFA) was conducted on the SFGE. The CFA scrutinises the construct validity of SFGE using a sample population from the "Long Live the Elderly!" program in Italy. Initial results indicate an acceptable fit, prompting the incorporation of Modification Indices to enhance model performance. The refined CFA demonstrates that the SFGE model effectively captures the multidimensional nature of frailty. The text underscores the timeliness of identifying frailty, emphasising the need for simple, fast, and predictive tools to screen large populations efficiently.
PubMed: 38944915
DOI: 10.1016/j.gerinurse.2024.06.022 -
Aging Jun 2024The genomic landscape of clear cell renal cell carcinoma (ccRCC) has a considerable intra-tumor heterogeneity, which is a significant obstacle in the field of precision...
Unfolding the mysteries of heterogeneity from a high-resolution perspective: integration analysis of single-cell multi-omics and spatial omics revealed functionally heterogeneous cancer cells in ccRCC.
The genomic landscape of clear cell renal cell carcinoma (ccRCC) has a considerable intra-tumor heterogeneity, which is a significant obstacle in the field of precision oncology and plays a pivotal role in metastasis, recurrence, and therapeutic resistance of cancer. The mechanisms of intra-tumor heterogeneity in ccRCC have yet to be fully established. We integrated single-cell RNA sequencing (scRNA-seq) and transposase-accessible chromatin sequencing (scATAC-seq) data from a single-cell multi-omics perspective. Based on consensus non-negative matrix factorization (cNMF) algorithm, functionally heterogeneous cancer cells were classified into metabolism, inflammatory, and EMT meta programs, with spatial transcriptomics sequencing (stRNA-seq) providing spatial information of such disparate meta programs of cancer cells. The bulk RNA sequencing (RNA-seq) data revealed high clinical prognostic values of functionally heterogeneous cancer cells of three meta programs, with transcription factor regulatory network and motif activities revealing the key transcription factors that regulate functionally heterogeneous ccRCC cells. The interactions between varying meta programs and other cell subpopulations in the microenvironment were investigated. Finally, we assessed the sensitivity of cancer cells of disparate meta programs to different anti-cancer agents. Our findings inform on the intra-tumor heterogeneity of ccRCC and its regulatory networks and offers new perspectives to facilitate the designs of rational therapeutic strategies.
PubMed: 38944814
DOI: 10.18632/aging.205974 -
Aging Jun 2024Cathepsin L (CTSL) has been implicated in aging and age-related diseases, such as cardiovascular diseases, specifically atherosclerosis. However, the underlying...
Cathepsin L (CTSL) has been implicated in aging and age-related diseases, such as cardiovascular diseases, specifically atherosclerosis. However, the underlying mechanism(s) is not well documented. Recently, we demonstrated a role of CUT-like homeobox 1 (CUX1) in regulating the p16-dependent cellular senescence in human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via its binding to an atherosclerosis-associated functional SNP (fSNP) rs1537371 on the locus. In this study, to determine if CTSL, which was reported to proteolytically activate CUX1, regulates cellular senescence via CUX1, we measured the expression of CTSL, together with CUX1 and p16, in human ECs and VSMCs undergoing senescence. We discovered that CUX1 is not a substrate that is cleaved by CTSL. Instead, CTSL is an upstream regulator that activates transcription indirectly in a process that requires the proteolytic activity of CTSL. Our findings suggest that there is a transcription factor in between CTSL and CUX1, and cleavage of this factor by CTSL can activate CUX1 transcription, inducing endothelial senescence. Thus, our findings provide new insights into the signal transduction pathway that leads to atherosclerosis-associated cellular senescence.
PubMed: 38944813
DOI: 10.18632/aging.205955 -
JAMA Health Forum Jun 2024Households have high burden of health care payments. Alternative financing approaches could reduce this burden for some households.
IMPORTANCE
Households have high burden of health care payments. Alternative financing approaches could reduce this burden for some households.
OBJECTIVE
To estimate the distribution of household health care payments across income under health care reform policies.
DESIGN, SETTING, AND PARTICIPANTS
Cross-sectional study with microsimulation used nationally representative data of the US population in 2030. Civilian, noninstitutionalized population from the 2022 Current Population Survey linked to expenditures from the 2018 and 2019 Medical Expenditure Panel Survey and 2022 National Health Expenditure Accounts were included.
EXPOSURE
Rate regulation of hospital, physician, and other health care professional payments equal to the all-payer mean in the status quo, spending growth target at 4% annual per capita growth, and single-payer health care financed through taxes.
MAIN OUTCOMES AND MEASURES
Household health care payments (out-of-pocket expenses, premiums, and taxes) as a share of compensation.
RESULTS
The synthetic population contained 154 456 records representing 339.5 million individuals, with 51% female, 7% Asian, 14% Black, 18% Hispanic White, 56% non-Hispanic White, and 5% other races and ethnicities (American Indian or Alaskan Native only; Native Hawaiian or other Pacific Islander only; and 2 or more races). In the status quo, mean household health care payments as a share of compensation was 24% to 27% (standard error [SE], 0.2%-1.2%) across income groups (median [IQR] 22% [4%-52%] below 139% of the federal poverty level [FPL]; 21% [4%-34%] for households above 1000% FPL [11% of the population]). Under rate setting, mean (SE) payments by households above 1000% FPL increased to 29% (0.6%) (median [IQR], 22% [6%-35%]) and decreased to 23% to 25% for other income groups. Under the spending growth target, mean (SE) payments decreased from 23% to 26% (SE, 0.2%-1.2%) across income groups. Under the single-payer system, mean (SE) payments declined to 15% (0.7%) (median [IQR], 4% [0%-30%]) for those below 139% FPL and increased to 31% (0.6%) (median [IQR], 23% [3%-39%]) for those above 1000% FPL. Uninsurance fell from 9% to 6% under rate setting due to improved Medicaid access, and to zero under the single-payer system.
CONCLUSIONS AND RELEVANCE
Single-payer financing based on the current federal income tax schedule and a payroll tax could substantially increase progressivity of household payments by income. Rate setting led to slight increases in payments by higher-income households, who financed higher payment rates in Medicare and Medicaid. Spending growth targets reduced payments slightly for all households.
Topics: Humans; Cross-Sectional Studies; Health Expenditures; Female; United States; Male; Adult; Middle Aged; Family Characteristics; Single-Payer System; Financing, Personal; Health Care Reform; Income; Aged
PubMed: 38944764
DOI: 10.1001/jamahealthforum.2024.1932 -
JAMA Health Forum Jun 2024The Centers for Medicare & Medicaid Services' mandatory End-Stage Renal Disease Treatment Choices (ETC) model, launched on January 1, 2021, randomly assigned...
IMPORTANCE
The Centers for Medicare & Medicaid Services' mandatory End-Stage Renal Disease Treatment Choices (ETC) model, launched on January 1, 2021, randomly assigned approximately 30% of US dialysis facilities and managing clinicians to financial incentives to increase the use of home dialysis and kidney transplant.
OBJECTIVE
To assess the ETC's association with use of home dialysis and kidney transplant during the model's first 2 years and examine changes in these outcomes by race, ethnicity, and socioeconomic status.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cross-sectional study used claims and enrollment data for traditional Medicare beneficiaries with kidney failure from 2017 to 2022 linked to same-period transplant data from the United Network for Organ Sharing. The study data span 4 years (2017-2020) before the implementation of the ETC model on January 1, 2021, and 2 years (2021-2022) following the model's implementation.
EXPOSURE
Receiving dialysis treatment in a region randomly assigned to the ETC model.
MAIN OUTCOMES AND MEASURES
Primary outcomes were use of home dialysis and kidney transplant. A difference-in-differences (DiD) approach was used to estimate changes in outcomes among patients treated in regions randomly selected for ETC participation compared with concurrent changes among patients treated in control regions.
RESULTS
The study population included 724 406 persons with kidney failure (mean [IQR] age, 62.2 [53-72] years; 42.5% female). The proportion of patients receiving home dialysis increased from 12.1% to 14.3% in ETC regions and from 12.9% to 15.1% in control regions, yielding an adjusted DiD estimate of -0.2 percentage points (pp; 95% CI, -0.7 to 0.3 pp). Similar analysis for transplant yielded an adjusted DiD estimate of 0.02 pp (95% CI, -0.01 to 0.04 pp). When further stratified by sociodemographic measures, including age, sex, race and ethnicity, dual Medicare and Medicaid enrollment, and poverty quartile, there was not a statistically significant difference in home dialysis use across joint strata of characteristics and ETC participation.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study, the first 2 years of the ETC model were not associated with increased use of home dialysis or kidney transplant, nor changes in racial, ethnic, and socioeconomic disparities in these outcomes.
Topics: Humans; Kidney Transplantation; Female; Male; Cross-Sectional Studies; Hemodialysis, Home; United States; Reimbursement, Incentive; Retrospective Studies; Kidney Failure, Chronic; Aged; Middle Aged; Medicare
PubMed: 38944762
DOI: 10.1001/jamahealthforum.2024.2055 -
Nature Communications Jun 2024JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the...
JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the Drosophila intestine, the TNF-type ligand, Eiger (Egr), is expressed exclusively by intestinal stem cells (ISCs) and enteroblasts (EBs), where it is induced by stress and during aging. Egr preferentially activates JNK signaling in a paracrine fashion in differentiated enterocytes (ECs) via its receptor, Grindelwald (Grnd). N-glycosylation genes (Alg3, Alg9) restrain this activation, and stress-induced downregulation of Alg3 and Alg9 correlates with JNK activation, suggesting a regulatory switch. JNK activity in ECs induces expression of the intermembrane protease Rhomboid (Rho), driving secretion of EGFR ligands Keren (Krn) and Spitz (Spi), which in turn activate EGFR signaling in progenitor cells (ISCs and EBs) to stimulate their growth and division, as well as to produce more Egr. This study uncovers an N-glycosylation-controlled, paracrine JNK-EGFR-JNK feedforward loop that sustains ISC proliferation during stress-induced gut regeneration.
Topics: Animals; Drosophila Proteins; ErbB Receptors; Intestines; MAP Kinase Signaling System; Drosophila melanogaster; Enterocytes; Stem Cells; Intestinal Mucosa; Drosophila; Glycosylation; Receptors, Invertebrate Peptide; Cell Proliferation; JNK Mitogen-Activated Protein Kinases; Signal Transduction; Cell Communication; Cell Differentiation; Epidermal Growth Factor; Membrane Proteins
PubMed: 38944657
DOI: 10.1038/s41467-024-49786-w -
Seizure Jun 2024The unique patho-clinical entity of late-onset epilepsy (LOE), distinguished by its distinct natural history, from its onset to the prognosis it portends, necessitates... (Review)
Review
The unique patho-clinical entity of late-onset epilepsy (LOE), distinguished by its distinct natural history, from its onset to the prognosis it portends, necessitates specialized care. We lack a universally accepted definition, but LOE is typically identified as epilepsy onset after the age of 60 or 65. Unlike epilepsy in younger individuals, LOE is almost by default focal in origin, secondary to acquired etiologies, and presents unique diagnostic and management challenges due to its atypical semiology, higher comorbidity burden, frailty, and increased risks of subsequent stroke and dementia. LOE clinics have been established to address these challenges, providing a multidisciplinary approach to optimize outcomes in patients with new-onset seizures beyond the fifth decade of life. LOE clinics are essential for comprehensive care, offering not only seizure management but also monitoring and addressing associated comorbidities. The care model involves collaboration among neurologists, primary care providers, cardiologists, mental health professionals, and social workers to manage LOE patients' complex needs effectively. The prevalence of cognitive dysfunction in LOE patients underscores the need for regular cognitive assessments and interventions. Biomarker research, particularly involving amyloid beta, offers promising avenues for early diagnosis and a better understanding of the interplay between LOE and Alzheimer's disease. Establishing LOE clinics in major referral centers can enhance provider expertise, improve patient outcomes, and facilitate research to advance diagnostic and therapeutic strategies. In conclusion, LOE clinics play a critical role in addressing the multifaceted needs of older adults with epilepsy, tailored to local resources and challenges, thus enhancing epilepsy care in an aging global population.
PubMed: 38944548
DOI: 10.1016/j.seizure.2024.06.026