Aging

BackgroundDNA methylation-based biomarkers have been widely used to predict biological age; however, most blood-derived data have been used in most existing models, and whether cheek mucosa can serve as an alternative indicator for methylation-based estimation of aging-related and clinical phenotypes is unclear. MethodsDNA methylation profiles from cheek mucosa and whole blood of 186 Japanese adults were analyzed using Illumina Infinium Methylation Screening Array (MSA). Models were constructed to predict chronological age, phenotypic age, and clinical laboratory biomarkers from cheek mucosa- and blood-derived methylation data. In addition to applying the ordinary elastic net method, a two-stage residual learning method incorporating existing blood-based epigenetic clocks was applied for more accurate prediction of biological age. Sex-stratified analyses and comparisons of selected CpG features across sexes and tissues were performed. ResultsCheek mucosa-derived MSA methylation data enabled accurate prediction of chronological age (R = 0.965) and phenotypic age (R = 0.964) using the two-stage method. The performance gain achieved by the two-stage approach was greater for phenotypic age than for chronological age. Multiple clinical laboratory biomarkers could be predicted using cheek mucosa-derived methylation data, particularly after sex stratification, including inflammatory, metabolic, thyroid-related, and sex hormone-related markers. Most biomarkers that could be predicted using blood-derived methylation data were also predicted using cheek mucosa-derived methylation data. However, the CpG sites selected for prediction showed minimal overlap across sexes and tissues despite overlap in the corresponding predictable phenotypes. ConclusionsCheek mucosa-derived DNA methylation profiles measured using the MSA can predict chronological age, phenotypic age, and multiple clinically relevant laboratory biomarkers, supporting the utility of cheek mucosa as a less invasive alternative for methylation-based assessment of biological aging and systemic physiological state.

ObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. MethodsMice with or without hepatocyte cyclin D1 (D1fl/fl or D1{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging. HighlightsO_LICyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression. C_LIO_LIAcute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1. C_LIO_LIHepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation. C_LIO_LICyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans. C_LI

Spinal fractures are an important contributor to disability worldwide, particularly in aging populations. However, comprehensive long-term comparisons between China and other major economies remain limited. Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed temporal trends in the incidence, prevalence, and years lived with disability (YLDs) of spinal fractures in China and the overall G20 from 1990 to 2021. Age-standardized rates were assessed using Joinpoint regression and age-period-cohort analysis. Future burden through 2050 was projected using autoregressive integrated moving average modeling, and decomposition analysis was performed to quantify the contributions of demographic and epidemiological factors. Between 1990 and 2021, China experienced substantial increases in absolute burden. Incident cases increased by 52.27%, prevalent cases by 113.66%, and YLDs by 107.21%. The age-standardized prevalence rate (ASPR) and age-standardized YLD rate (ASYR) increased significantly, whereas the age-standardized incidence rate (ASIR) showed a non-significant upward trend. In contrast, the overall G20 aggregate showed increasing absolute case numbers but significantly declining age-standardized rates. Age-period-cohort and age-specific analyses indicated that older adults represented the main burden-bearing population. Projections suggested that Chinas ASIR may decline by 2050, whereas prevalence and YLD burden, particularly among males, may remain relatively high compared with the overall G20 level. Decomposition analysis identified population aging as the major driver of burden growth. China experienced a rising burden of spinal fractures over the past three decades, in contrast to declining age-standardized trends in the overall G20 aggregate. These findings highlight the substantial role of population aging in shaping spinal fracture burden and provide epidemiological evidence for prevention planning and aging-related health policy.

Aging can alter macrophage functions through changes in intracellular processing, mitochondrial activity, and chronic inflammatory activation; however, whether aging-associated macrophage deregulation contributes to tumor-associated multinucleated syncytial formation remains poorly understood. Here, we investigated the role of aging macrophages in promoting tumor-like multinucleated syncytia and explored the underlying metabolic mechanisms. Immunohistochemical analyses of metastatic tissue sections from patients with prostate, breast, and lung cancers demonstrated enrichment of CD68+/panCK+ multinucleated tumor-like osteoclast syncytia in elderly patients. Using ex vivo co-culture systems, aged bone marrow-derived macrophages exhibited significantly increased propensity to generate multinucleated syncytia containing proliferative Ki67-positive cancer-associated nuclei. These syncytia displayed attenuated mitochondrial oxidative phosphorylation (OXPHOS) programs characterized by reduced oxygen consumption rates and decreased expression of mitochondrial respiratory proteins, such as ATP5a and SDHB. Pharmacologic inhibition of STAT6 further enhanced syncytial formation and suppressed OXPHOS-associated programs, whereas treatment with the EP2 antagonist C52 partially restored mitochondrial gene expression and reduced syncytial formation. Together, these findings identify a previously unrecognized aging-associated mechanism linking macrophage deregulation, attenuated STAT6-associated mitochondrial programs, and tumor-like multinucleated syncytial formation.

Our research is only as good as our tools allow it to be. The fruit fly Drosophila has been a fundamental discovery platform in uncovering evolutionarily conserved biological underpinnings of ageing, due in large part to an ever-expanding functional genetic toolbox which permits fine-tuneable and cell-type-specific modulation of gene expression with relative ease. However, many existing gene expression systems present limitations for studying fly ageing, including off-target effects for inducing agents that allow temporal control. More recently-generated tools such as the auxin-based gene expression system (AGES) therefore present opportunities as potential alternatives in our methodological repertoire for ageing research. Here we have evaluated the AGES system in a variety of contexts in Drosophila ageing. We find that AGES can effectively induce transgene expression across a range of ages, albeit with tissue-specific efficiency. However, we also observe several phenotypes from auxin feeding, even in non-AGES genotypes, that may confound studies focused on ageing research, including reduced body mass and reduced survival under starvation and oxidative stress conditions. We also observe phenotypes from activating the AGES machinery, including shortened lifespan, that could present challenges for using AGES in longevity-based studies. Nevertheless, we find that AGES can be used to recapitulate at least some effects of well-established pro-longevity interventions - for instance reduced fecundity from expression of a dominant-negative form of the insulin receptor - reinforcing the value of AGES in certain domains. Taken together, our results underscore the need for caution and comprehensive controls in ageing studies that rely on functional genetics, regardless of the chosen genetic toolset.

Background: It is well-established that males have a higher mortality risk than females. Immune cells and their function are known to undergo characteristic changes during aging, and immune cells are known to have sex differences. Immune cells and their function have been linked to mortality risk, but no studies have investigated to what degree, if at all, Immune Cell Biomarkers (ICBs) contribute to the known differences in mortality risk by sex. Methods: Using participant data from the Health and Retirement Study (n = 8,822), we applied multivariable linear regressions adjusting for age, cytomegalovirus (CMV) serostatus, sex, and race/ethnicity to identify differences by sex in 48 immune cell biomarker (ICB, e.g. T cells, B cells, Monocytes, etc.) percentages and counts (measured in 2016). We studied how the associations between ICBs and mortality risk differ by sex using stratified Cox Proportional Hazard (CPH) models. We estimated how inclusion of sex explained the relationship between ICBs and all-cause mortality, and conversely, how inclusion of individual and all ICBs combined explain the relationship between sex and all-cause mortality using multivariable modeling approaches. Results: Differences in ICBs by sex range between 2-38% (39/48 statistically significant). 9 ICBs were significantly associated with mortality risk in the entire sample. While different ICBs were significantly associated with mortality risk in the stratified analyses, particularly with respect to monocyte, B cell, and NK cell populations, adjusting for sex modestly influenced the hazard ratios of the ICBs (sex: 8 ICBs, percent change <5.4%). Furthermore, individual and cumulative contributions of ICBs in explaining the differences in mortality risk by sex were not significant.

Cellular senescence is a tumor-suppressive program characterized by irreversible growth arrest; however, senescent cells can also promote inflammation and alter the tumor microenvironment through the senescence-associated secretory phenotype (SASP). Although SASP induction is regulated by pathways such as p38/NF-{kappa}B/I{kappa}B{zeta}, the mechanisms that restrain excessive or persistent SASP remain largely unknown. Here, we investigated the role of the Ets family transcription factor EHF in SASP regulation during cellular senescence. In IMR-90 human fibroblasts undergoing oncogene-induced senescence, EHF expression was upregulated after the onset of canonical senescence phenotypes. EHF knockdown did not substantially affect senescence establishment but increased SASP-related gene expression. Conversely, overexpression of full-length EHF suppressed SASP-related gene induction during senescence, whereas an ETS-domain-deficient EHF mutant failed to do so, suggesting that this EHF-mediated SASP suppression requires its DNA-binding domain. Furthermore, knockdown of NFKBIZ, which encodes I{kappa}B{zeta} and is induced downstream of NF-{kappa}B signaling, reduced EHF expression during senescence; however, NFKBIZ overexpression increased EHF and SASP-related gene expression. These results link EHF induction to the p38/NF-{kappa}B/I{kappa}B{zeta} inflammatory axis and support a model in which the inflammatory pathway that induces SASP also engages EHF as a negative regulator of SASP. Finally, conditioned medium from senescent cells promoted HCT116 cancer cell migration, and this activity showed a further increase after EHF knockdown. These findings suggest that EHF suppresses senescence-associated inflammatory responses and may function as a senomorphic effector that attenuates SASP-related inflammation without substantially affecting senescence establishment.

BackgroundThe increase in human lifespan without a proportional increase in healthspan imposes a substantial burden on individuals and society. Exceptionally long-lived individuals and members of long-lived families exhibit compression of multi-morbidity. Genetics, and in particular rare protein-altering variants, appear to play an important role in their longevity. MethodsIn this study, we employed a targeted pathway approach to provide functional evidence of the significance of rare variants in the insulin/insulin-like growth factor 1 signalling - mechanistic target of rapamycin (IIS/mTOR) signalling pathway identified in long-lived individuals. To this end, we used CRISPR/Cas9 to introduce these rare genetic variants into mouse embryonic stem cells (mESCs). We subsequently assessed several functional readouts that have previously been associated with lifespan regulation in model organisms and/or IIS/mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathway activity. ResultsFunctional characterisation revealed that the variants exhibit both shared and distinct effects on the signalling pathways. Principal component analysis of omics-based datasets showed that the variants clustered into two groups, a distribution that corresponds with the grouping observed for a subset of functional readouts. All variant mESC lines exhibited a downregulation in IIS/mTOR and MAPK/ERK signalling pathway activity as well as an increase in Foxo3 expression and FOXO3 binding activity. We identified alterations in lipid and mitochondrial metabolism, including a reduction in mitochondrial DNA levels, which were mostly shared among all variants. All variant mESC lines exhibited a signature implying increased pluripotency. The effects on stress resistance and growth rate diverged between the two variant groups, with partially opposing effects. Group 1 demonstrated a reduced growth rate and increased resistance to a subset of stressors, while Group 2 demonstrated an increased growth rate and reduced resistance to a subset of stressors. ConclusionsHere, we provide evidence that rare genetic variants in the IIS/mTOR and MAPK/ERK signalling pathways identified in long-lived human individuals result in shared functional effects associated with longevity in model organisms. These insights can serve as a foundation to better understand the role of rare variants in the insulin signalling network in the regulation of human longevity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/728260v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1bf5ebdorg.highwire.dtl.DTLVardef@e4e5dcorg.highwire.dtl.DTLVardef@1aee276org.highwire.dtl.DTLVardef@95f170_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background Preterm birth (PTB) rates among Hispanic/Latina individuals in the United States have risen over the past decade. Data suggests this rise may be driven in part by psychosocial stress. Leukocyte telomere length (LTL), a marker of cumulative cellular aging that shortens under chronic stress, may capture stress-related biological vulnerability, but has not been examined as a potential population-level contributor to PTB in Hispanic/Latina pregnancies. Objective To examine the association between mid-pregnancy maternal LTL and PTB in a population-based Hispanic/Latina cohort. Methods In a case-control study nested within a California singleton birth cohort (n = 436 Hispanic/Latina individuals; 215 PTB, 221 term births), LTL was measured by quantitative PCR from biobank specimens collected from 15 to 20 weeks of gestation. Covariates from linked birth certificate and hospital discharge records were included. Logistic regression estimated ORs and 95% CIs of PTB by LTL examined continuously and by percentile category (<=10th, 11th-89th, >=90th) with and without adjustment for covariates. Results Mean and median LTL did not differ between PTB and term births. LTL at or below the 10th percentile was associated with elevated odds of PTB relative to full-term birth (12.6% versus 4.3%; ORc = 3.2, 95% CI 1.3-7.9), persisting after partial (ORadj1 = 3.2, 95% CI 1.3-8.3) and full covariate adjustment (ORadj2 = 3.4, 95% CI 1.3-9.3). Subgroup analyses showed consistent directional patterns across PTB subgroups and for early term birth (ORadj2 = 5.1, 95% CI 1.5-17.0). Conclusions Mid-pregnancy maternal LTL <=10th percentile was associated with more than three times the odds of PTB, with risk concentrated at the extreme low tail of the distribution. Consistent with a cumulative allostatic load model, markedly short LTL at mid-gestation may reflect elevated stress-related biological risk for preterm delivery. These findings support upstream investment in stress reduction and prospective LTL research in high-burden populations.

Autophagy is widely proposed to decline with age; however, direct evidence for this across cell and tissue types in humans remains limited. Furthermore, it remains unknown whether interventions that improve physiological health during aging can modify autophagic activity in humans. Here, we performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort spanning the adult lifespan. RNA-seq of primary dermal fibroblasts and induced neurons (iNs) revealed increased transcription of many autophagy-related genes with age, most markedly in fibroblasts. The impact of age on autophagic activity, measured using autophagy flux assays, was cell type- and sex-dependent, and uncoupled from autophagy-gene transcription. Autophagy flux decreased with age in male fibroblasts, was unchanged in female fibroblasts, and increased in female iNs. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became more heterogeneous with age and trended higher in older individuals, independent of sex. Although autophagy flux levels did not match across different cell types, higher autophagy flux in all cell types was associated with reduced physical function in older adults ([&ge;]70 years). Importantly, autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function. These findings indicate that autophagy is regulated in a cell type-, sex-and physiological function-dependent manner during human aging, and highlight PBMC autophagy flux as a potentially modifiable, blood-accessible readout of physiological state in older adults.

Total body irradiation (TBI) can impair the bone marrow (BM) microenvironment and dysregulate the fates of BM-residing cells by overproducing reactive oxygen species (ROS) and inflammatory mediators. This study aims to investigate the potency and mechanism of Deinococcus radiodurans-derived deinoxanthin (DEIX) in mitigating TBI-mediated injuries in the BM microenvironment and BM-resident cells. C57BL/6 mice were divided into control, TBI, TBI+DEIX, and/or DEIX groups, in which the mice were exposed to sub-lethal TBI (5 Gy) or in combination with oral DEIX supplementation (25 mg/kg body weight). While the DEIXs effect on BM and BM-resident cells was determined after five weeks of TBI, RNA sequence profiling on the mouse group-derived BM cells was performed after two weeks of TBI. Supplementation with DEIX protected mice against TBI-mediated decrease in bone mineral density of trabecular bones. Supplemental DEIX suppressed BM microenvironmental impairment and the induction of oxidative stress and senescence in BM cells of TBI-exposed mice. That suppression was orchestrated by the DEIX-induced restoration of TBI-stimulated disorders in osteogenic, osteoclastogenic, and adipogenic activation in the BM. Ex vivo assays using BM cells supported the notion that DEIX restores TBI-mediated defects in BM cell function, including colony formation, migration, and differentiation. RNA sequence profiling demonstrated DEIXs potency to modulate the expression of genes that regulate cellular and systemic immune responses, cell proliferation and differentiation, and bone metabolism. Collectively, our results highlight the roles and associated mechanisms of DEIX in mitigating TBI-mediated microenvironmental impairment and in regulating BM-resident cells.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women?s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] [&ge;] 2%) and large CHIP (VAF [&ge;] 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non-DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non-DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

Up to 50% of adults with colorectal cancer (CRC) are at risk of progressive involuntary loss of skeletal muscle mass and function known as cachexia. Available options to prevent and treat cachexia in cancer survivors are currently limited. Long-chain polyunsaturated fatty acids (LC-PUFAs) and their bioactive metabolites, termed specialized pro-resolving lipid mediators (SPMs), promote the resolution of inflammation and support muscle growth and repair. However, prior studies of cachexia have mainly focused on fish oil supplements, and it is not fully understood how different individual omega-3 (n-3) and omega-6 (n-6) LC-PUFAs mediate CRC-induced muscle wasting. In addition, the crosstalk between cancer cells, the host immune system, and skeletal muscle cells in response to LC-PUFA treatments remains unclear. This study aimed to examine the effects of n-3 and n-6 LC- PUFAs on CRC-induced muscle wasting and the underlying cellular and molecular mechanisms involved. Using murine C2C12 skeletal muscle cells and CT26 colorectal carcinoma cells, we investigated the impacts of LC- PUFAs including arachidonic acid (ARA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid (DPA, 22:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) on CT26-induced muscle cell wasting in the presence or absence of lipoxygenase (LOX) inhibitors such as NDGA or BLX-3887. We also examined the lipidomic profile of C2C12-CT26 co-cultures in response to individual LC-PUFA treatments. Our results suggest that LC- PUFAs including ARA, EPA, DHA, and DPA each individually protect against CRC-induced muscle cell wasting in vitro, and these protective effects are dependent on 15-LOX activity. Furthermore, we found that C2C12-CT26 co-culture produced mature SPMs in response to individual PUFA treatments. Taken together, this study suggests that individual n-3 and n-6 LC-PUFAs can mitigate CRC-associated cachexia primarily by producing 15-LOX- derived bioactive lipid mediators.

Chemotherapeutic treatment of breast cancer with Doxorubicin (DOX) can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Exposure of triple-negative breast cancer (MDA-MB-231), hormone-responsive (MCF-7) and HER2+ (MDA-MB-453) cells, and primary spine osteoblasts to DOX showed significant induction of p21-positive senescent cells. DOX and senolytics (RG-7112, o-Vanillin) treatment of co-culture spheroids showed a significant additive effect in reducing tumor sphere viability and growth, indicating reduced metastatic potential. This was correlated with reduced SASP in triple-negative and hormone responsive lines and decreased levels of senescent cells in all subtypes and primary stromal cells, while proliferation was decreased, and apoptosis increased across all breast cancer subtypes. Future chemotherapeutic treatment in breast cancer models may be optimized by adding senolytic drugs to more effectively clear senescent tumor and stromal cells, reducing risk for relapse and metastatic potential, while allowing for tissue regeneration in the bone metastatic environment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/724653v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@c4cb8forg.highwire.dtl.DTLVardef@105219org.highwire.dtl.DTLVardef@17e0517org.highwire.dtl.DTLVardef@802bd2_HPS_FORMAT_FIGEXP M_FIG C_FIG Senolytics selectively eliminate senescent cancer and stromal cells and enhance Doxorubicin efficacy in a 3D bone-like tumor microenvironment model.

Evidence from many countries shows that later life cognitive health is shaped by childhood poverty. However, whether it is associated with neurodegenerative biomarkers measured in population settings remains unclear. Methods We conducted a pooled analysis of 5,473 adults aged [&ge;]50 years from Denmark, Sweden and Germany participating in Wave 6 (2015) of the Survey of Health, Ageing and Retirement in Europe. Neurodegenerative biomarkers (neurofilament light chain, glial fibrillary acidic protein and phosphorylated tau) were assayed from dried blood spots. Childhood poverty was constructed as a latent variable from retrospective life histories. Weighted Poisson regression models estimated associations adjusting for age, sex, education, marital status and wealth in later life. Marginal predictions along age and across country were derived. Results Childhood poverty was strongly associated with higher NfL concentrations ({beta}=1.66, p<0.001), but not with GFAP or p-tau217. Predicted values indicated substantially elevated NfL among the childhood poor (10.3 pg/mL vs 2.0 pg/mL for the non-poor). Age profiles showed widening disparities: the childhood poor in midlife exhibited higher NfL levels than the oldest old who grew up not poor. No consistent differences were observed for GFAP or p-tau217. Findings were robust and similar across all three countries with different histories and health systems. Conclusions Childhood poverty is associated with markedly elevated levels of NfL in later life, suggesting long-term neuroaxonal injury consistent with life course shaping of brain health. Moreover, the evidence implies substantial acceleration of neurobiological ageing. These findings emphasise the importance of early-life interventions for brain health in ageing populations.

The VACS 2.0 Frailty Index was developed using the VA health records system to identify frailty and predict mortality in older Veterans that were living with HIV. Systemic inflammatory indices have been associated with frailty, but little is known about the association between frailty and immunosenescence. We aim to investigate the potential link between soluble inflammatory indices, T cell expression of exhaustion and senescence markers, and frailty as measured by the VACS 2.0 index. We analyzed a one-time blood draw for plasma levels of inflammatory indices, T cell subsets and expression of exhaustion and senescence markers, and calculated VACS 2.0 index scores in a cohort of 30 older (>65 years) Veteran participants. We found that VACS 2.0 scores correlated with the number of prescribed medications in the older Veterans. Soluble TNF receptor levels strongly correlated with VACS 2.0 frailty scores. How these soluble TNF receptors are generated and whether they mechanistically contribute to frailty warrants further investigation.

Autophagy is a hallmark of aging, but autophagy-related proteins have not been exclusively targeted to attenuate the progressive decline in physical function associated with aging. Here, we combined Tat-Beclin1, an autophagy agonist, and endurance training to determine whether Tat-Beclin1 enhances exercise adaptation in old male mice. Tat-Beclin1 was administered intraperitoneally (TB group, 15 mg/kg, 2x/week) as a standalone therapy, or in combination with endurance training (TB+Exe group, 70% of maximal running speed 3x/week) for 1 month in 23-month-old male C57BL/6J mice. Control groups were age-matched cage controls and exercise-only groups. Animals were assessed for grip strength, endurance capacity on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). TB+Exe led to significant increases in grip strength, endurance capacity, and balance and coordination performance beyond those observed in the TB and Exe groups alone. Autophagy markers, including Beclin1, the LC3B-II/I ratio, and p62, did not differ among groups. A proteomic analysis of the G/P muscle revealed that TB upregulated biological processes involved in muscle contraction and adaptation, whereas TB+Exe increased mitochondrial bioenergetic processes and, surprisingly, upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. We conclude that combining Tat-Beclin1 and endurance training may represent a new approach to attenuate aging-related decline in physical function. New & NoteworthyWe show evidence that combining Tat-Beclin1 and endurance training (TB+Exe) resulted in greater improvements in physical function in 24-month-old male mice than either standalone therapy. We also show that TB+Exe upregulates traditional exercise-like biological processes and unexpectedly upregulates acute-inflammatory proteins (e.g., orosomucoid-1), which are thought to improve physical function in preclinical studies. Our study suggests that TB may be a new drug enhancing physical function, especially when combined with endurance training in old male mice.

We have recently demonstrated that treatment of aged mice with a pan-ERR agonist reverses age-related increase in urinary albumin, decrease in podocyte density, impaired mitochondrial function, and inflammation. The contribution of individual isoforms of ERRs however has not been determined. Since the aging kidney showed a possible compensatory increased expression of ERR{gamma} in the podocytes, in the face of decreased ERR expression, in the present study we aimed to determine the role of ERR{gamma} in aging podocyte. To this end, we cross bred ERR{gamma} floxed mice with podocin-Cre mice to achieve a podocyte-specific ERR{gamma} deletion. While these mice at 3 months of age showed no effect on albuminuria compared to the wild type, when the mice were aged to 21 months of age, there was a significant increase in albuminuria and decrease in podocyte density. Furthermore, we found that the podocyte deletion of ERR{gamma} primarily targeted the expression of mitochondrial biogenesis regulator PGC-1, and mitochondrial fatty acid oxidation enzymes CPT1a and MCAD in the kidney. Electron Microscopy (EM) revealed thickened glomerular basement membrane and diffuse podocyte foot process effacement, as well as severe mitochondrial damage including cristae abnormalities, fragmentation, and changes indicative of altered fusion and fission dynamics. Fluorescence Lifetime Imaging Microscopy (FLIM) to determine NADH and FAD lifetimes indicate a metabolic shift from mitochondrial oxidative phosphorylation towards glycolysis, and decrease in mitochondrial redox capacity. Considering a significantly decreased expression of ERR in aging podocytes plus its traditional role in mitochondrial function, these studies using podocyte ERR{gamma} deletion suggested an overlapping mechanism for ERR/ERR{gamma} to act as modulators of age-related mitochondrial dysfunction and age-related kidney disease.

ObjectiveTo examine associations of BMI-related polygenic scores (PGSs) with BMI-for-age z-score (BMIz), height-for-age z-score (HAZ), and weight; assess sex-specific effects; and test PGS-by-diet interactions in youth experiencing the double burden of malnutrition. MethodsIn this cross-sectional study of Filipino youth aged 6-19 years, we analyzed genome-wide genotype, anthropometric, and dietary data from two 24-hour recalls. Four ancestry-standardized BMI PGSs were evaluated using linear regression adjusted for age, sex, and ancestry principal components, with platform-specific estimates combined by fixed-effects meta-analysis. ResultsAll four PGSs were positively associated with BMIz ({beta} range: 0.119 - 0.320). The strongest association was observed for the multi-ancestry score PGS005202 ({beta} = 0.320; P = 2.39 x 10-9; {Delta}R2 = 4.98%). No PGS was associated with HAZ. PGS005202 and PGS005279 were associated with higher weight independent of HAZ. A significant PGS000716-by-sex interaction was observed for BMIz (q = 0.034), with an association in boys ({beta} = 0.253; P = 0.002) but not in girls ({beta} = -0.007; P = 0.93). No PGS-by-diet interaction remained significant after multiple-testing correction. ConclusionsBMI-related PGSs were associated with adiposity-related traits, but not linear growth, in Filipino youth. Findings support sex-stratified analyses and further evaluation of ancestry-inclusive PGSs in similar pediatric settings.

ABSTRACTUlcerative colitis is a chronic inflammatory bowel disease that can progress from dysplasia to cancer. Inflammatory responses are critical drivers in this process, typically triggered by epithelial lesions and the ensuing infiltration of microbiota into the interstitial layer. Here, we focus on the pro-inflammatory state of the interstitial fibroblasts, which promotes immune infiltration and augments disease progression. The study aims to provide a mechanistic link how fibroblasts of the colitis-associated microenvironment integrate inflammatory signals, microbial infiltration and cellular memory. To this end, we investigated a large number of primary colon fibroblasts obtained from normal, colitis and colon cancer samples using a range of in vitro approaches and an in vivo co-inoculation cancer model. mRNA sequencing analysis identified that the disease-associated fibroblasts are exhibit a cellular inflammatory status, which involves the injury-induced senescence pathway. Using CXCL8, a potent chemokine upregulated in colitis and cancer colon fibroblasts, as a paradigm, this inflammatory status is triggered by the activation of the NF{kappa}B signaling via immune-derived cytokines (TNF, IL-1{beta}), bacterial signals (LPS) and the microbiome itself using mycoplasma as a paradigm. Finally, iPSC reprogramming studies indicate that fibroblasts from ulcerative colitis retain an epigenetic memory that sustains elevated CXCL8 expression. Together, our findings demonstrate that the senescence associated secretory phenotype of colon fibroblasts is a robust indicator for inflammation-driven colon tumorigenesis.