npj Aging

Background: Accelerated biological aging (BioAgeAccel) has been implicated in type II diabetes (T2D) mellitus development; however, its dynamic changes and their links to T2D incidence, mortality and glycemic traits remain unclear. Methods: Leveraging repeated measures from the UK Biobank, we first calculated two BioAgeAccel metrics (KDMAccel and PhenoAgeAccel) and derived three burdens (slope, cumulative, and relative cumulative change). We then assessed associations of BioAgeAccel transitions and these burdens with incident T2D and mortality. Secondary analyses extended the two primary outcomes by incorporating glucose, HbA1c, and six IR surrogates, which were also evaluated as potential mediators. Results: Among 13,751 included participants, 412 (3.0%) new T2D cases and 609 (4.4%) all-cause deaths were identified within a median follow-up of 9.5 years. Dynamic transition from non-accelerated to accelerated aging was markedly related to elevated T2D risk (KDMAccel: HR=1.65 [1.24~2.20]; PhenoAgeAccel: HR=1.50 [1.12~2.00]) and all-cause mortality risk (KDMAccel: HR=1.32 [1.06~1.64]; PhenoAgeAccel: HR=2.17 [1.73~2.71]). BioAgeAccel burdens demonstrated dose-response effects, with cumulative BioAgeAccel showing the greatest influence on T2D (KDMAccel: HR=1.25 [1.03~1.51]; PhenoAgeAccel: HR=1.26 [1.06~1.49]) and all-cause mortality (KDMAccel: HR=1.25 [1.07~1.47]; PhenoAgeAccel: HR=1.51 [1.31~1.74]). Similar association patterns were observed for all the eight glycemic traits. Mediation analyses revealed that these glycemic traits on average mediated 19~32% of the KDMAccel burden-T2D effect and 16~24% of the PhenoAgeAccel burden-T2D effect. Incorporating BioAgeAccel burden into FINDRISC significantly enhanced prediction accuracy, reaching up to 10.9% improvement in some specific aging transition statuses. Conclusion: Dynamic biological aging trajectories and BioAgeAccel burdens are independently related to elevated risks of T2D and all-cause mortality, partly via glycemic dysregulation, highlighting biological aging as a potential intervention target.

The nematode C. elegans has long served as a gold-standard model organism in aging research, particularly since the discovery of long-lived mutants in conserved aging pathways including daf-2 (IGF1) and age-1 (PI3K). Its short lifespan and small size make it highly suitable for high throughput experiments. While numerous molecules have been tested for their effects on C. elegans lifespan, consensus is still lacking regarding the most effective and reproducible compounds. Confounding effects, especially those related to drug-bacteria interactions, remain a contentious issue in the literature. In this study, we evaluated 16 of the most frequently reported lifespan-extending molecules in C. elegans, examining their effects on lifespan with two different diets (live and UV-killed OP50). In addition, we assessed the compounds impact on bacterial growth, their effects on various nematode strains, and the impact of the starting age of treatment. Our findings first confirmed robust lifespan extension with many, but not all, of the 16 tested compounds from the literature, and revealed that some of them could be combined to get synergistic effects. Additionally, we showed that some of these compounds also extend lifespan in the fly D. melanogaster, demonstrating a conserved effect across species. Finally, by expanding our screen to a broader pool of molecules, we identified novel lifespan-extending compounds in C. elegans.

The role of diet in aging is pivotal, yet existing research offers inconsistent findings regarding the impact of specific diets on human aging. We conducted a systematic investigation into the relationship between dietary factors and aging, exploring potential causal links between macronutrient intake and aging. Utilizing data from the UK Biobank baseline survey and a 24-hour dietary assessment survey, we employed a High-dimensional Fixed Effects (HDFE) model to examine dietary factors association with aging. Multivariable Mendelian Randomization (MVMR) and Semiparametric Nonlinear Mendelian Randomization (NLMR) techniques assessed causal links between macronutrient consumption and aging. HDFE analysis indicated that a healthier diet was generally linked to better aging outcomes, with various dietary components correlating with aging. For instance, plant-based food intake was associated with increased telomere length and/or reduced phenotypic age, while animal-based food consumption correlated with adverse aging effects. MVMR revealed the benefits of carbohydrate intake on aging, reducing phenotypic age ({beta}C=C-0.0025; 95% CI=[-0.0047, -0.0003]; p = 0.026) and increasing whole-brain grey matter volume ({beta}C=C0.0262; 95% CI=[0.007, 0.046]; p = 0.008). Overall, our study underscores diets significant role in biological aging, highlighting the potential advantages of a carbohydrate-rich diet in promoting healthy aging.

Cellular senescence plays a critical role in chronological aging and is implicated in the onset and progression of multiple age-related disorders. Targeting senescent cells represents a promising strategy to reduce disease burden and improve healthspan. Here we report the senotherapeutic properties of salvianolic acid (SA) family members, specifically A (SAA), B (SAB) and E (SAE). From a natural medicinal agent library, we identified selective cytotoxicity of these SA compounds against senescent cells across diverse senescence types and cell lineages. Mechanistically, SAA, SAB and SAE enhance ROS production and target glutathione S-transferase Pi1 (GSTP1), a redox homeostasis modulator, inducing both apoptosis and ferroptosis in senescent cells. Incorporation of SAs into chemotherapeutic regimens enhanced anticancer efficacy and prolonged post-treatment survival. Intermittent SA administration improved physical function and increased healthspan and lifespan in aged mice. Collectively, our study establishes SAs as an emerging class of natural senolytics (phenolic acids) with the capacity to delay aging and alleviate age-related pathologies in advanced life.

Cognitive decline, particularly Alzheimers disease, represents a significant global health concern. While traditional risk factors are well documented, an evolutionary perspective grounded in life history theory offers critical insights into the intergenerational dynamics influencing cognitive aging. This study empirically analyzed the relationship between reproductive history and late-life cognitive performance in women, as measured by the Montreal Cognitive Assessment Colombian version (MOCA-Col). Specifically, we examined the moderating role of the number of grandchildren on the association between parity and cognitive performance. Using an observational, cross-sectional design with a sample of 145 women (mean age = 69.9 years), a cumulative ordinal logistic regression model was fitted to MOCA-Col scores, incorporating age and the interaction between the standardized number of children and grandchildren. A higher number of children was significantly associated with lower odds of being in a better cognitive category ({beta} = -0.869, SE = 0.305, p = 0.0104, OR = 0.42). Crucially, a significant positive interaction between number of children and number of grandchildren was observed ({beta} = 0.354, SE = 0.093, p < 0.001, OR = 1.42), indicating that the negative association between parity and cognition progressively attenuated as the number of grandchildren increased. This evidence supports human life history models and the grandmother hypothesis, suggesting that intergenerational investment may mitigate the cumulative biological costs of reproduction. The findings reflect an evolutionary trade-off between early reproductive effort and later somatic maintenance.

The process of aging increases the risk of developing age-related diseases, which come at great societal healthcare costs and suffering to individuals. Meanwhile, targeting the basic mechanisms of aging can reduce the risk of developing age-related diseases during aging, essentially resulting in a healthy aging process. Multiple aging pathways exist, which over past decades have systematically been confirmed through gene knockout or overexpression studies in mammals and the ability to increase healthy lifespan. In this work, we perform transcriptome-based drug screening to identify small molecules that mimic the transcriptional profiles of long-lived genetic interventions in mammals. We identify one small molecule whose transcriptional effects mimic diverse known genetic longevity interventions: compound 60 (Cmpd60), which is a selective inhibitor of histone deacetylase 1 (HDAC1) and 2 (HDAC2). In line with this, in a battery of molecular, phenotypic, and bioinformatic analyses, in multiple disease cell and animal models, we find that Cmpd60 treatment rejuvenates multiple organ systems. These included the kidney, brain, and heart. In renal aging, Cmpd60 reduced partial epithelial-mesenchymal transition (EMT) in vitro and decreased fibrosis in vivo. For the aging brain, Cmpd60 reduced dementia-related gene expression in vivo, effects that were recapitulated when treating the APPSWE-1349 Alzheimer mouse. In cardiac aging, Cmpd60 treatment activated favorable developmental gene expression in vivo and in line with this, improved ventricular cardiomyocyte contraction and relaxation in a cell model of cardiac hypertrophy. Our work establishes that a systemic, two-week treatment with an HDAC1/2 inhibitor serves as a multi-tissue, healthy aging intervention in mammals. This holds potential for translation towards therapeutics that promote healthy aging in humans.

BackgroundThe potential factors beyond HbA1c that increase the risk of cardiovascular disease and age more quickly in people with diabetes are not yet clear. This study sought to determine the prospective associations between discrepancies in observed and predicted HbA1c levels, also known as the hemoglobin glycation index (HGI), and cardiovascular disease risk. Additionally, the interactions of HGI with accelerated aging in relation to cardiovascular disease risk were evaluated. MethodThis cross-sectional study included 9167 adults from the National Health and Nutrition Examination Survey 1999-2010. The HGI is used to assess individual blood glucose variability, and phenotypic age acceleration is employed to evaluate accelerated aging. Regression analysis, restricted cubic spline and mediation analysis explore the potential roles of phenotypic age acceleration in the relationship between HGI and CVD mortality. ResultsAmong the 9167 eligible participants (aged 20 years or older), 4390 (47.9%) were males, and the median (IQR) age was 48.0 (15.0) years; 4403 (48.0%) had prediabetes and diabetes, and 985 (10.7%) had cardiovascular disease. Restricted cubic splines showed that the association between HGI and CVD risk was nonlinear (p < 0.001). The greater the negative value of the HGI was, the greater the risk of CVD, and the association was independent of age, sex and HbA1c. Mediation analyses confirmed that phenotypic age acceleration acted as a mediator in the association between HGI and CVD risk (mediated effect: OR, 68.7%, 95% CI: 36.4%-153%, P=0.002). Conclusion and RelevanceThe HGI serves as a robust biomarker for assessing the acceleration of aging, regardless of HbA1c levels, and is associated with increased susceptibility to cardiovascular disease, particularly among individuals characterized by negative HGI.

BackgroundErgothioneine (ergothioneine) is a naturally occurring antioxidant with emerging evidence supporting its role in cellular protection and anti-aging. However, clinical data on its cosmetic benefits remain limited. ObjectiveTo evaluate the effects of daily oral supplementation with DR.ERGO(R) ergothioneine capsules on skin condition in healthy women reporting signs of skin aging. MethodsIn this 8-week, randomized, double-blind, placebo-controlled trial, 66 women aged 35-59 years were assigned to receive either DR.ERGO(R) ergothioneine (30 mg/day) or placebo. Skin parameters including melanin index, erythema index, glossiness, elasticity (R2, R5, R7), spot count, wrinkle count were evaluated at baseline, 4 weeks, and 8 weeks. ResultsCompared to placebo, the DR.ERGO(R) ergothioneine group showed significantly greater improvements in melanin and erythema reduction, skin glossiness, elasticity, and wrinkle and spot reduction (all p < 0.01). No adverse events were reported. ConclusionContinuous oral intake of DR.ERGO(R) ergothioneine significantly improved skin aging parameters, with excellent safety and tolerability. These findings suggest DR.ERGO(R) ergothioneine may serve as an effective oral anti-aging agent.

BackgroundDNA methylation plays a key role in mediating the anti-aging effects of glucose-lowering drugs. This study aims to systematically explore the potential anti-aging effects of target genes of FDA-approved glucose-lowering drugs and the underlying epigenetic mediators. MethodWe conducted a two-sample Mendelian randomization (MR) study to investigate the putative causal relationships between the gene expression levels of glucose-lowering drug targets and 10 aging-related phenotypes, followed by a two-step MR to estimate the mediation effect of DNA methylation. Drug candidates were selected according to the latest review of clinical drug use for type 2 diabetes, and their target genes were obtained from the DGIdb database. Tissue-specific cis-expression quantitative trait loci (eQTLs) from GTEx consortium were selected as genetic instruments to proxy the expression level of drug-target genes. Glycemic phenotypes were used as positive controls to validate the instruments. The cis- and trans-methylation QTLs of Cytosine-phosphate-Guanine sites near the drug target genes were obtained from GoDMC consortium. Additionally, we performed enrichment analyses focused on tissue specificity and aging pathways to further corroborate our findings. ResultsWe obtained 194 target genes interacted with 36 FDA-approved anti-diabetic drugs, of which the tissue-specific eQTLs were used to proxy the drug target effects. MR showed strong evidence that 9 interacting genes of 6 glucose-lowering drugs showed anti-aging potential on one or more aging-related phenotypes mediated by DNA methylation: EHMT2, HSPA4, IGF2BP2, IRS1, LPL, NDUFAF1, NDUFS3, SLC22A3 and TCF7L2. These genes were distributed in 17 tissues, especially in the central nervous system, suggesting a potential neural component in their anti-aging effects. For instance, expression of EHMT2 in several brain basal ganglia regions, which the gene interacted with Tolazamide, showed a protective effect on frailty (odds ratio[OR] in caudate =1.02, 95%CI=1.01-1.04, FDR adjusted P=1.69x10-2; OR in putamen=1.02, 95%CI=1.01-1.03, PFDR=3.37x10-2, OR in nucleus accumbens=1.02, 95%CI=1.01-1.04, PFDR=3.37x10-2). These associations were externally validated by searching literature evidence in existing EWAS and TWAS studies, as well as evidence from enrichment analyses. ConclusionsThis study prioritizes nine glucose-lowering genes as anti-aging drug targets in specific tissues and prioritizes their epigenetic regulation through DNA methylation for future drug development.

Calorie restriction (CR) slows aging and increases healthy lifespan in model organisms. We tested if CR slowed biological aging in humans using DNA methylation analysis of blood samples from N=197 participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) randomized controlled trial. We quantified CR effects on biological aging by comparing change scores for six epigenetic-clock and Pace-of-Aging measures between n=128 CR-group and n=69 ad-libitum-control-group participants at 12- and 24-month follow-ups. CR effects were strongest for DunedinPACE Pace of Aging (12-month Cohens d=0.3; 24-month Cohens d=0.2, p<0.01 for both), followed by DunedinPoAm and the GrimAge epigenetic clock, although effects for these measures were not statistically different from zero (p>0.08). CR effects for other epigenetic clocks were in the opposite direction (all p>0.15). CALERIE intervention slowed Pace of Aging but showed minimal effect on epigenetic clocks hypothesized to reflect longer term accumulation of aging burden.

Aging triggers physiological changes in organisms, which are tightly interlinked to metabolic changes. Senolytics are being developed. However, metabolic responses to natural senescence and the molecular intricacies of how senolytics confer antiaging benefits remain enigmatic. We performed a metabolomics study on natural senescence based on the C.elegans model. The results suggest that age-dependent metabolic changes of natural aging occur in C. elegans. Betaine was identified as a crucial metabolite in the natural aging process. To explore the common pathway coregulated by different senolytics prolonging nematodes lifespan, we fed nematodes three antiaging drugs metformin, quercetin, and minocycline. Our data show that the coregulated metabolic pathways associated with aging include the forkhead box transcription factor (FoxO), p38-mitogen-activated protein kinase (MAPK) and the target of rapamycin (mTOR) signaling pathway, etc. Three antiaging drugs raised betaine levels, consistent with high betaine levels in the younger nematode. Supplement of betaine prolonged the lifespan of nematodes via stimulating autophagy and improving antioxidant capacity. Altogether, our data support proof-of-concept evidence that betaine at appropriate concentrations can extend the lifespan of nematodes.

Atherosclerosis (AS) is a chronic inflammatory disease closely linked to vascular senescence, yet the specific molecular mechanisms connecting aging processes to AS pathogenesis remain incompletely understood. This study integrated transcriptomic data from GEO datasets (GSE100927 and GSE43292) to identify vascular aging-related differentially expressed genes (VARDEGs). Following batch effect correction, 28 VARDEGs were screened and subjected to functional enrichment, protein-protein interaction (PPI) network analysis, and immune infiltration assessment. Seven hub genes (MMP9, APOE, TNF, ICAM1, PPARG, CYBA, and NCF2) were identified and experimentally validated via qRT-PCR, confirming their significant upregulation in AS samples. Receiver operating characteristic (ROC) analysis demonstrated high diagnostic accuracy for six of these genes (AUC > 0.7), with TNF exhibiting superior performance. Immune infiltration analysis revealed profound alterations in 28 immune cell types, particularly monocytes and T cells, which correlated strongly with hub gene expression. Furthermore, single-cell RNA sequencing analysis (GSE184073) localized the expression of core genes predominantly to monocytes and T cells, highlighting TNF overexpression in T cells as a potential critical driver. Finally, molecular docking simulations suggested that curcumin exhibits strong binding affinity to these hub genes, particularly PPARG, providing a mechanistic basis for its therapeutic potential. Collectively, this study elucidates the landscape of vascular aging-related genes in AS, identifies novel diagnostic biomarkers, and proposes potential therapeutic targets involving immune modulation and natural compounds.

BackgroundPrediabetes is a disorder that affects the metabolic function of the body, and it can lead to heart disease, stroke, and type 2 diabetes (T2D). Previous studies have reported a correlation between T2D and exacerbated senescence, however, none have reported a link between prediabetes and senescence. Hence, this systematic review protocol and meta-analysis will be the first, to the best of our knowledge, to provide detailed guidance on all steps taken in the synthesis and meta-analysis of data reporting the correlation of prediabetes with senescence by identifying changes to biological aging indices. Methods and analysisThe PRISMA 2015 reporting protocol preparation standards were followed in the creation of this protocol. The search for pertinent studies will be undertaken by the framework for Arksey and OMalley reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-ScR). Clinical studies published in English from January 2003 to March 2023 with observational methods will be used, including cross-sectional, comparative cross-sectional, case-control, and cohort study designs with normal/non-diabetic, prediabetic, and type 2 diabetic cases reporting on senescence and changes in blood-based biomarker levels in a multi-ethnic population aged 25-45 years. An extensive search of relevant studies will be conducted in the following databases: PubMed, Google Scholar, Cochrane Library, ScienceDirect, Web of Science, Scopus, WHO Global Health Library, and African Journals Online. In addition, all the results will be examined for eligibility by two reviewers (NAM, NCM). Any differences between the two authors will be settled by a third reviewer (GAM), to ensure the overall quality of the findings. To find additional relevant studies, authors will also look through reference lists, grey literature sources, and peer-reviewed journals. The risk of bias will be examined using the Downs and Black checklist. To assess statistical heterogeneity of the studies, a standard chi-square test will be used with a significance level of P 0.10 indicating that there is no true heterogeneity between the studies. For the meta-analysis and to analyse the sensitivity of the data, Review Manager (RevMan) software (version 5.4) will be used to populate forest plots that will display the effect estimates and confidence intervals from each study. The strength of the evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results and ConclusionThis protocol aims to provide guidance on how to investigate articles that reported on the correlation of prediabetes with exacerbated senescence by identifying common pathways utilized and changes induced to biomarkers of biological aging. The results from this protocol will highlight research gaps in the impact of prediabetes on aging and provide suggestions for future research. In addition, it will provide evidence-based information to give guidance to policymakers on treatment decisions to improve patient outcomes. Ethics and DisseminationNo ethical approval is required as the data under consideration have already been published and no additional data will be requested from participants. The results of this review will be disseminated through a peer-reviewed publication and presented at pertinent conferences. Registration DetailsThe International Prospective Registry of Systematic Reviews (PROSPERO) has been used to register this protocol, registration number (CRD42023407084) dated 05/04/2023.

AD pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and help ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC can significantly penetrate the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. Additionally, we discovered that the treated mices hippocampus had a significantly lower amyloid beta load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/654834v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1176bbforg.highwire.dtl.DTLVardef@a2e2cdorg.highwire.dtl.DTLVardef@1d824f5org.highwire.dtl.DTLVardef@1628a30_HPS_FORMAT_FIGEXP M_FIG This illustration was created by using biorender.com C_FIG

Aging is one of the primary drivers for the decline of female fertility, and oocyte quality is the main cause for ovary aging, which is related with infertility. Although some effective anti-aging natural components have been reported, highly efficient strategies for reversing ovary aging remain lacking. In this study, we reported that peptide elamipretide reserved ovary function for female fertility during maternal aging. Our findings demonstrated that elamipretide improved aged human oocyte maturation and fertilization. Elamipretide injection increased the litter size of aged mice, and improved oocyte quality with the reverse of follicle and embryo development defect. Metabolomic and transcriptomic analyses demonstrated that multiple biological processes in oocytes were significantly reserved. Both nuclear maturation and cytoplasmic maturation of aged oocytes were improved, showing with enhancing cytoskeletal dynamics, mitochondrial metabolism and organelle rearrangement. In vitro supplementation during culture also restored oocyte developmental competence in both mouse and porcine oocytes. Mechanistic analysis suggested that elamipretide reversed age-related ovarian damage via synergistic activation of the Vitamin B6-VEGF axis. Therefore, our study proposed a new peptide therapy for aging-induced infertility, showing that elamipretide reverses aged oocyte quality for fertility by promoting both nuclear and cytoplasmic maturation through the coordination with VEGF signaling pathway.

Growth and aging are fundamental features of animal life. The march from fertilization to oblivion comes in enormous variety: days and hundreds of cells for nematodes, decades and trillions of cells for humans.1-4 Since Verhulst (18385) proposed the Logistic Equation - exponential growth with a countervailing linear decline in rate - biologists have searched for ever better density-dependent growth equations,6-12 none of which accurately capture the relationship between size and time for real animals.13-15 Furthermore, while growth and aging run in parallel, whether the relationship is causal has yet to be determined. Similarly unknown has been the reason behind the exponential Force of Mortality, described by Gompertz in 1825 for all-cause mortality16 and reported by Levin et al. in 2020 for COVID-19.17 Here we report that examination in units of numbers of cells, N, Cellular Phylodynamic Analysis,6 reveals that growth, lifespan, and mortality, are linked to the reduction in the fraction of cells dividing, occurring by a simple expression, the Universal Mitotic Fraction Equation. Lifespan is correlated with an age when fewer than one-in-a-thousand cells are dividing, quantifying the long-appreciated mechanism of aging, the failure of cells to be rejuvenated by dilution with new materials made and DNA repaired at mitosis.29-31 These observations provide practical mathematical tools for comprehending and managing the challenges of growth and aging, for such tasks as deciphering COVID-19 lethality and its amelioration by vaccination.

Aging is a complex, multifactorial process driven by various cellular and molecular mechanisms, including telomere shortening, oxidative stress, and the decline of proteostasis, all of which contribute to replicative senescence and age-related diseases. Cycloastragenol (CA), a triterpenoid saponin derived from Astragalus membranaceus, has shown potential for its ability to activate telomerase, suggesting therapeutic benefits in delaying cellular aging. In this study, we explored the effects of novel CA derivatives, obtained through biotransformation as telomerase activators, on the NRF2/proteasome/telomerase axis and their potential to delay replicative senescence in human primary epidermal keratinocytes (HEKn). Our findings reveal that these CA derivatives significantly enhance NRF2 nuclear activity, leading to the upregulation of key cytoprotective enzymes essential for mitigating oxidative stress. Notably, these derivatives exhibited efficacy at much lower concentrations compared to CA, demonstrating their potential for enhanced therapeutic application. The derivatives also markedly increased proteasome activity, particularly in the {beta}1 and {beta}5 subunits, thereby preserving proteostasis--a critical factor in preventing the accumulation of damaged proteins associated with aging. Furthermore, continuous treatment with these derivatives sustained stimulatory effects, which was evidenced by increased NRF2, proteasome, and hTERT protein levels even in senescent cells and extended cellular lifespan. Additionally, we explored the impact of CA derivatives on p53-mediated pathways, demonstrating that these compounds effectively modulate the p53/p21 axis, reducing cell cycle arrest and promoting cellular proliferation. Moreover, the derivatives exhibited neuroprotective properties by attenuating glutamate-induced excitotoxicity, further underscoring their potential as multi-targeted anti-aging agents. In conclusion, our study provides strong evidence that novel CA derivatives act on multiple fronts to enhance NRF2 activity, maintain proteostasis, and modulate telomerase and p53 pathways, most at lower doses compared to CA. These actions collectively contribute to the delay of replicative senescence and the promotion of cellular longevity, positioning CA derivatives as potent candidates for developing multi-targeted anti-aging therapies that address the complex interplay of aging-related cellular processes. HighlightsO_LITelomerase-active CA derivatives enhance NRF2 activity and proteasome activity, leading to cytoprotection at lower doses than CA. C_LIO_LICA derivatives modulate the p53 pathway and cell cycle, prolonging cellular lifespan and delaying replicative senescence. C_LIO_LICA derivatives protect cells against glutamate-excitotoxicity along with decreased p53 protein levels. C_LI

Olshansky and collaborators have recently proposed that the era of continuous extension of human lifespans has finally come to an end1. By analysing thirty years of recent demographic data (1990-2020) from ten populations (the eight longest-lived nations, plus Hong Kong and the USA), they rejected the claims made by Oeppen and Vaupel at the start of the century2 (and more recently by Vaupel and collaborators3) that human longevity was still far from approaching an upper limit. However, on closer examination the results by Olshansky and colleagues seem to complement rather than directly challenge the radical life extension hypothesis. The reason is that the latter was based not on country-level demographic patterns but instead on a best-practice life expectancy trend resulting from the succession of annual world-leading populations. Here we present an update based on data from the last two decades that confirms Oeppen and Vaupels original insights and demonstrates that both female and male lifespans continue to linearly increase at a global scale. This remarkably long trend observed since 1840 remains at odds with our expectation that human lifespans must at some point hit a biologically imposed ceiling.

Epidemiological studies have revealed that the elderly and those with co-morbidities are most susceptible to COVID-19. To understand the genetic link between aging and the risk of COVID-19, we conducted a multi-instrument Mendelian randomization analysis and found that the genetic variation that leads to a longer lifespan is significantly associated with a lower risk of COVID-19 infection. The odds ratio is 0.32 (95% CI: 0.18 to 0.57; P = 1.3 x 10-4) per additional 10 years of life, and 0.62 (95% CI: 0.51 to 0.77; P = 7.2 x 10-6) per unit higher log odds of surviving to the 90th percentile age. On the other hand, there was no association between COVID-19 susceptibility and healthspan (the lifespan free of the top seven age-related morbidities). To examine the relationship at the phenotypic level, we applied various biological aging clock models and detected an association between the biological age acceleration and future incidence and severity of COVID-19 infection for all subjects as well as for the individuals free of chronic disease. Biological age acceleration was also significantly associated with the risk of death in COVID-19 patients. Our findings suggest a causal relationship between aging and COVID-19, defined by genetic variance, the rate of aging, and the burden of chronic diseases.

Background: The role of biological age acceleration (BioAgeAccel) in the dynamic progression from single cardiovascular-kidney-metabolic disease (CKMD) to multimorbidity, and subsequently to dementia and mortality remains elusive. Methods: We conducted a longitudinal study with data of 433,911 UK Biobank participants. Cardiovascular-kidney-metabolic multimorbidity (CKMM) was defined as the coexistence of two or more CKMDs, including cardiovascular disease (CVD), stroke, type 2 diabetes (T2D), and chronic kidney disease. Biological aging was measured via PhenoAge and KDM-BA. Multistate models examined the association between BioAgeAccel and disease transitions, ranging from healthy to the first occurrence of CKMD (FCKMD), then progression to CKMM, dementia, and mortality. Restricted mean survival time estimated the disease transition time or life expectancy between states. Results: BioAgeAccel was significantly associated with increased risks across all disease transitions. Specifically, during CKMM progression, the hazard ratios (HRs) of the transition from healthy to FCKMD were 1.24 [95%CI 1.23-1.25] for PhenoAgeAccel and 1.16 [1.15-1.17] for KDM-BA-Accel. For subsequent transition to CKMM, the HRs were 1.20 [1.18-1.22] and 1.19 [1.17-1.21], respectively. In dementia-related transitions, PhenoAgeAccel showed the higher risk for CKMM to dementia (HR=1.13 [1.04-1.22]) than for the transition from healthy or from FCKMD to dementia. These associations were further moderated by age, physical activity, educational, and lifestyle factors. BioAgeAccel also accelerated disease progression and reduced life expectancy; for example, during CKMM progression, BioAgeAccel shortened the time between disease transitions by about 1.09 years from healthy to FCKMD, and an additional 1.75 years to CKMM. Regarding life expectancy, individuals with CKMM experienced an average reduction of about 1.36 years under PhenoAge, while those with dementia showed a decrease of about 0.77 years. Among individuals with CVD or T2D as the initial diagnosis, the impact of BioAgeAccel on progression to CKMM or dementia was stronger. Conclusions: BioAgeAccel exerts significant promotive role in the onset of CKMD and their subsequent progression to CKMM, dementia, and mortality, helping identify high-risk individuals. Implementing biological age assessments and health lifestyle interventions in middle-aged populations serves as an effective strategy for alleviating the burden of CKMDs and dementia.