The Journals of Gerontology: Series A

In both mice and humans the misexpression of many genes lacking CpG islands (CGI- genes) increases with age, promoting inflammation and degenerative changes (Lee et al. 2021, ref. 1). In light of this recent discovery, we have revisited and expanded upon our previous work on gene expressions vs. aging and mortality in the three-generation CEPH (Centre dEtudes du Polymorphisme Humain) Utah (CEU) families (Kerber et al. 2009, ref. 2). That study examined gene expressions in lymphoblastoid cell lines (LCLs) established in the early 1980s from all three CEU generations, in relation to age at blood draw, and in relation to the long-term survival of the grandparent generation. The 2009 study did not, however, consider the CGI status of genes, and it excluded from analysis genes not expressed in all of the subjects; therefore, the contribution to variation in age-at-death of inter-individual variation in the misexpression of genes with increasing age was not investigated. For the current study, after categorizing genes by their CGI status (- or +), we now find that most CGI- gene expressions in the LCLs increased with donor age, and after adjustment for donor age and sex, were positively associated with mortality risks. In contrast, most CGI+ gene expressions decreased with donor age, with higher expressions associated with decreased mortality risks. Of 7025 genes with known CGI status with expression detected in sufficient numbers of subjects from the grandparent generation to allow testing of association with mortality, 1834 genes were expressed in all subjects LCLs across all three generations, and 5191 were expressed in some, but not all subjects. We found the set of "not always expressed" genes to be highly enriched for CGI- genes. Furthermore, 49.4% of the CGI- genes were never expressed from ages 0-14, but expressed sometimes or always at older ages; in contrast, only 22.3% of the CGI+ genes were never expressed from ages 0-14, but expressed at older ages. These data support the model proposed by Lee et al. 2021, whereby tissue-restricted CGI- gene expressions become increasingly misexpressed during aging, contributing to loss of cellular identity, multiple aging-related pathologies, and ultimately death.

BackgroundThe brain-body energy-conservation model proposes that signals from metabolically active senescent cells, including growth differentiation factor 15 (GDF15), prompt the brain to downregulate systemic energy expenditure, leading to functional decline. However, large-scale human studies testing this hypothesis are lacking. We examined whether circulating GDF15 is associated with physiological and cognitive ageing phenotypes and whether it mediates the relationship between psychological stress and muscle strength. MethodsWe analyzed data from the UK Biobank, a prospective cohort of over 500,000 adults. Circulating GDF15 concentrations were measured using Olink proteomics. Outcomes included insulin resistance (TG/HDL-C ratio), maximum heart rate during fitness testing, hand grip strength, C-reactive protein, telomere length, fluid intelligence, and physical activity. Psychological stress was assessed via self-report. Associations were evaluated using multivariate linear regression adjusting for age and sex. Mediation analysis tested whether GDF15 mediated the association between stress and grip strength. ResultsHigher GDF15 was significantly associated with reduced grip strength ({beta} = -0.180, p < 0.001), higher insulin resistance, lower maximum heart rate, higher C-reactive protein, shorter telomere length, diminished fluid intelligence, and reduced physical activity (all p < 0.001). Mediation analysis demonstrated that GDF15 partially mediated the association between psychological stress and grip strength (indirect effect = -0.053, 95% CI -0.074 to -0.033). ConclusionThese findings support the brain-body energy-conservation model, suggesting that GDF15 serves as a systemic signal linking psychological and cellular stress to declines in physiological and cognitive function. Targeting GDF15 pathways may represent a novel strategy to mitigate stress-related ageing processes. Graphical Abstract CaptionChronic psychological stress increases circulating GDF15, which signals the brain and contributes to systemic ageing phenotypes including reduced muscle strength, lower maximum heart rate, shorter telomere length, higher insulin resistance, and decreased physical activity. Mediation analysis in the UK Biobank (N = 500,000) demonstrated that GDF15 partially mediates the association between stress and reduced muscle strength, supporting the brain-body energy-conservation model. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/25330886v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1294813org.highwire.dtl.DTLVardef@13aef95org.highwire.dtl.DTLVardef@473fa1org.highwire.dtl.DTLVardef@1a27edd_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundAgeing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and AnalysisThis trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70+. Participants will be randomised to one of three arms (Metformin MR 1500mg, Fisetin 100mg or Spermidine 15mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-{beta}-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and DisseminationEthical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial RegistrationREPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839. Trial Registration Data Set O_TBL View this table: org.highwire.dtl.DTLVardef@1db6074org.highwire.dtl.DTLVardef@1997837org.highwire.dtl.DTLVardef@a39a11org.highwire.dtl.DTLVardef@d7e6eforg.highwire.dtl.DTLVardef@7a5b7f_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1C_FLOATNO O_TABLECAPTIONTrial Registration Data Set C_TABLECAPTION C_TBL

With no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2x10-6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.

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.

Mitochondrial diseases (MDs) are caused by variants in the mitochondrial (mtDNA) or nuclear (nDNA) genome and encompass a diverse disease spectrum, whilst mitochondrial dysfunction more broadly is implicated in aging and neurodegeneration, with distinct and overlapping phenotypic features. Recent population genomic studies reveal pathogenic MD variation to be common in the population and somatic mtDNA variants accumulate from the seventh decade. Cumulative burden of mtDNA variation, quantified using mitochondrial genome constraint measures, may mediate mitochondrial dysfunction generally. However, the clinical relevance of incidentally identified variation for MDs, and of mitochondrial constraint measures for aging and neurodegeneration, is unclear. We have quantified pathogenic mtDNA and nDNA variation, as well as measures of mitochondrial genome constraint in the Medical Genome Reference Bank (MGRB), a cohort of healthy older individuals. We evaluated association of identified pathogenic MD variants with clinical features relevant to MD across four domains including physical function, cognitive function, endocrine-metabolic function and mood. Associations of mitochondrial genome constraint with clinical measures of aging and neurodegeneration were also explored. No significant associations between MD variants and phenotypes were identified, although surprisingly, mood measures appeared healthier for variant carriers compared to non-carriers. Summed mtDNA constraint showed significant inverse association with blood pressure and a trend toward inverse association with physical function. Measures of cognitive function did not demonstrate association with summed or mean mitochondrial genome constraint. Pathogenic MD variants are relatively common in the population and may be carried through to old age in good health, emphasising the importance of clinical context for counselling. Mitochondrial genome constraint measures warrant further evaluation as a surrogate biomarker for mitochondrial genome quality and mitochondrial dysfunction.

IntroductionThe disproportionate increase in lifespan compared to health span over the past decades results in a growing proportion of life marked by diseases, even if incidence rates are falling in some cases. However, not everyone ages at the same pace and some people remain in good health and preserve physical and cognitive function into old age. To quantify inter-individual differences in the biological aging process, numerous indicators of biological age have been developed. While these markers have often been validated individually, comparisons in the same people are scarce, complicating their evaluation and translation into clinical practice. MethodsIn this study, we analyzed 16 measures of biological aging including epigenetic clocks, proteomics clock, telomere length, and SkinAge, laboratory composite markers (BioAge, Allostatic Load), psychological aging, and Brain Age. These age markers were evaluated cross-sectionally as well as longitudinally in the context of age-associated outcomes covering frailty, mobility, cognitive function, depressive symptoms, autonomy in daily life, nutrition, morbidity, and chronic disease in participants of the Berlin Aging Study II (BASE-II). ResultsLongitudinal data was available for 1,083 participants with a mean age of 68.3 years at baseline (52% women) and an average follow-up period of 7.4 years. Correlation among markers of aging from different domains was low (r[&le;]0.31). Allostatic Load Index and DunedinPACE showed the strongest and most consistent cross-sectional and longitudinal associations with age-associated phenotypes, including morbidity, cardiovascular health, and frailty. Both biomarkers individually increased the accuracy of a logistic regression model trained to predict incident cases of Metabolic Syndrome, high cardiovascular risk (Lifess Simple 7) as well as incident frailty (Frieds frailty index) 7.4 years after baseline examination by up to 24 percentage points. ConclusionOur findings support the previously shown distinction between indicators of aging and provide a comprehensive overview of their individual strengths and weaknesses in the context of wide variety of age-associated phenotypes. Furthermore, we show their distinct ability to predict aging-related adverse outcomes and suggest a potential use-case in longitudinal prediction modelling.

The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (ds = -1.82 to -1.28, Ps < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = -0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = -1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = -0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (ds = -2.30 to -1.32, Ps < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HRs = 2.92 to 3.03, Ps < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.

Background: Mitochondrial dysfunction is a hallmark of ageing and is implicated in the pathogenesis of sarcopenia. Genetically confirmed mitochondrial disease provides a biologically definitive model of impaired oxidative phosphorylation against which novel functional assessments can be validated. We investigated whether a brief, submaximal, non-ischaemic intermittent isometric handgrip exercise protocol combined with Near Infra-Red Spectroscopy (NIRS) could detect distinct muscle oxygenation signatures in mitochondrial disease and sarcopenia. Methods: Adults with genetically confirmed mitochondrial disease (n=10, 7 female) and group-matched controls (n=19, 11 female), underwent assessment of maximal grip force, handgrip relaxation kinetics and a 3-minute intermittent submaximal isometric handgrip test (40% maximal voluntary contraction, 1Hz contraction/relaxation) with continuous force recording at 2000Hz and simultaneous NIRS. Findings were compared with 23 community-dwelling older adults from the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse cohort (n=23, 13 female) including seven with probable or confirmed sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Results: Participants with mitochondrial disease demonstrated an attenuated reduction in tissue saturation index (TSI) during exercise compared with controls (TSI % {middle dot} s150-180s: -59.9 {+/-} 94.5 vs -175.1 {+/-} 128.4; p=0.02). Total haemoglobin (THb) responses did not differ between groups (p=0.10). In contrast, participants with probable or confirmed sarcopenia showed exaggerated reduction in TSI compared with non-sarcopenic participants (TSI % {middle dot} s150-180s: -256.5 {+/-} 146.0 vs -121.2 {+/-} 95.2; p=0.05), while THb responses remained similar. The association between sarcopenia and TSI differed by sex (interaction coefficient -240, p=0.016), with greater TSI reductions observed in males with sarcopenia. Differences in TSI between mitochondrial disease and control groups were independent of age and sex. No statistically significant associations were observed between THb responses and age, sex or force production. Conclusions: A brief, non-ischaemic handgrip exercise protocol combined with NIRS identified divergent muscle oxygenation responses in mitochondrial disease and sarcopenia. The attenuated TSI response observed in genetically confirmed mitochondrial disease is consistent with impaired oxygen utilisation secondary to defective oxidative phosphorylation, whereas the exaggerated TSI reduction observed in sarcopenia suggests a distinct physiological mechanism, potentially involving impaired oxygen delivery, reduced muscle efficiency, or both. This portable and non-invasive approach has significant potential as a physiological biomarker for mechanistic studies and clinical trials in ageing and neuromuscular disease. More broadly, our findings demonstrate how biologically defined rare diseases can provide a powerful framework for interpreting mechanisms in common heterogeneous age-related conditions.

BackgroundSex-specific immune responses may contribute to variable vulnerability for Covid-19 between females and males. We tested whether there is a long-term mortality difference between sexes for other microbes (viral and bacterial) response burden among older people. MethodsSeven-year follow-up study consisted of 382 home-dwelling people aged 75-90 years (65.2% females) with a history cardiovascular disease. At baseline, serum immunoglobulin G antibodies were assayed against herpesviruses (CMV, HSV-1 and HSV-2) and bacteria (Chlamydophila pneumoniae, Mycoplasma pneumonia, and Helicobacter pylori). Titers were summed up as herpes (HB) or bacterial response burden (BB) and divided into tertiles. Hazard ratios (HR) of total mortality with 95% CIs were calculated using Cox regression. ResultsThe overall HB was lower and BB higher among males than females (P<0.001). There was a significant sex/HB (P=0.01) and sex/BB (P=0.03) interaction with mortality. Multivariable-adjusted (age, body mass index, C-reactive protein, and comorbidity index) mortality HRs for increasing HB sex-specific tertiles were 1.0 (reference), 1.34 (95% CI 0.62-2.88), and 2.66 (1.25-5.64) for males and 1.0, 1.30 (0.76-2.21), and 1.30 (0.77-2.22) for females. The significant age-adjusted association between BB and mortality in males attenuated after multivariable adjustments, HR (top-vs-bottom tertile) 1.74 (0.93-3.25). In females, no association with BB was observed. Using HB and BB as continuous variables supported the findings with tertiles. ConclusionsAlthough being lower in older males than females, higher Herpesviridae response burden was associated with increased 7-year mortality risk among males, not among females. Immune responses to common microbes may contribute to sex differences in longevity and mortality. Key points- Gender differences in vulnerability during Covid-19 has increased interested in sex-related responses to infections - We used IgG titers of Herpesviridae and bacteria as surrogate markers for variably recurrent reactivation - Although Herpesviridae response burden was generally lower among males than females, within sexes higher Herpesviridae burden strongly predicted 7-year mortality among males but not females - Long-term virus burden, like Herpesviridae, may partly explain shorter longevity and higher mortality among males with weaker immune systems

Abstract Background: The influence of taurine on biological ageing remains unclear, particularly whether it acts as a causal driver or a functional biomarker. We aimed to disentangle the distinct roles of plasma taurine relative abundance, dietary taurine supply, and genetic metabolic capacity on all-cause mortality and unhealthy ageing. Methods: This prospective study used data from the Korean Genome and Epidemiology Study (2001~2022). A subcohort of 2,321 participants (mean age 56.5 years; 51.4% female) with complete metabolomic, dietary, and genomic data was analyzed. Three independent pathways were evaluated: (1) plasma taurine/total amino acid (AA) ratio, (2) dietary taurine to protein ratio, and (3) a weighted genetic risk score (GRS) from 21 SNPs in taurine biosynthesis and transport genes. Primary outcomes were all-cause mortality and unhealthy ageing (Physiological Healthy Ageing Index [PHAI] score [&le;] 25th percentile). Results: A higher plasma taurine/total AA ratio was consistently associated with improved ageing outcomes. Participants in the highest quartile showed 29% lower all-cause mortality (Hazard Ratio [HR], 0.71; 95% Confidence Interval [CI], 0.52-0.98; P for trend = .04) and lower risk of PHAI-based unhealthy ageing (HR, 0.77; 95% CI, 0.59-1.00; P for trend = .04) versus the lowest quartile. Dietary taurine-to-protein ratio was not associated with mortality (P for trend = .70), nor was the GRS (P for trend = .74). Conclusions: The protective association of taurine was linked to its relative abundance within the systemic amino acid pool, rather than dietary intake or genetic predisposition, supporting taurine as a functional biomarker of metabolic efficiency rather than a deterministic causal driver of ageing.

Biological aging, the decline in physiological resilience that increases our vulnerability to disease and death as we grow older, can be measured from standard clinical-laboratory panels. Measurement of biological aging from laboratory data embedded in electronic health records (EHRs) could enhance precision healthcare. However, suitability of EHR-embedded laboratory records for this purpose is uncertain. We evaluated feasibility of EHR biological age measurement in a cohort of n=4,313 cardiothoracic-surgery patients at a large US Hospital and tested whether measured biological aging was associated with patient outcomes. Patients who were biologically older prior to surgery more often died or experienced adverse outcomes as compared to those measured to be biologically younger. Postoperative biological-aging trajectories were associated with length of intensive-care-unit (ICU) stays and in-hospital death. EHR laboratory data provide an opportunity for scalable implementation of biological aging measurement within healthcare systems, with potential to enhance patient monitoring and risk stratification.

In many countries, lifespan has been increasing faster than healthspan, leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging and to plan personalized interventions to extend healthspan. We used data from the Berlin Aging Study II (BASE-II, 60-80 years of age at baseline, average follow-up 7.4{+/-}1.5 years, range 3.9-10.4, n=1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: Insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15), high sensitivity C-reactive protein (CRP), interleukin-6 (IL 6), muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty index (FI), cognitive health, blood pressure, and epigenetic age (DunedinPACE). Cox proportional hazard regression analyses were performed to investigate the predictive role for all-cause mortality and to identify subgroups of the three most frequent causes of death observed in BASE-II. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry. In adjusted models of all-cause mortality, HGS, IL 6, standing balance, cognitive health, and epigenetic age (DunedinPACE) significantly predicted mortality, with the epigenetic age (DunedinPACE) emerging as the strongest predictor. In contrast, CRP, Gait Speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FI and TUG were not associated with mortality. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set comprising muscle mass, standing balance, and epigenetic age (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65).

BackgroundSeveral definitions exist for multimorbidity, frailty or polypharmacy, but no formal definition exists for "complex health needs". We aimed to identify and characterise older people with complex health needs based on healthcare resource use (unplanned hospitalisations or polypharmacy) or frailty. MethodsIn this cohort study, data was extracted from UK primary care records (CPRD GOLD), with linked Hospital Episode Statistics inpatient data. People aged >65 on 1st January 2010, registered in CPRD for [&ge;]1 year were included. We identified complex health needs as the top quintile of unplanned hospitalisations, number of prescribed medicines, and electronic frailty index. We characterised all three cohorts, and quantified point-prevalence and incidence rates of preventative medicines use. ResultsOverall, 90597, 110225 and 116076 individuals were included in the hospitalisation, frailty, and polypharmacy cohorts respectively. Frailty and polypharmacy cohorts had the highest bi- directional overlap. Most comorbidities such as diabetes and chronic kidney disease were more common in the frailty and polypharmacy cohorts compared to the hospitalisation cohort. Generally, prevalence of preventative medicines use was highest in the polypharmacy cohort compared to the other two cohorts: For instance, one-year point-prevalence of statins was 64.2% in the polypharmacy cohort vs. 60.5% in the frailty cohort. ConclusionsThree distinct groups of older people with complex health needs were identified. Compared to the hospitalisation cohort, frailty and polypharmacy cohorts had more comorbidities and higher preventative therapies use. Research is needed into the benefit-risk of different definitions of complex health needs and use of preventative therapies in the older population.

BackgroundFrailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults. ObjectivesThe primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults ([&ge;] 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. MethodsCommunity-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. ConclusionThis study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty.

BackgroundLong Interspersed Nucleotide Element-1 (LINE-1, or L1) sequences occupy approximately 17% of the human genome. L1 RNA expression, required for embryogenesis, is low in middle childhood, but increases in adults, eroding heterochromatin and leading to ectopic gene misexpressions, sterile chronic inflammation, and physiological deterioration. To our knowledge, no studies have yet tested whether adults with high L1 RNA levels for their age are shorter-lived, and whether the women with higher L1 RNA levels have shorter reproductive lifespans, as would be expected if higher L1 RNA expressions accelerate both systemic and reproductive aging. MethodsThe RNA levels of 127 subfamilies of L1 elements in lymphoblastoid cell lines (LCLs) from 43 grandmothers and 43 grandfathers of the three-generation Utah CEPH (Centre dEtude du Polymorphisme Humain) families were obtained from the Genetic European Variation in Disease (GEUVADIS) project. Survival and reproductive lifespan data for these subjects were obtained from the University of Utah. The sum of the RNA levels across all 127 L1 element subfamilies (a.k.a. total L1 RNA level), and the variance of RNA levels across the 127 subfamilies, were calculated for each research subject and tested for associations with longevity in both sexes and with age at last birth (ALB) for the women. ResultsWomen in the top half of summed L1 RNA expressions, or in the top half of variance in RNA expression across the L1 subfamilies, had significantly higher mortality rates than women in the bottom half for those measures (for top half vs. bottom half total L1 RNA levels, Hazard Ratio (HR) 4.00, 95% CI 1.50-10.67, P = 0.0057; for top half vs. bottom half variance across the L1 subfamilies, HR 3.84, 95% CI 1.49-10.72, P = 0.0068). No significant associations of L1 RNA levels, or their variance, with mortality were observed in the full set of 43 men; however, restricting the analysis to the men who were 68 years or older at blood draw and survived at least four years after the blood draw (n = 31) revealed significantly higher mortality rates, within this subset of men, for those in the top half of total L1 RNA levels vs. men in the bottom half (HR 2.79, 95% CI 1.11-7.05, P = 0.03). Among the 37 women whose ALB was [&ge;] 30 years, the approximate age when fertility begins to decline, higher total L1 RNA levels were associated, though not significantly, with a younger ALB. However, selecting for relatively healthy individuals by restricting the analyses to women who were younger than 75.5 years at blood draw and survived at least five years after the blood draw (n = 27) revealed a strong association of higher intra-individual variance in L1 RNA expression across the 127 L1 subfamilies with a younger ALB (Pearson r = -0.44, p = 0.02). ConclusionsThese results from a small cohort of research subjects lend support to the hypothesis that the regulation of L1 RNA expressions in adults significantly influences the rates of both systemic and reproductive aging. Expanded studies of similar design are needed to further test this hypothesis.

Background Ageing clocks are promising non-invasive tools to assess biological ageing, but they generally cannot guide intervention. We aimed to develop a urinary peptidomic ageing clock, expected to react to intervention, and to test whether the resulting age acceleration predicts all-cause mortality and adverse health outcomes. Methods In this retrospective multi-cohort study, urinary peptides were measured by capillary electrophoresis-mass spectrometry (CE-MS). An unconditioned clock (UPBioAge) was developed in a kidney function-preserved derivation cohort (n = 1,811), then conditioned on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) by Filtrate-Aware Calibration (FAC) fitted in an independent kidney-diverse cohort (n = 7,798), resulting in k-UPBioAge. Age prediction accuracy was evaluated in three cohorts independent of model development. Kidney-conditioned age acceleration (k-UPBioAgeAcc) was related to all-cause mortality and incident disease in a clinically enriched follow-up cohort (n = 7,469; 625 deaths; median follow-up 3.95 years) using Cox models adjusted for age, sex, comorbidities, body-mass index, mean arterial pressure and eGFR. Findings After standard age-bias correction, k-UPBioAge estimated chronological age with a calibrated holdout mean absolute error of 4.91 years (r = 0.945), and 5.43-5.47 years in two validation cohorts (one population cohort and the other samples analysed in an external site). Each SD increment in k-UPBioAgeAcc was associated with all-cause mortality (HR 1.48, 95% CI 1.35-1.63), incident coronary artery disease (1.44, 1.27-1.63), heart failure (1.27, 1.14-1.42) and chronic kidney disease progression (1.35, 1.05-1.73). The association did not differ by sex (P for interaction = 0.33), and none of four comorbidity interactions survived correction for multiple testing (adjusted P = 0.65-0.72), but no association was evident in participants with an eGFR of 15-29 mL/min/1.73 m2 (n = 433, 84 deaths) or macroalbuminuria (n = 92, 34 deaths). Interpretation Multiple urinary peptides are significantly associated with ageing, enabling the establishment of a robust biological ageing clock. As urine is generated in the kidney, a urinary ageing clock is affected by kidney function, mandating correction. The corrected urinary peptide-based biological ageing clock is affected by disease, and may warrant evaluation for monitoring or guiding personalised interventions.

Despite recent evidence of the ability of systemic and organ-specific proteomic aging clocks to predict a large range of age-related diseases, their utility in cancer research remains largely underexplored. In this study, we evaluated the predictive ability of systemic and organ-specific proteomic aging clocks for (i) all-cause mortality, (ii) cancer-related mortality, and (iii) cancer incidence in a sample of Finnish twins (N = 401, mean age at baseline 62.3 years) with Olink proteomic data. Participants were followed for a mean of 10.6 years (SD +- 1.6), with estimates from four systemic and 18 organ-specific proteomic aging clocks calculated at baseline. Cox proportional hazards regression models adjusted for sex and age at baseline identified 15 proteomic aging clocks as significant predictors of all-cause mortality (Ncases = 28) after multiple testing correction (FDR < 0.05), with 11 remaining significant after lifestyle adjustment (Ncases = 27). For several clocks, effect sizes were large, with hazard ratios (HR) approximately doubling per one standard deviation (SD) increase in clock estimates. In predicting cancer-related deaths among participants without a prior cancer diagnosis at baseline (Ncases = 9), only the Immune clock showed a significant positive association after multiple testing correction in basic (HR = 2.94, 95% CI: 1.88-4.59) and lifestyle-adjusted models (HR = 3.31, 95% CI: 1.78-6.17). No associations with cancer incidence (Ncases = 34 basic, Ncases = 31 adjusted) survived multiple testing correction, although several nominal associations were observed. In conclusion, our findings suggest that proteomic aging clocks are strong predictors of all-cause and cancer-specific mortality, independent of lifestyle factors. Proteomic aging clocks may further serve as valuable tools for stratifying cancers by mortality risk.

Frailty is a complex trait. Twin studies and a high-powered Genome Wide Association Study (GWAS) conducted in the UK Biobank have demonstrated a strong genetic basis of frailty. The present study utilized summary statistics from this GWAS to create and test the predictive power of frailty polygenic risk scores (PRS) in two independent samples - the Lothian Birth Cohort 1936 (LBC1936) and the English Longitudinal Study of Ageing (ELSA) aged 67-84 years. Multiple regression models were built to test the predictive power of frailty PRS at five time points. Frailty PRS significantly predicted frailty at all-time points in LBC1936 and ELSA, explaining 2.1% ({beta} = 0.15, 95%CI, 0.085-0.21) and 1.6% ({beta} = 0.14, 95%CI, 0.10-0.17) of the variance, respectively, at age [~]68/[~]70 years (p < 0.001). This work demonstrates that frailty PRS can predict frailty in two independent cohorts, particularly at early ages ([~]68/[~]70). PRS have the potential to be valuable instruments for identifying those at risk for frailty and could be important for controlling for genetic confounders in epidemiological studies.

Research on aged individuals from developed countries show that lifestyle factors such as diet, physical activity, stress, smoking, and sleep quality impact aging. However, other relevant factors may influence aging in less-studied populations, such as Brazilian cohorts. This study aimed to analyze immunosenescence profile of individuals living in an endemic area for several infectious diseases in Brazil. We showed that these individuals exhibited accelerated epigenetic aging and increased production of IL-12p70, IL-17A, and IL-9. Production of inflammatory mediators IL-12p70, IL-6, IL-1{beta}, IL-2, and IL-1ra in individuals with flu-like symptoms and those with COVID-19 was higher among residents in endemic areas than in residents from a control non-endemic area. Furthermore, residents of the endemic area had a more prominent inflammatory profile during viral infection and a different pattern of plasma mediators when compared to residents of a non-endemic area. It suggests that these two cohorts had specific immune signatures regardless of the presence or the type of infection at study. Therefore, we demonstrated that there were distinct patterns of immune responses and epigenetic aging depending on the environment the individuals live in. These observations add a layer of diversity to the studies of human aging by including less represented individuals.