The Journals of Gerontology: Series A

BackgroundGrowth differentiation factor 15 (GDF-15) is a member of the TGF{beta} superfamily secreted by many cell types and found at higher blood concentrations as chronological age increases (1). Given the emergence of GDF-15 as a key protein associated with aging, it is important to understand the multitude of conditions with which circulating GDF-15 is associated. MethodsWe pooled data from 1,174 randomly selected Health ABC Study (Health ABC) participants and 1,503 Cardiovascular Health Study (CHS) participants to evaluate the risk of various conditions and age-related outcomes across levels of GDF-15. The primary outcomes were (1) risk of mobility disability and falls; (2) impaired cognitive function; (3) and increased risk of cardiovascular disease and total mortality. ResultsThe pooled study cohort had a mean age of 75.4 +/-4.4 years. Using a Bonferroni-corrected threshold, our analyses show that high levels of GDF-15 were associated with a higher risk of severe mobility disability (HR: 2.13 [1.64, 2.77]), coronary heart disease (HR: 1.47 [1.17, 1.83]), atherosclerotic cardiovascular disease (HR: 1.56 [1.22, 1.98]), heart failure (HR: 2.09 [1.66, 2.64]), and mortality (HR: 1.81 [1.53, 2.15]) when comparing the highest and lowest quartiles. For CHS participants, analysis of extreme quartiles in fully adjusted models revealed a 3.5-fold higher risk of dementia (HR: 3.50 [1.97, 6.22]). ConclusionsGDF-15 is associated with several age-related outcomes and diseases, including mobility disability, impaired physical and cognitive performance, dementia, cardiovascular disease, and mortality. Each of these findings demonstrates the importance of GDF-15 as a potential biomarker for many aging-related conditions.

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 ([≥] 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.

BackgroundKetone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on the inflammatory and metabolic aging pathways underpinning frailty in in vivo models. Ketone esters (KEs) are compounds that induce hyperketonemia without dietary changes and that may impact physical and cognitive function in young adults. The functional effects of KEs have not been studied in older adults. ObjectivesOur long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Here, we report the exploratory functional and quality-of-life outcome measures collected during a 12-week safety and tolerability study of KE (NCT05585762). DesignRandomized, placebo-controlled, double-blinded, parallel-group, pilot trial of 12-weeks of daily KE ingestion. SettingThe Clinical Research Unit at the Buck Institute for Research on Aging, California. Participants: Community-dwelling older adults ([≥] 65 years), independent in activities of daily living, with no unstable acute medical conditions (n = 30). InterventionSubjects were randomly allocated (1:1) to consume 25 g daily of either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil. MeasurementsLongitudinal change in physical function, cognitive function and quality of life were assessed as exploratory outcomes in n = 23 completers (n = 11 PLA, n = 12 KE). A composite functional outcome to describe the vigor-frailty continuum was calculated. Heart rate and activity was measured throughout the study using digital wearables. ResultsThere were no statistically significant longitudinal differences between groups in exploratory functional, activity-based or quality of life outcomes. ConclusionDaily ingestion of 25 g of KE did not affect exploratory functional or quality-of-life end points in this pilot cohort of healthy older adults. Future work will address these endpoints as primary and secondary outcomes in a larger trial of pre-frail older adults.

AbstractsO_ST_ABSImportanceC_ST_ABSCross-sectional assessment of epigenetic clocks provides information on the pace of aging. Whether longitudinal acceleration or deceleration of epigenetic clocks over time provides additional mortality prediction is unknown. ObjectiveTo test the independent associations of baseline levels and longitudinal changes in epigenetic clocks with mortality DesignLongitudinal study SettingInCHIANTI, a population-based study of community dwelling individuals in Tuscany, Italy. Participants699 InCHIANTI study participants aged 21-95 years at baseline with longitudinal measurements of DNA methylation. ExposureBaseline levels and longitudinal changes in seven epigenetic clocks, including two first-generation clocks developed using chronological age for reference (Hannum Clock, Horvath Clock), three second-generation clocks developed using time-to-death for references (DNAmPhenoAge, DNAmGrimAge, DNAmGrimAge Version 2), and two third-generation clocks developed using longitudinal rate of change of multiple phenotypes for reference (DunedinPOAm_38, DunedinPACE). Main Outcomes and MeasuresMortality was the primary outcome. Cox regression was used to estimate independent associations of baseline and longitudinal changes in epigenetic clocks with mortality. ResultsAdjusting for age, sex, study sites, and epigenetic clock at the baseline, longitudinal changes of the following epigenetic clocks were associated with mortality: Hannum clock (aHR = 1.14, 95% CI:[1.03, 1.26]), DNAmPhenoAge (aHR = 1.23, 95% CI: [1.10,1.37]), DNAmGrimAge (aHR = 1.13, 95% CI: [1.02,1.26]), DNAmGrimAge Version 2 (aHR = 1.18, 95% CI:[1.06,1.31]), and DunedinPOAm_38 (aHR = 1.15, 95%CI: [1.01,1.30]). Conclusions and RelevanceOur findings confirm that epigenetic clocks capture a dimension of health that is predictive of mortality and add the notion that time changes of epigenetic age reflect changes in health that additionally and independently contribute to mortality prediction. Future studies should test whether interventions that slow down the rate of epigenetic aging are associated with longer healthspan and lifespan. Key PointsQuestion: Is the rate of change in epigenetic clock associated with differential mortality? Findings: In 699 adults with followed for up to 24 years, faster longitudinal changes in epigenetic clocks (Hannum clock, DNAmPhenoAge, DNAmGrimAge, DNAmGrimAge version 2, DunedinPOAm_38, DunedinPACE) were significantly associated with higher mortality, independent of baseline epigenetic age and other confounders. Meaning: Independent of chronological age, epigenetic clock and change over time of epigenetic clock independently predicted the risk of death. Interventions that slow down the pace of epigenetic aging may enhance healthy longevity.

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

BackgroundIntrinsic capacity (IC) is a key marker of healthy ageing, which captures an individuals physical and mental capacities, measured across five domains: cognitive, locomotor, psychological, vitality, and sensory. Although genetic factors are known to influence both general IC and its individual domains, existing IC indices have been developed primarily using phenotypic data, without accounting for the underlying biological architecture across domains. In this study, we developed a multi-trait polygenic score (Mt-PGS) model for IC by integrating polygenic scores derived from a broad set of phenotypes spanning the five IC domains and examined its validity. MethodsUsing data from 13,085 participants of the Canadian Longitudinal Study on Aging (CLSA), we computed PGSs for 63 phenotypes related to IC domains. A supervised machine-learning model was applied to develop a mt-PGS model for IC and identify the optimal set of polygenic predictors. The validity of the mt-PGS IC score was evaluated by comparing it with a phenotype-based IC score and by examining its association with mortality. ResultsOur analysis identified PGSs for 33 phenotypes with non-zero coefficients, jointly explaining 2.23% of the variance in IC. Several of the strongest contributors were most closely aligned with vitality-related phenotypes in the literature (including body mass index, grip strength, fat-free mass, diastolic blood pressure, and chronic obstructive pulmonary disease), acknowledging cross-domain relevance, and that predictors from all five IC domains were represented. The mt-PGS IC score was consistent with the phenotype-based IC score, positively correlated with the phenotype-based IC score and was inversely associated with mortality (OR = 0.04; 95% CI: 0.005 - 0.379). ConclusionOur findings support the multisystem biological basis of IC, demonstrating that an mt-PGS model integrating diverse phenotypes is associated with the phenotype-based IC score. PGSs for the phenotypes frequently related to vitality in the literature were the strongest predictors, recognizing that several of these phenotypes may span multiple domains, and that all domains contributed to the model. If replicated across different ancestries and settings, these findings may serve as a foundation for future research for the potential integration of genetic information into IC frameworks.

BackgroundLong COVID is characterized by persistent symptoms affecting one or more organ systems for at least 3 months following a SARS-CoV-2 infection. The pathophysiologic mechanisms of this complex disease are poorly understood. Beyond the described symptoms of fatigue, dyspnea, myalgias, among others, Long COVID can affect the patients ability to work and function in society compared to their baseline. Frailty is defined as the decline of physiologic reserve that leads to increased vulnerability to stressors and poor health outcomes. Our study aimed to examine the characteristics of frailty seen in patients with Long COVID compared to the frailty seen in aging patients with multimorbidity. MethodsThis is a retrospective cohort study conducted in the Miami Veterans Affairs Medical Center (VAMC). The data used to calculate the Fried phenotype through the Johns Hopkins frailty calculator was collected from two separate clinics, a Long COVID clinic and a Geriatric Frailty clinic. We obtained the VA Frailty Index from VA CDW (Corporate Data Warehouse). ResultsWe included 106 patients from the Long COVID clinic and 97 from the frailty clinic. Patients from the Long COVID clinic were significantly younger than those from the frailty clinic (60{+/-}12.6 vs.. 79.8{+/-}5.8, p<0.01). In the standard frailty group, weakness and slowness were the predominant features present in both the frail and pre-frail groups, with increasing exhaustion and lower activity in the frail group. Patients with frailty in the Long COVID group experienced exhaustion and low activity at a higher rate than those in the Geriatric frailty clinic. ConclusionsLong COVID may predispose patients to develop a subtype of frailty ("post-viral frailty") that presents with a higher frequency of exhaustion and low activity. This frailty appears phenotypically different from the frailty encountered in geriatric patients with multimorbidity, which presents more often with slowness and weakness as the initial drivers.

Aging and obesity are primary risk factors for chronic conditions such as hypertension and diabetes. However, a mechanistic correlation between these risk factors has not been fully established. Using a historical birth cohort from Chile, we delve into the relationship between obesity and accelerated aging, spanning cellular to systemic levels. The cohort, comprising men and women in their late 20s, had their BMI recorded since birth, with 57% having obesity since childhood or adolescence. Our aim was to investigate if persistent obesity since childhood or adolescence leads to the display of molecular aging features in young adulthood. We also sought to determine whether cardiometabolic health issues accompanied this early aging phenotype. We used inferential statistics and data mining for analysis. Results show that persistent obesity since childhood or adolescence leads to epigenetic changes, telomere shortening, chronic inflammation, impaired nutrient sensing, mitochondrial stress, and diminished intercellular communication, resembling a compound network of interactions. This obesity-induced accelerated aging phenotype coincided with persistent decline of the cardiometabolic profile. Implications of our findings are significant and suggest that integrating molecular markers with clinical and epidemiological data could be valuable in identifying individuals at increased disease risk due to accelerated aging.

Most deaths from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection occur in older subjects. We assessed age effects and clinical utility of serum SARS-CoV-2 immunoglobulin G (IgG), immunoglobulin M (IgM), and neutralizing antibodies and serum inflammatory markers. Serum IgG, IgM, and neutralizing antibody levels were measured using chemiluminescence assays from Diazyme (Poway, CA), while serum interleukin-6 (IL-6), C reactive protein (CRP), and ferritin were measured with immunoassays obtained from Roche (Indianapolis, IN). In 79,005 subjects, IgG and IgM levels were positive ([&ge;]1.0 arbitrary units [AU]/mL) in 5.29% and 3.25% of subjects, respectively. In antibody positive subjects, median IgG levels were 3.93 AU/mL if <45 years of age, 10.18 AU/mL if 45-64 years of age, and 10.85 AU/mL if [&ge;]65 years of age (p<0.0001). In SARS-CoV-2 RNA positive cases, family members and exposed subjects (n=1,111), antibody testing was found to be valuable for case finding, and persistent IgM levels were associated with chronic symptoms. In non-hospitalized and hospitalized subjects assessed for SARS-CoV-2 RNA (n=278), median IgG levels in AU/mL were 0.05 in negative subjects (n=100), 14.83 in positive outpatients (n=129), and 30.61 in positive hospitalized patients (n=49, p<0.0001). Neutralizing antibody levels correlated significantly with IgG (r=0.875; p<0.0001). Two or more of the criteria of IL-6 [&ge;]10 pg/mL, CRP [&ge;]10 mg/L, and/or IgM >1.0 AU/mL occurred in 97.7% of inpatients versus 1.8% of outpatients (>50-fold relative risk, C statistic 0.986, p<0.0001). Our data indicate that: 1) IgG levels are significantly higher in positive older subjects, possibly to compensate for decreased cellular immunity with aging; 2) IgG levels are important for case finding in family clusters; 3) IgG levels are significantly correlated with neutralizing antibody levels; 4) persistently elevated IgM levels are associated with chronic disease; and 5) markedly elevated IL-6, hs-CRP, and/or positive IgM accurately identify SARS-CoV-2 RNA positive subjects requiring hospitalization.

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.

Aging is associated with colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in aging via modulating gut-BM axis. Mice of age 2-3 (Young) or 22-24 months (Old) were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated by using FITC-dextran. Lgr5+Olfm4+ intestinal stem cells (ISCs), Wnt3a and {beta}-catenin were evaluated by immunohistochemistry or western blotting. Fecal microbiome was analyzed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Cecal or serum bacterial metabolites were analyzed. The pro-myelopoietic potential of cecal supernatants (CS) was tested in the Young-BM cells. MrgD was expressed in ISCs, which was decreased in the Old. Increased intestinal permeability in aging was reversed by Ala. In the colon organoids, Ala increased Wnt3a levels that were antagonized by the NF449, SQ22536 or 666-15. Ala restored phospho-CREB and active {beta}-catenin levels that were decreased in the Old colon-organoids. Ala increased the richness and {beta}-diversity of the aging microbiome and decreased Bacillota/Bacteroidota. Ala decreased the CD80+ and increased CX3CR+ cells in the Old colons. Old-CS induced myelopoiesis in vitro in BM cells with higher number of monocytes and pro-inflammatory macrophages which was not observed in the CS derived from Ala-treated Old mice. Ala is a promising pharmacological agent for reversing the leaky gut of aging by restoring homeostasis in the gut-BM axis.

Chronological age is commonly used to study aging, but biological aging may more accurately reflect cumulative life experiences and psychosocial stressors. This study examines whether epigenetic clocks function as markers of resilience by assessing how marital status transitions are associated with biological aging and health outcomes in later life. Using data from 1,449 non-Hispanic White participants in the Health and Retirement Study, we analyzed thirteen epigenetic clocks derived from DNA methylation profiles. Ordinary least squares and Cox regression models assessed the associations between marital transitions, depressive symptoms, and mortality, adjusting for genetic and social factors. Interaction terms tested whether epigenetic clocks moderated these associations. Results showed that divorce and widowhood were linked to accelerated epigenetic aging. Marital status changes were associated with increased depressive symptoms but not with mortality risk. GrimAge and DunedinPACE moderated the relationship between marital disruption and depressive symptoms, while Zhang and GrimAge moderated the relationship with mortality risk. Biologically older individuals, particularly men, exhibited greater resilience to these transitions. These findings raise the possibility that epigenetic clocks reflect accumulated life experiences and psychosocial adaptation, potentially including elements of resilience in older adults.

BackgroundAging impairs thermogenic and metabolic flexibility, increasing metabolic disease risk. We examined six aging male mouse strains for responses to chronic topical menthol, a pharmacological cold mimetic. Material and methodsMale (C57BL/6J, A/J, BALB/c, C3H/hej, DBA/2J, and FVB/NJ) mice were treated with 4g/kg of 10% menthol weight per volume cream once per day or vehicle as control using finger application for 15 days. After last application, core body temperature measurement, BAT thermography, Nesting behaviour, and metabolic tolerance test were performed, and gene expression was analysed in BAT. ResultsMenthol improved core temperature recovery via thermogenesis and enhanced insulin sensitivity across all strains. However, effects on BAT mass, nesting behaviour, and gluconeogenesis were strain-dependent. ConclusionCollectively, these findings highlight that genetic background modulates metabolic responses to cold mimetics, informing future precision strategies for age-related metabolic disorders.

Background & AimThe current study examined cross-sectional and longitudinal associations between nocturia and frailty in a cohort of men and women aged 60 years and older, as evidence on this topic was lacking. MethodsBaseline and follow-up data from the Berlin Aging Study II (n=1671) assessed on average 7.1 (IQR 6.2-8.7) years apart were analyzed. Self-reported nocturia was dichotomized into </[&ge;] 2 micturitions per night, and frailty was assessed using the Fried Frailty Phenotype. Covariables were identified a priori based on a review of the existing literature. ResultsAt baseline, 70.2% of the participants were robust, 28.9% were pre-frail, and 0.9% were frail; 254 participants (23.6%) had self-reported nocturia. In longitudinal analyses, the prevalence and incidence of frailty at follow-up significantly increased when nocturia was present at baseline. Over the median follow-up of 7.1 years, there were 41 incident frailty cases (IR 5.15, 95% CI 3.79-7.00 per 1000 person-years). After adjusting for age, sex, morbidity burden, and baseline frailty status, baseline nocturia was associated with a 2.23-fold increased risk (95% CI 1.17-4.18) of frailty at follow-up. ConclusionNocturia is linked to a higher risk of developing frailty in older adults, both women and men.

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.

Cellular senescence is a prominent accomplice of aging. The expression of gene p16ink4a has been established as a biomarker of cellular senescence in humans and animal models. However, it has not been extensively studied in clinical settings in the context of natural aging and the development of age-related diseases. Here, we report the results of a natural aging study that provided an assessment of cellular senescence and a battery of measures of clinical status, quality of life (QOL), and physical performance in 250 community-dwelling participants across age continuum. This report focused on analyzing predictive relationships between cellular senescence and different clinical assessments. Our results suggest that clinical labs and QOL assessments produce distinct groupings of participants, yet both have strong predictive associations with p16ink4a. Furthermore, the highest accuracy of p16ink4a prediction requires subsets of measurements representing diverse aspects of each assessment, pointing towards a system-level role of p16ink4a. Our analysis also led to an assessment-based composite indexes that strongly correlate with p16ink4a expression. Our study underscores p16ink4as association with both earlier signs of physiological decline (based on clinical labs) and the later onset of health issues limiting the quality of life.

Angiotensin-converting enzyme 2 (ACE2) has been identified as a critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This has led to extensive speculation on the role of ACE2 in disease severity, and in particular, whether variation in its expression can explain higher mortality in older individuals. We examine this question in mouse lung and show that 24-month old mice have significantly reduced ACE2 mRNA expression relative to 3-month old mice. The differences appear to be localized to ciliated cells.

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimers disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment ameliorates cognitive decline and enhances neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal marked sex differences in neurogenic capacity and treatment responsiveness. While diterpenoid treatment enhanced hippocampal neurogenesis and cognitive performance in males, these effects were largely absent in females. Overall, female SAMP8 mice exhibited reduced baseline neurogenesis and a diminished response to therapy, underscoring the importance of considering biological sex in the design of therapeutic strategies for age-related cognitive decline.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the US (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the {beta}3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained {beta}3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic {beta}3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Our study provides foundational evidence for targeting adipose thermogenesis to improve age-related metabolic dysfunction.

ImportancePeople who complete more education live longer lives with better health. New evidence suggests that these benefits operate through a slowed pace of biological aging. If so, measurements of the pace biological aging could offer intermediate endpoints for studies of how interventions to promote education will impact healthy longevity. ObjectiveTo test the hypothesis that upward educational mobility contributes to a slower pace of biological aging and increased longevity. DesignProspective cohort study. SettingWe analyzed data from three generations of participants in the Framingham Heart Study: the Original cohort, enrolled beginning in 1948, the Offspring cohort, enrolled beginning in 1971, and the Gen3 cohort, enrolled beginning in 2002. Follow-up is on-going. Data analysis was conducted during 2022-2023 using data obtained from dbGaP (phs000007.v33). ParticipantsWe constructed a three-generation database to quantify intergenerational educational mobility. We linked mobility data with blood DNA methylation data collected from the Offspring cohort in (2005-2008) (n=1,652) and the Gen3 cohort in 2009-2011 (n=1,449). These n=3,101 participants formed our analysis sample. ExposureWe measured educational mobility by comparing participants educational outcomes with those of their parents. OutcomesWe measured the pace of biological aging from whole-blood DNA-methylation data using the DunedinPACE epigenetic clock. For comparison purposes, we repeated analysis using four other epigenetic clocks. Survival follow-up was conducted through 2019. ResultsParticipants who were upwardly mobile in educational terms tended to have slower DunedinPACE in later life (r=-0.18, 95% CI [-0.23,-0.13], p<0.001). This pattern of association was similar across generations and held in within-family sibling comparisons. 402 Offspring-cohort participants died over the follow-up period. Upward educational mobility was associated with lower mortality risk (HR=0.89, 95% CI [0.81,0.98] p=0.014). Slower DunedinPACE accounted for roughly half of this association. Conclusions and RelevanceOur findings support the hypothesis that interventions to promote educational attainment will slow the pace of biological aging and promote longevity. Epigenetic clocks, like DunedinPACE, have potential as near-term outcome measures of intervention effects on healthy aging. Experimental evidence is needed to confirm findings.