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.

IF1 protein inhibits F1F0 ATP hydrolysis (and not F1F0 ATP synthesis). Across investigated species more IF1 protein, and less F1F0 ATP hydrolysis, correlates with greater maximal lifespan. Increased IF1 protein, and decreased F1F0 ATP hydrolysis, safely reduces a biomarker of aging in mice. Body temperature decrease, in mice administered with a small molecule drug that selectively inhibits F1F0 ATP hydrolysis (which doesnt inhibit F1F0 ATP synthesis), is evidence that F1F0 ATP hydrolysis is used for metabolic heat generation in vivo. Instrumental to homeothermy, which is a new fundamental discovery. A further discovery is that cancer cells subvert F1F0 ATP hydrolysis to drive their distinctive Warburg metabolism and so selective drug inhibition of F1F0 ATP hydrolysis exerts potent anticancer activity. When the body is in an ambient temperature of 37{degrees}C (or more), no metabolic heat generation is needed for the body to be at 37{degrees}C, and so a large dose of a F1F0 ATP hydrolysis inhibiting anticancer drug may be administered, which may slow aging. So, here might be an entirely new class of anticancer drugs that may (when appropriately used) help, instead of harm, normal cells. Distinct from present anticancer drugs, which greatly harm normal cells, causing horrific side-effects, which kill many and cause many others to abandon cancer treatment. In short, this paper teaches how mammals metabolically generate heat, why different mammal species have different maximal lifespans, and new anticancer drugs, that are predicted to slow aging. SIGNIFICANCEHas nature taught us how to slow aging? Different mammal species age at different rates, conferring different maximal lifespans. For example, the maximal lifespan of a mouse is 4 years, while that of a bowhead whale is 211 years. So, aging is modifiable. But how? A clue might be body size: smaller mammal species tend to age faster than larger ones. In geometry, by its square-cube law, smaller objects have a greater surface-area to volume ratio than larger objects. Meaning smaller mammal species more readily lose their metabolically generated heat. And so, per unit time, each gram of a smaller mammal species needs to generate more metabolic heat than each gram of a larger mammal species, to keep their body temperature around 37{degrees}C. The chemical reactions that the body uses to obtain energy from food (e.g., to keep the body warm) produce harmful by-products: Reactive Oxygen Species (ROS), which cause molecular damage. The accumulation of which might be aging. Per unit time, each gram of a smaller mammal species generates more metabolic heat, uses more food, produces more ROS, and ages more. Newly reported herein is a chemical reaction that homeotherms use to generate heat (F1F0 ATP hydrolysis). By the 2nd Law of Thermodynamics, whenever energy converts from one form to another, some of this energy must be dissipated as heat (no energy conversion can be 100% efficient). Ive discovered, in homeotherms, ATP synthase enzyme hydrolyses some of the ATP it synthesizes (i.e., performs F1F0 ATP hydrolysis). Causing futile cycling between ATP synthesis and ATP hydrolysis, conditional upon passing and pumping protons along a concentration gradient respectively. So, cyclically interconverting between potential and chemical energies, which (by the inefficiency of energy conversions) generates heat to maintain body temperature. Across a set of mammal species: per unit time, each gram of smaller (shorter-living) mammal species do more of this heat generating reaction (F1F0 ATP hydrolysis) than each gram of larger (longer-living) mammal species. Because they have less IF1 protein (activity per unit mass), where IF1 protein selectively inhibits F1F0 ATP hydrolysis (doesnt inhibit F1F0 ATP synthesis). Across these mammal species, maximal lifespan is inversely proportional to the use (per unit time per unit mass) of F1F0 ATP hydrolysis. That drives the inverse proportionality between metabolic rate per unit mass and maximal lifespan, which causes the inverse proportionality between heart rate and maximal lifespan, observed across these mammal species. Increased IF1 protein, and decreased F1F0 ATP hydrolysis, safely reduces a biomarker of aging in mice. So, correlational and interventional data. My interpretation of data herein is that different mammal species have different maximal lifespans because of different IF1 protein activity (per unit mass). Where more IF1 protein activity (per unit mass) confers longer lifespan. A small-molecule drug that selectively inhibits F1F0 ATP hydrolysis, which doesnt inhibit F1F0 ATP synthesis, is shown to dose-dependently reduce metabolic heat generation (and metabolic rate thereby) in mice. Higher dose reduces it more. Such a drug is predicted to slow aging. Indeed, its mechanism of action (selectively inhibiting F1F0 ATP hydrolysis) is shown to safely decrease intracellular ROS concentration in mice. Less metabolic heat generation doesnt necessarily mean lower body temperature. Body temperature can be the same with less metabolic heat generation by proportionally greater body insulation, such as wearing more or better clothing, and/or a conducive ambient temperature. A human, in typical clothing, is most comfortable at an ambient temperature around 20.3{degrees}C. But much of the world is hotter, at least for part of the year, especially when close to the equator (43% of the worlds population lives in the tropics). Such a drug might, by dose-dependently reducing metabolic heat generation, increase thermal comfort in hot places, possibly slowing aging. To illustrate: a relatively small drug dose might increase a clothed persons preferred ambient temperature to 23{degrees}C, a higher dose to 27{degrees}C, an even higher dose to 32{degrees}C, and so on. When metabolic heat generation is low, the preferred ambient temperature is close to 37{degrees}C. When the ambient temperature is 37{degrees}C or more, no metabolic heat generation is needed for the body to be at 37{degrees}C. I predict when such a drug is applied topically to a small body part, such as to the face in a cosmetic cream, it will reduce metabolic heat generation at that location, reducing metabolic rate and thereby slow aging there. Wherein heat transfer from the rest of the body, via blood flow, maintains this body part at around 37{degrees}C, because topical use cant reduce body temperature at any ambient temperature. Less F1F0 ATP hydrolysis, enough predicted to slow aging by two-thirds, has been proven safe in mice, at least when localized to a body part. Slowing the aging of even just a small part of the body has cosmetic and - because many diseases of aging are highly localized (for example, to the eyes: e.g., Age-Related Macular Degeneration) - medical applications. Probably the incidence and progression of age-related diseases correlates with age/aging because aging is causal to them, and so a single drug that slows aging might confer therapeutic benefit for many, varied diseases of aging. Such diseases must be beaten to avert the otherwise coming demographic/economic crisis in which too much of the population suffers, and is debilitated by, at least one of them. A drug to slow aging is a desperate want and has been since the dawn of mankind. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/466310v4_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1862f22org.highwire.dtl.DTLVardef@8061f6org.highwire.dtl.DTLVardef@9f65f0org.highwire.dtl.DTLVardef@dd9f11_HPS_FORMAT_FIGEXP M_FIG C_FIG

A key factor in aging and many age-related diseases is the decline in nicotinamide adenine dinucleotide (NAD+) levels. Preclinical studies demonstrate promising results for NAD+ boosting in improving conditions of disease or aging. However, only a limited number of human studies have shown meaningful improvements in physiological function or quality of life with NAD+ boosting supplements. This randomized, double-blind, placebo-controlled study (Clinicaltrails.gov identifier: NCT06505967) investigated the impact of Qualia NAD+(R), a novel NAD+ supporting nutraceutical containing nicotinamide riboside (NR) and a variety of synergistic vitamins, minerals, and botanicals, on blood NAD+ levels and healthy aging, as assessed by quality of life surveys. MethodsStudy participants were randomly allocated to consume either Qualia NAD+ or placebo for 28 days. NAD+ levels were measured at baseline and study end using a validated, self-administered, dried blood spot assay. Quality of life measures were assessed weekly. Independent samples t-tests were used to compare NAD+ levels between study arms. Questionnaire data were compared using linear mixed-effects regression modeling. ResultsSixty-three healthy adults (n = 28 Qualia NAD+, n=35 placebo) enrolled in the study and had their NAD+ levels assessed. Qualia NAD+ increased NAD+ levels by 67% compared to 4% with placebo (p < 0.001). Qualia NAD+ improved emotional well-being versus placebo at multiple timepoints (p < 0.05). Aging female symptoms improved in overall and somatic categories at day 28 (p < 0.05). No improvements in aging symptoms were observed for males. ConclusionsQualia NAD+ increased NAD+ levels, enhanced quality of life in all participants, and alleviated some aging symptoms in females greater than placebo. The increase in NAD+ levels with Qualia NAD+ was greater than in most previous clinical trials of NAD+ supporting products at similar dosing, suggesting potential synergy between NR and the complementary nutrients in the product.

AbstractBrain aging is a complex process influenced by various lifestyle, environmental, and genetic factors, as well as by age-related and often co-existing pathologies. MRI and, more recently, AI methods have been instrumental in understanding the neuroanatomical changes that occur during aging in large and diverse populations. However, the multiplicity and mutual overlap of both pathologic processes and affected brain regions make it difficult to precisely characterize the underlying neurodegenerative profile of an individual from an MRI scan. Herein, we leverage a state-of-the art deep representation learning method, Surreal-GAN, and present both methodological advances and extensive experimental results that allow us to elucidate the heterogeneity of brain aging in a large and diverse cohort of 49,482 individuals from 11 studies. Five dominant patterns of neurodegeneration were identified and quantified for each individual by their respective (herein referred to as) R-indices. Significant associations between R-indices and distinct biomedical, lifestyle, and genetic factors provide insights into the etiology of observed variances. Furthermore, baseline R-indices showed predictive value for disease progression and mortality. These five R-indices contribute to MRI-based precision diagnostics, prognostication, and may inform stratification into clinical trials.

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.

BackgroundNicotinamide adenine dinucleotide (NAD) is a crucial coenzyme involved in cellular energy homeostasis whose levels decline notably with aging, which has prompted interest in NAD+ boosting to help combat age-related diseases and dysfunction. Numerous clinical trials have demonstrated safety and efficacy for B3 vitamins, such as nicotinamide riboside (NR), to increase NAD+ levels and augment the NAD+ metabolome. Limited impact on clinically relevant outcomes or quality of life have been demonstrated, however. ObjectiveThis randomized, double-blind, placebo-controlled, remote pilot study examined the effects of supplementation with Qualia NAD+(R) on whole blood NAD+ levels and quality of life measures. MethodsStudy participants consumed Qualia NAD+ daily for 28 consecutive days. NAD+ levels were the primary outcome and measured using a self-administered, non-invasive blood spot assay test conducted at baseline and at study end. Quality of life questionnaires were the secondary outcomes and reported bi-weekly. NAD+ levels and questionnaire data were analyzed using a linear mixed-effects model to compare within-group and between-group differences over time as compared to baseline. Independent t-tests were utilized to compare safety and tolerability between study groups. ResultsTwenty-five healthy adults aged 40 - 65 (56% female) consumed Qualia NAD+ (n = 9) or placebo (n = 16) Overall, Qualia NAD+ significantly increased NAD+ levels an average of 74% compared to a 4% increase observed in the placebo group (p < 0.001). Within-groups comparisons for Qualia NAD+, and changes in NAD+ levels comparing Qualia NAD+ and placebo were also significant (p < 0.001). Improvements in the overall and somatic categories (p = 0.02 and p = 0.04) were observed for males only comparing baseline to the end of the study. No adverse events were reported. ConclusionsQualia NAD+, a novel nutraceutical formulated with multiple vitamins, nutrients, and botanical compounds, effectively increased whole blood NAD+ levels and may improve some symptoms of aging in males. Clinicaltrials.gov identifier: NCT06812416.

Mouse lifespan studies are slow and costly, limiting the number of interventions that have demonstrated robust anti-aging effects. This highlights the need for rapid early-stage screening tools capable of assessing both efficacy and potential side effects. Here, we present a short-term performance assay designed to rapidly profile functional benefits and early toxicity of longevity interventions in mice. Over an 8-week period, mice received one of five candidate anti-aging treatments: 17-estradiol, rapamycin + Smer28, berberine + resveratrol, sildenafil and pinealon. The protocol longitudinally monitored body weight and temperature, and food intake, alongside post-treatment assessments of grip strength, locomotor activity, Y-maze cognition, social behavior, and hematological and urinary parameters. The screen revealed compound-specific phenotypes: 17-estradiol induced significant weight loss, increased grip strength, and dorsal alopecia, consistent with metabolic remodeling. Sildenafil reduced basal body temperature and preserved locomotor activity. Berberine + resveratrol decreased food intake and fasting glucose without major changes in physical performance, resembling caloric restriction-like metabolic effects. Rapamycin + Smer28 modestly improved strength and sociability but induced anemia in 2 of 5 mice, indicating potential dose-dependent toxicity. Pinealon showed a trend toward improved working memory without detectable adverse effects. This multi-parametric approach enables discover healthspan extending interventions facilitating prioritization and dose refinement before committing to full lifespan studies. Finally, to our knowledge, this represents the first comprehensive preclinical aging study in mice fully funded through tokenized decentralized science (DeSci), demonstrating how community-governed, on-chain funding can support resource-intensive in vivo research.

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.

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.

Body composition (adiposity and muscle depots) is strongly associated with cardiometabolic risk. However, using body composition measures for future disease risk prediction is difficult as they may reflect total body size or typical aging rather than poor health. We used data from the UK Biobank (UKB) and the German National Cohort (NAKO) to calculate age-, sex-, and height-specific z-scores for body composition measures (subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle (SM), SM fat fraction (SMFF), and intramuscular adipose tissue (IMAT)) and describe changes across the lifespan. Multivariable Cox regression assessed the prognostic value of z-score categories (low: z<-1; middle: z=-1 to 1; high: z>1) for incident diabetes, major adverse cardiovascular events (MACE), and all-cause mortality beyond traditional cardiometabolic risk factors in the UKB. Among 66,608 individuals (mean age: 57.7{+/-}12.9 y; mean BMI: 26.2{+/-}4.5 kg/m2, 48.3% female), SAT, VAT, SMFF, and IMAT were positively, and SM negatively associated with age. In multivariable-adjusted Cox regression, z-score risk categories had hazard ratios of up to 2.69 for incident diabetes (high VAT category), 1.41 for incident MACE (high IMAT), and 1.49 for all-cause mortality (low SM) compared to middle categories. Body composition shows distinct age-related changes across the lifespan. Z-scores of age-, sex-, and height-adjusted body composition measures identify individuals at risk and predict cardiometabolic outcomes and mortality beyond traditional risk factors. Our open-source tool facilitates the clinical translation of age-specific body composition assessments and supports future research. One Sentence SummaryAge-, sex-, and height-adjusted body composition z-scores predict cardiometabolic outcomes and enable clinical translation of body composition data.

BackgroundAutophagy and mitophagy are essential for cellular homeostasis and play key roles in longevity and healthy aging, whereas their age-associated decline contributes to the development of age-related diseases. The identification of small-molecule activators of these pathways therefore represents an important therapeutic objective. MethodsIn this study, we investigated a series of compounds based on a 2'-deoxycitidine-derived scaffold and systematically analyzed the impact of structural substitutions on their ability to induce autophagy and mitophagy. Chemical optimization and functional assays were combined with pathway analysis, cellular readouts of proteostasis, and in vivo lifespan assessment in Caenorhabditis elegans. ResultsThe lead compound enhanced autophagy predominantly via activation of the AMPK-ULK1 signaling pathway and induced mitophagy in a Parkin-independent manner. It promoted autophagosome formation and facilitated functional clearance of aggregation-prone mutant huntingtin. Conjugation of the lead compound with the mitochondria-targeting Cy5 dye further potentiated mitophagy induction, likely through preferential mitochondrial accumulation, while reducing cytotoxicity. Importantly, the conjugated compound significantly extended C. elegans lifespan at lower concentrations compared with the unconjugated analogue. ConclusionsTogether, these results identify a promising chemical scaffold for the development of auto-and mitophagy activators and validate mitochondria-targeted conjugation as an effective strategy to enhance their biological performance. The demonstrated in vivo efficacy supports the potential relevance of these compounds for interventions aimed at preserving proteostasis and mitochondrial quality control, with possible implications for geroprotective applications.

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).

The aging paradox describes improvements in emotional wellbeing as a function of aging, despite declines in cognition. Conversely, late life depression has been associated with increased cognitive decline in aging. We sought to understand these seemingly contradictory patterns of cognitive and mental health in older age. Building on cognitive reserve, affective reserve, and brain reserve models of aging, we developed three alternative algorithmic approaches to group N=22,686 participants from the UK Biobank into different profiles of aging. Our results revealed that aging profiles identified using our data-driven brain reserve model, which incorporated measures of cognition, neuroticism, and brain volume, achieved the highest validation results. Importantly, only two of the four aging profiles were characterized by the aging paradox (i.e., improved emotionality and decreased cognition with age). We identified one profile characterized by particularly low levels of neuroticism and relative resilience to cognitive decline. Another profile benefited from relatively preserved brain volumes, potentially driven by younger ages and/or higher socioeconomic status. Conversely, we identified two profiles with poorer health characteristics, including one profile with elevated cardiovascular risk. Taken together, these findings enrich our understanding of the emotion paradox and highlight the value of taking a nuanced and stratified approach when studying aging. In the future, aging profiles could be used to target preventative strategies to address modifiable risk factors and improve lifespan and healthspan.

Life expectancy continues to increase in the high-income world due to advances in medical care; however, quality of life declines with increasing age due to normal aging processes. Current research suggests that various aspects of aging are genetically modulated and thus may be slowed via genetic modification. Here, we show evidence for epigenetic modulation of the aging process in the brain from over 1800 individuals as part of the Framingham Heart Study. We investigated the methylation of genes in the protocadherin (PCDH) clusters, including the alpha (PCHDA), beta (PCDHB), and gamma (PCDHG) clusters. Reduced PCDHG, elevated PCDHA, and elevated PCDHB methylation levels were associated with substantial reductions in the rate of decline of regional white matter volume as well as certain cognitive skills, independent of overall accelerated or retarded aging as estimated by a DNA clock. These results are likely due to the different effects of the expression of genes in the alpha, beta, and gamma PCHD clusters and suggest that experience-based aging processes related to a decline in regional brain volume and select cognitive skills may be slowed via targeted epigenetic modifications.

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.

Clinical healthy aging recommendations are disease-centric and reactive rather than focusing on holistic, organismal aging. In contrast, biological age (BA) estimation informs risk stratification by predicting all-cause mortality, however current BA clocks do not pinpoint aging mechanisms making it difficult to intervene clinically. To generate actionable BA clocks, we developed and validated a principal component (PC)-based clinical aging clock (PCAge) that identifies signatures (PCs) associated with healthy and unhealthy aging trajectories. We observed that by intervening in PC-specific space, angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) normalize several modifiable clinical parameters, involved in renal and cardiac function as well as inflammation. Proactive treatment with ACE-I/ARBs appeared to significantly reduce future mortality risk and prevented BA acceleration. Finally, we developed a reduced BA clock (PC_mAge), based directly on PCAge, which has equivalent predictive power, but is optimized for immediate application in clinical practice. Our Geroscience approach points to mechanisms associated with BA providing targets for preventative medicine to modulate biological process(es) that drive the shift from healthy functioning toward aging and the eventual manifestations of age-related disease(s).

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.

The effect of biological aging on brain structure is widespread and apparent. However, little is understood regarding which regions exhibit similarities in vulnerability, and what biological processes drive regional patterns of senescence-associated atrophy. Here, we investigated whether associations between age and brain structure exhibit distinct patterns of regional vulnerability, and if so, whether they are related to patterns of cerebral physiology which also show age-related decline. Using both data-driven and hypothesis-driven approaches, we identified recurring patterns of accelerated and delayed decline across the lifespan. Notably, the results mapped using unsupervised clustering methods mirrored the organization of major arterial flow territories, suggesting that vascular architecture may serve as a key organizing principle in brain aging. These results provide support for future research on aging and neurodegenerative disorders that aim to link patterns of structural deterioration to physiological processes that may be useful for identifying at risk individuals and developing novel therapeutics.

Aging is a complex process with interindividual variability, which can be measured by aging biological clocks. Aging clocks are machine-learning algorithms guided by biological information and associated with mortality risk and a wide range of health outcomes. One of these aging clocks are transcriptomic clocks, which uses gene expression data to predict biological age; however, their functional role is unknown. Here, we profiled two transcriptomic clocks (RNAAgeCalc and knowledge-based deep neural network clock) in a large dataset of human postmortem prefrontal cortex (PFC) samples. We identified that deep-learning transcriptomic clock outperforms RNAAgeCalc to predict transcriptomic age in the human PFC. We identified associations of transcriptomic clocks with psychiatric-related traits. Further, we applied system biology algorithms to identify common gene networks among both clocks and performed pathways enrichment analyses to assess its functionality and prioritize genes involved in the aging processes. Identified gene networks showed enrichment for diseases of signal transduction by growth factor receptors and second messenger pathways. We also observed enrichment of genome-wide signals of mental and physical health outcomes and identified genes previously associated with human brain aging. Our findings suggest a link between transcriptomic aging and health disorders, including psychiatric traits. Further, it reveals functional genes within the human PFC that may play an important role in aging and health risk.