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Biological age (BA) has been proposed to evaluate the aging status instead of chronological age (CA). Our study shows evidence that there might be multiple "clocks" within the whole-body system: systemic aging drivers/clocks overlaid with organ/tissue-specific counterparts. We utilize multi-omics data, including clinical tests, immune repertoire, targeted metabolomic molecules, gut microbiomes, physical fitness examinations, and facial skin examinations, to estimate the BA of different organs (e.g., liver, kidney) and systems (immune and metabolic system). The aging rates of organs/systems are diverse. People's aging patterns are different. We also demonstrate several applications of organs/systems BA in two independent datasets. Mortality predictions are compared among organs' BA in the dataset of the United States National Health and Nutrition Examination Survey. Polygenic risk score of BAs constructed in the Chinese Longitudinal Healthy Longevity Survey cohort can predict the possibility of becoming centenarian.

Ribosomal proteins are thought to primarily facilitate biogenesis of the ribosome and its ability to synthesize protein. However, in this study, we show that Rpl22-like1 (Rpl22l1) regulates hematopoiesis without affecting ribosome biogenesis or bulk protein synthesis. Conditional loss of murine Rpl22l1 using stage or lineage-restricted Cre drivers impairs development of several hematopoietic lineages. Specifically, Tie2-Cre–mediated ablation of Rpl22l1 in hemogenic endothelium impairs the emergence of embryonic hematopoietic stem cells. Ablation of Rpl22l1 in late fetal liver progenitors impairs the development of B lineage progenitors at the pre-B stage and development of T cells at the CD44−CD25+ double-negative stage. In vivo labeling with O-propargyl-puromycin revealed that protein synthesis at the stages of arrest was not altered, indicating that the ribosome biogenesis and function were not generally compromised. The developmental arrest was associated with p53 activation, suggesting that the arrest may be p53-dependent. Indeed, development of both B and T lymphocytes was rescued by p53 deficiency. p53 induction was not accompanied by DNA damage as indicated by phospho-γH2AX induction or endoplasmic reticulum stress, as measured by phosphorylation of EIF2α, thereby excluding the known likely p53 inducers as causal. Finally, the developmental arrest of T cells was not rescued by elimination of the Rpl22l1 paralog, Rpl22, as we had previously found for the emergence of hematopoietic stem cells. This indicates that Rpl22 and Rpl22l1 play distinct and essential roles in supporting B and T cell development.

Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends life span across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in life-span extension in wild-type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts high-fat diet (HFD)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine fibroblast growth factor 21 (FGF21) expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21−/− mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy-deficient (Beclin-1flox/+Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occur through systemic changes in metabolism, involving multiple mechanistic pathways.

Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Here, we found levels of FKBP5 are significantly reduced in HD R6/2 and zQ175 mouse models and human HD isogenic neural stem cells and medium spiny neurons derived from induced pluripotent stem cells. Moreover, FKBP5 interacts and colocalizes with HTT in the striatum and cortex of zQ175 mice and controls. Importantly, when we decreased FKBP5 levels or activity by genetic or pharmacological approaches, we observed reduced levels of mHTT in our isogenic human HD stem cell model. Decreasing FKBP5 levels by siRNA or pharmacological inhibition increased LC3-II levels and macroautophagic/autophagic flux, suggesting autophagic cellular clearance mechanisms are responsible for mHTT lowering. Unlike rapamycin, the effect of pharmacological inhibition with SAFit2, an inhibitor of FKBP5, is MTOR independent. Further, in vivo treatment for 2 weeks with SAFit2, results in reduced HTT levels in both HD R6/2 and zQ175 mouse models. Our studies establish FKBP5 as a protein involved in the pathogenesis of HD and identify FKBP5 as a potential therapeutic target for HD. Abbreviations : ACTB/β-actin: actin beta; AD: Alzheimer disease; BafA1: bafilomycin A1; BCA: bicinchoninic acid; BBB: blood brain barrier; BSA: bovine serum albumin; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; DTT: dithiothreitol; FKBPs: FK506 binding proteins; HD: Huntington disease; HTT: huntingtin; iPSC: induced pluripotent stem cells; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MES: 2-ethanesulfonic acid; MOPS: 3-(N-morphorlino)propanesulfonic acid); MSN: medium spiny neurons; mHTT: mutant huntingtin; MTOR: mechanistic target of rapamycin kinase; NSC: neural stem cells; ON: overnight; PD: Parkinson disease; PPIase: peptidyl-prolyl cis/trans-isomerases; polyQ: polyglutamine; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; PTSD: post-traumatic stress disorder; RT: room temperature; SQSTM1/p62: sequestosome 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TBST:Tris-buffered saline, 0.1% Tween 20; TUBA: tubulin; ULK1: unc-51 like autophagy activating kinase 1; VCL: vinculin; WT: littermate controls.

Over the past decade, significant attention has been given to repurposing Food and Drug Administration approved drugs to treat age-related diseases. In contrast, less consideration has been given to natural bioactive compounds. Consequently, there have been limited attempts to translate these compounds. Autophagy is a fundamental biological pathway linked to aging, and numerous strategies to enhance autophagy have been shown to extend lifespan. Interestingly, there are a number of natural products that are reported to modulate autophagy, and here we describe a number of them that activate autophagy through diverse molecular and cellular mechanisms. Among these, Urolithin A, Spermidine, Resveratrol, Fatty Acids and Phospholipids, Trehalose and Lithium are featured in detail. Finally, we outline possible strategies to optimise and increase the translatability of natural products, with the overall aim of delaying the ageing process and improving human healthspan.

Mitochondrial dysfunction is a major driver of aging. Mitochondrial failure potentiates multiple declines in the homeostatic network that maintains health and precipitates many hallmarks of aging. Mitochondria are not just for energy production; the organelle also serves as an important signaling hub that coordinates many essential cellular processes such as ion homeostasis, redox biology, lipid metabolism, and cell death. Thus, maintaining mitochondrial fitness through a balanced act of replacement and removal is central for cellular homeostasis and organismal health. Here, we update the latest understanding on the multifaceted mechanisms underlying mitochondrial biogenesis and quality control turnover by the lysosome (mitophagy). Alterations in the synthesis and clearance of mitochondria during aging and age-related diseases are highlighted. Finally, we look at the supplementation of mitochondrial metabolite NAD+ and pomegranate polyphenol urolithin A to forestall decline in mitochondrial synthesis and mitophagy, and the potential to enhance coupling between both processes for longevity interventions.

After decades of fruitful work in model organisms, aging research is moving increasingly into the realm of human studies. Many interventions have been proposed targeting pathways identified in nonvertebrates, and a major challenge is to test their efficacy in extending human healthspan. For model organisms like yeast, the past has been fruitful, but where does the future lead? Here we summarize yeast as a model for aging research, pointing to impactful discoveries that have been generated, and discuss the future for research in this simple yet powerful organism. Myriad tools exist to manipulate yeast cells and measure molecular outcomes, but what are the right questions to ask in a climate of increasing difficulty for basic biology funding?

We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied. Ministry of Health (MOH) Published version This work is supported by the National Innovation Challenge on Active and Confident Ageing Programme, Ministry of Health of Singapore (Award No.: MOH/NIC/COG06/2017) and the National University of Singapore Society (NUSS) Choir Dementia Research Fund. The funders played no role in the study design, data acquisition, analysis, or manuscript preparation. The views expressed are those of the authors and are not an official view of the institutions or funders.

Highlights • Aging is the largest risk factors for severity and mortality in adult COVID-19. • Severe cases of COVID-19 are related to vascular damage with evidence of direct viral infection in the endothelial cells. • Increase risk of COVID-19 death are also highly related to disease with lower vascular Nitric Oxide (NO) level. • Vascular viral defence by endothelial nitric oxide synthase (eNOS) derive NO may be the protecting factor for the young. • eNOS polymorphism could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries., The COVID-19 pandemic poses an imminent threat to humanity, especially to the elderly. The molecular mechanisms underpinning the age-dependent disparity for disease progression is not clear. COVID-19 is both a respiratory and a vascular disease in severe patients. The damage endothelial system provides a good explanation for the various complications seen in COVID-19 patients. These observations lead us to suspect that endothelial cells are a barrier that must be breached before progression to severe disease. Endothelial intracellular defences are largely dependent of the activation of the interferon (IFN) system. Nevertheless, low type I and III IFNs are generally observed in COVID-19 patients suggesting that other intracellular viral defence systems are also activated to protect the young. Intriguingly, Nitric oxide (NO), which is the main intracellular antiviral defence, has been shown to inhibit a wide array of viruses, including SARS-CoV-1. Additionally, the increased risk of death with diseases that have underlying endothelial dysfunction suggest that endothelial NOS-derived nitric oxide could be the main defence mechanism. NO decreases dramatically in the elderly, the hyperglycaemic and the patients with low levels of vitamin D. However, eNOS derived NO occurs at low levels, unless it is during inflammation and co-stimulated by bradykinin. Regrettably, the bradykinin-induced vasodilation also progressively declines with age, thereby decreasing anti-viral NO production as well. Intriguingly, the inverse correlation between the percentage of WT eNOS haplotype and death per 100K population could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries. These changes with age, low bradykinin and NO, may be the fundamental reasons that intracellular innate immunity declines with age leading to more severe COVID-19 complications.

Brain ageing is the main risk factor to develop dementia and neurodegenerative diseases, associated with a decay in the buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway to cope with ER stress, to the functional deterioration of the brain during aging. Genetic disruption of the ER stress sensor IRE1α accelerated cognitive and motor decline during ageing. Exogenous bolstering of the UPR by overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue indicated that XBP1s expression attenuated age-related alterations to synaptic function and pathways linked to neurodegenerative diseases. Overall, our results demonstrate that strategies to manipulate the UPR in mammals may sustain healthy brain ageing.

At a recent symposium on aging biology, a debate was held as to whether or not we know what biological aging is. Most of the participants were struck not only by the lack of consensus on this core question, but also on many basic tenets of the field. Accordingly, we undertook a systematic survey of our 71 participants on key questions that were raised during the debate and symposium, eliciting 37 responses. The results confirmed the impression from the symposium: there is marked disagreement on the most fundamental questions in the field, and little consensus on anything other than the heterogeneous nature of aging processes. Areas of major disagreement included what participants viewed as the essence of aging, when it begins, whether aging is programmed or not, whether we currently have a good understanding of aging mechanisms, whether aging is or will be quantifiable, whether aging will be treatable, and whether many non-aging species exist. These disagreements lay bare the urgent need for a more unified and cross-disciplinary paradigm in the biology of aging that will clarify both areas of agreement and disagreement, allowing research to proceed more efficiently. We suggest directions to encourage the emergence of such a paradigm.

The budding yeast Saccharomyces cerevisiae has relatively short lifespan and is genetically tractable, making it a widely used model organism in ageing research. Here, we carried out a systematic and quantitative investigation of yeast ageing with single-cell resolution through transcriptomic sequencing. We optimized a single-cell RNA sequencing (scRNA-seq) protocol to quantitatively study the whole transcriptome profiles of single yeast cells at different ages, finding increased cell-to-cell transcriptional variability during ageing. The single-cell transcriptome analysis also highlighted key biological processes or cellular components, including oxidation-reduction process, oxidative stress response (OSR), translation, ribosome biogenesis and mitochondrion that underlie ageing in yeast. Remarkably, we uncovered a molecular marker, FIT3, that was linked to mitochondrial DNA loss and indicated the early heterogeneity during ageing in yeast. We also analyzed the regulation of transcription factors and further characterized the distinctive temporal regulation of the OSR by YAP1 and proteasome activity by RPN4 during ageing in yeast. Overall, our data profoundly reveal early heterogeneity during ageing in yeast and shed light on the ageing dynamics at the single cell level.

Evidence from neuroimaging and genetic studies supports the concept that brain aging mirrors development. However, it is unclear whether mechanisms linking brain development and aging provide new insights to delay aging and potentially reverse it. This study determined biological mechanisms and phenotypic traits underpinning brain alterations across the lifespan and in aging by examining spatio-temporal correlations between gene expression and cortical volumes using datasets d with the age range from 2 to 82 years. We revealed that a large proportion of genes whose expression was associated with cortical volumes across the lifespan were in astrocytes. These genes, which showed up-regulation during development and down-regulation during aging, contributed to fundamental homeostatic functions of astrocytes. Included among these genes were those encoding components of cAMP, Ras, and retrograde endocannabinoid signaling pathways. Genes associated with cortical volumes in the same data aged above 55 years were also enriched for the sphingolipid, renin-angiotensin system (RAS), proteasome, and TGF-β signaling pathway, which is linked to senescence-associated secretory phenotypes. Neuroticism, drinking, and smoking were the common phenotypic traits in the lifespan and aging, while memory was the unique phenotype associated with aging. These findings provide biological mechanisms mirroring development and aging as well as unique to aging.

Yeast cells lower their intracellular methionine level in response to glucose restriction to regulate metabolism and life span., Caloric restriction (CR) is known to extend life span across species; however, the molecular mechanisms are not well understood. We investigate the mechanism by which glucose restriction (GR) extends yeast replicative life span, by combining ribosome profiling and RNA-seq with microfluidic-based single-cell analysis. We discovered a cross-talk between glucose sensing and the regulation of intracellular methionine: GR down-regulated the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration; external supplementation of methionine cancels the life span extension by GR. Furthermore, genetic perturbations that decrease methionine synthesis/uptake extend life span. These observations suggest that intracellular methionine mediates the life span effects of various nutrient and genetic perturbations, and that the glucose-methionine cross-talk is a general mechanism for coordinating the nutrient status and the translation/growth of a cell. Our work also implicates proteasome as a downstream effector of the life span extension by GR.

A long-standing problem is how cells that lack one of the highly similar ribosomal proteins (RPs) often display distinct phenotypes. Yeast and other organisms live longer when they lack specific ribosomal proteins, especially of the large 60S subunit of the ribosome. However, longevity is neither associated with the generation time of RP deletion mutants nor with bulk inhibition of protein synthesis. Here, we queried actively dividing RP mutants through the cell cycle. Our data link transcriptional, translational, and metabolic changes to phenotypes associated with the loss of paralogous RPs. We uncovered translational control of transcripts encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites associated with 1C metabolism. Loss of 1C enzymes increased the longevity of wild type cells. 1C pathways exist in all organisms and targeting the relevant enzymes could represent longevity interventions.

Donor age and recipient age are factors that influence transplantation outcomes. Aside from age-associated differences in intrinsic graft function and alloimmune responses, the ability of young and old cells to exert either rejuvenating or aging effects extrinsically may also apply to the transplantation of hematopoietic stem cells or solid organ transplants. While the potential for rejuvenation mediated by the transfer of youthful cells is currently being explored for therapeutic applications, aspects that relate to accelerating aging are no less clinically significant. Those effects may be particularly relevant in transplantation with an age discrepancy between donor and recipient. Here, we review recent advances in understanding the mechanisms by which young and old cells modify their environments to promote rejuvenation- or aging-associated phenotypes. We discuss their relevance to clinical transplantation and highlight potential opportunities for therapeutic intervention.

Current therapeutics for glioblastoma multiforme (GBM) treatment are unsatisfactory due to their limited ability to control the progression from tumour margins. In this work, organic nanoparticles (NPs) are synthesized by co-encapsulating a fluorogen with aggregation-induced emission to generate a bright red emission for imaging and a semiconducting polymer to offer NIR absorption for photothermal therapy. The NPs are further modified with different ratios of two targeting ligands, folate and cRGD peptide. The best ratio that performs specific and efficient GBM targeting is screened out through in vitro and ex vivo fluorescence imaging analysis. The NPs with an FA to cRGD ratio of 25 : 75 exhibit superior ability to target GBM cells in vitro and also show efficient accumulation at the GBM margin and in the tumour interior after in vivo administration. The progression of GBM can be greatly suppressed through photothermal therapy, which provides a simple but promising strategy for GBM treatment.

An increase in cell size with age is a characteristic feature of replicative aging in budding yeast. Deletion of the gene encoding Whi5 results in shortened duration of G1 and reduced cell size, and has been previously suggested to increase replicative lifespan. Upon careful analysis of multiple independently derived haploid and homozygous diploid whi5Δ mutants, we find no effect on lifespan, but we do confirm the reduction in cell size. We suggest that instead of antagonizing lifespan, the elongated G1 phase of the cell cycle during aging may actually play an important role in allowing aged cells time to repair accumulating DNA damage. Keywords: Cell cycle regulation, Replicative aging, Saccharomyces cerevisiae

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1α accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging.One Sentence SummaryThe IRE1/XBP1 pathway dictates when and how brain function declines during aging.

Intermittent fasting (IF) is a lifestyle intervention comprising a dietary regimen in which energy intake is restricted via alternating periods of fasting and ad libitum food consumption, without compromising nutritional composition. While epigenetic modifications can mediate effects of environmental factors on gene expression, no information is yet available on potential effects of IF on the epigenome. In this study, we found that IF causes modulation of histone H3 lysine 9 trimethylation (H3K9me3) epigenetic mark in the cerebellum of male C57/BL6 mice, which in turn orchestrates a plethora of transcriptomic changes involved in the robust metabolic switching processes commonly observed during IF. Interestingly, both epigenomic and transcriptomic modulation continued to be observed after refeeding, suggesting that memory of the IF-induced epigenetic change is maintained at the locus. Notably though, we found that termination of IF results in a loss of H3K9me3 regulation of the transcriptome. Collectively, our study characterizes a novel mechanism of IF in the epigenetic-transcriptomic axis, which controls myriad metabolic process changes. In addition to providing a valuable and innovative resource, our systemic analyses reveal molecular framework for understanding how IF impacts the metaboloepigenetics axis of the brain.Highlights○ Intermittent fasting (IF) and refeeding modifies epigenome in the cerebellum○ Integrative epigenomic and transcriptomic analyses revealed metabolic switching○ IF affects the metaboloepigenetics axis in regulating metabolic processes○ Integrative analyses revealed a loss of epigenetic reprogramme following refeeding

It has been nearly three decades since the budding yeast Saccharomyces cerevisiae became a significant model organism for aging research and it has emerged as both simple and powerful. The replicative aging assay, which interrogates the number of times a "mother" cell can divide and produce "daughters", has been a stalwart in these studies, and genetic approaches have led to the identification of hundreds of genes impacting lifespan. More recently, cell biological and biochemical approaches have been developed to determine how cellular processes become altered with age. Together, the tools are in place to develop a holistic view of aging in this single-celled organism. Here, we summarize the current state of understanding of yeast replicative aging with a focus on the recent studies that shed new light on how aging pathways interact to modulate lifespan in yeast.

Introduction: Alzheimer’s Disease (AD) is a progressive neurodegenerative condition in which individuals exhibit memory loss, dementia, and impaired metabolism. Nearly all previous sin-gle-treatment studies to treat AD have failed, likely because it is a complex disease with multiple un-derlying drivers contributing to risk, onset, and progression. Here, we explored the efficacy of a mul-ti-therapy approach based on the disease risk factor status specific to individuals with AD diagnosis or concern. Methods: Novel software from uMETHOD Health was designed to execute a precision-medicine-based approach to de¬velop personalized treatment recommendations with the goal of slowing or re-versing biologic drivers of AD. AD-associated inputs encompassed genomic data, bio-specimen measurements, imaging data (such as MRIs or PET scans), medical histories, medications, allergies, co-morbidities, relevant lifestyle factors, and results of neuropsychological testing. Algorithms were then employed to prioritize physiologic and lifestyle states with the highest probability of contributing to disease status, and these priorities were incorporated into a personalized care plan, which was de-livered to physicians and supported by health coaches to increase adherence. The sample included 40 subjects with Subjective Cognitive Decline patients (SCD), and Mild Cognitive Impairment Patients (MCI). Results: Software analysis was completed for 40 individuals. They remained on their treatment plan for an average of 8.4 months, equal to 2.8 iterations of care plans. 80% of individuals overall showed improved memory function scores or held steady, as meas¬ured by standardized cognitive evaluations. Cognitive assessments showed significant improvement in the SCD group (Composite P value .002, Executive P value .01), and the CNS-VS Executive domain showed significant results in the com-bined group as well (P value .01). There was also biomarker improvement over time observed from the blood panels. 8 out of 12 selected biomarkers showed slight, though statistically non-significant, improvement overall for symptomatic individuals, and 6 out of 12 for the overall population. Only one biomarker, homocysteine, showed significant improvement, though (P values .03, .04, .002). Conclusions: Our analysis of these individuals lead to several interesting observations to¬gether sug-gesting that AD risk factors comprise a network of interlocking feedback loops that may be modifia-ble. Our findings indicate previously unidentified connectivity between AD risk factors, suggesting that treatment regimens should be tailored to the individual and multi-modal to simultaneously return sev¬eral risk factors to a normative state. If successfully performed, the possibility to slow progression of AD and possibly reverse aspects of cognitive decline may become achievable.

Hutchinson-Gilford Progeria is an accelerated aging syndrome caused by permanently farnesylated mutant lamin A, termed progerin. Recently, the FDA approved Lonafarnib, a farnesyltransferase inhibitor, to treat progeria, while Koblan and colleagues used novel gene editing methods to target the root cause of this disease by correcting the LMNA mutation.

APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding β-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Furthermore, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA (The Cancer Genome Atlas) data for colorectal cancer outcomes. Transcriptional patterns exhibited evidence of activated canonical Wnt signaling in both types of adenomas, with Apc-mutant adenomas also exhibiting unique changes in pathways related to proliferation, cytoskeletal organization, and apoptosis. Apc-mutant adenomas were characterized by increased expression of the glial nexin Serpine2, the human ortholog, which was increased in advanced human colorectal tumors. Our results support the hypothesis that APC-mutant colorectal tumors are transcriptionally distinct from APC-wild-type colorectal tumors with canonical WNT signaling activated by other mechanisms, with possible implications for stratification and prognosis. Significance: These findings suggest that colon adenomas driven by APC mutations are distinct from those driven by WNT gain-of-function mutations, with implications for identifying at-risk patients with advanced disease based on gene expression patterns. Cancer Res; 78(3); 617–30. ©2017 AACR.

Alcohol is one of the most widely encountered drugs in the world and is credited with a wealth of health interactions. Light to moderate regular consumption (14–28 g daily) can promote heart health, protect against Type II diabetes, and likely extend overall lifespan. However, higher consumption rates lead to the detrimental effects more widely associated with ethanol consumption, including decreased motor control, cardiotoxicity, insulin resistance, and liver disease. Despite high consumption rates in the elderly population, there has been little focus on alcohol's multifaceted effects in the context of aging. Ethanol interacts with numerous genetic targets that are already associated with aging (such as mitigation of the mechanistic target of rapamycin and activation of FOXO3A), and its dose-dependent lifespan extension depends on still poorly understood connections to these pathways. This review focuses on ethanol's relationship to aging and lifespan in multiple animal models, and it demonstrates how understanding the complicated role of this ubiquitous chemical could be vital in order to apply our knowledge of mechanisms mediating the aging process to the human population. Keywords: Alcohol, Ethanol, Lifespan, Healthspan, Aging, Hormesis

Population aging is among the most important global transformations. Compared to European and North American countries, Chile is among the countries with the fastest growth of life expectancy at birth during recent decades. The aging of Chile's population is related to the improvement of living conditions, but also entails risks that tend to be associated with a rapid economic growth accompanied by large income inequalities and a chronic deficit of basic social benefits. The rapid demographic transition towards an aged population has unfolded in a context of poor development of public policies to tackle the opportunities and needs associated with an aging society. This article provides a brief overview of current Chilean public policy on aging, with a focus on healthy aging as defined by World Health Organization. The discussion addresses core challenges to successfully achieve healthy aging in Chile.

Summary Sgf73, a core component of SAGA, is the yeast orthologue of ataxin‐7, which undergoes CAG–polyglutamine repeat expansion leading to the human neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Deletion of SGF73 dramatically extends replicative lifespan (RLS) in yeast. To further define the basis for Sgf73‐mediated RLS extension, we performed ChIP‐Seq, identified 388 unique genomic regions occupied by Sgf73, and noted enrichment in promoters of ribosomal protein (RP)‐encoding genes. Of 388 Sgf73 binding sites, 33 correspond to 5′ regions of genes implicated in RLS extension, including 20 genes encoding RPs. Furthermore, half of Sgf73‐occupied, RLS‐linked RP genes displayed significantly reduced expression in sgf73Δ mutants, and double null strains lacking SGF73 and a Sgf73‐regulated, RLS‐linked RP gene exhibited no further increase in replicative lifespan. We also found that sgf73Δ mutants display altered acetylation of Ifh1, an important regulator of RP gene transcription. These findings implicate altered ribosomal protein expression in sgf73Δ yeast RLS and highlight altered acetylation as a pathway of relevance for SCA7 neurodegeneration.

Near-infrared (NIR) activatable upconversion nanoparticles (UCNPs) enable wireless-based phototherapies by converting deep-tissue-penetrating NIR to visible light. UCNPs are therefore ideal as wireless transducers for photodynamic therapy (PDT) of deep-sited tumors. However, the retention of unsequestered UCNPs in tissue with minimal options for removal limits their clinical translation. To address this shortcoming, biocompatible UCNPs implants are developed to deliver upconversion photonic properties in a flexible, optical guide design. To enhance its translatability, the UCNPs implant is constructed with an FDA-approved poly(ethylene glycol) diacrylate (PEGDA) core clad with fluorinated ethylene propylene (FEP). The emission spectrum of the UCNPs implant can be tuned to overlap with the absorption spectra of the clinically relevant photosensitizer, 5-aminolevulinic acid (5-ALA). The UCNPs implant can wirelessly transmit upconverted visible light till 8 cm in length and in a bendable manner even when implanted underneath the skin or scalp. With this system, it is demonstrated that NIR-based chronic PDT is achievable in an untethered and noninvasive manner in a mouse xenograft glioblastoma multiforme (GBM) model. It is postulated that such encapsulated UCNPs implants represent a translational shift for wireless deep-tissue phototherapy by enabling sequestration of UCNPs without compromising wireless deep-tissue light delivery. Ministry of Education (MOE) Nanyang Technological University This work was supported by National University of Singapore’s start up grants, R-183-000-413-733 and R-185-000-363-733; Singapore’s Ministry of Education grants (MOE 2016-T3-1-004, R-397-000-274-112, R-397-000-270-114); and a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant.

A long-standing problem is how cells that lack one of the highly similar ribosomal proteins (RPs) often display distinct phenotypes. Some may reflect general effects due to lower growth rate and ribosome levels, but a number of diverse phenotypes cannot be explained through this mechanism. Yeast and other organisms live longer when they lack specific ribosomal proteins, especially of the large 60S subunit of the ribosome. However, longevity is neither associated with the generation time of RP deletion mutants nor with bulk inhibition of protein synthesis. Here, we comprehensively queried actively dividing RP paralog mutants through the cell cycle. Our data link transcriptional, translational, and metabolic changes to phenotypes associated with the loss of paralogous RPs. We uncovered specific translational control of transcripts encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites associated with 1C metabolism. Loss of 1C enzymes, such as the serine hydroxymethyltransferase Shm2p increased the longevity of wild type cells. These results provide a molecular basis for paralog-specific phenotypes in ribosomal mutants and underscore the significance of 1C metabolic pathways in mechanisms of cell division and cellular aging. 1C pathways exist in all organisms, including humans, and targeting the relevant enzymes could represent longevity interventions.

Not all individuals age at the same rate. Methods such as the 'methylation clock' are invasive, rely on expensive assays of tissue samples and infer the ageing rate by training on chronological age, which is used as a reference for prediction errors. Here, we develop models based on convoluted neural networks through training on non-invasive three-dimensional (3D) facial images of approximately 5,000 Han Chinese individuals that achieve an average difference between chronological or perceived age and predicted age of ±2.8 and 2.9 yr, respectively. We further profile blood transcriptomes from 280 individuals and infer the molecular regulators mediating the impact of lifestyle on the facial-ageing rate through a causal-inference model. These relationships have been deposited and visualized in the Human Blood Gene Expression-3D Facial Image (HuB-Fi) database. Overall, we find that humans age at different rates both in the blood and in the face, but do so coherently and with heterogeneity peaking at middle age. Our study provides an example of how artificial intelligence can be leveraged to determine the perceived age of humans as a marker of biological age, while no longer relying on prediction errors of chronological age, and to estimate the heterogeneity of ageing rates within a population.

How diet is related with cognition and health has not been systematically examined in Asians whose eating habits are very different from their counterparts in the West and the biological mechanisms underlying such links are not well known yet. The diet and healthy aging (DaHA) study is a community-based longitudinal study conducted to examine the role of diet and nutrition in promoting cognitive, emotional, and physical health among community-living elderly Singaporeans. The first wave of DaHA, conducted from 2011 to 2017, provided detailed information on diet and baseline cognitive function and health from 1010 community-living elderly in Singapore. Biomarkers of oxidative stress, systemic inflammation, and genetic information were collected. The ongoing second wave of DaHA is conducted from 2017 to 2020, which provides follow- up assessments using established cognitive tests and clinical tools. This well-characterized cohort, with its archived biological samples and high-quality data on diet and lifestyle factors will allow researchers to explore the relationships among diet, nutrition, genes, cognition, mental and physical health in an extremely cost-effective manner. Translations of the research findings into clinical and public health practices will potentially help to promote cognitive health at the population level and reduce healthcare costs related to cognitive impairment. National Medical Research Council (NMRC) Published version This work is supported by the following grants awarded to Dr Lei Feng: the National University of Singapore Virtual Institute for the Study of Ageing [grant number VG-8]; the Alice Lim Memorial Fund, Singapore [grant number ALMFA/2010]; the National Medical Research Council of Singapore [grant number NMRC/TA/ 0053/2016].

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA., Aging, 12 (24), ISSN:1945-4589

H2S is an endogenous gasotransmitter that plays an important role in physiological conditions. In this issue, Das et al. provide evidence that SIRT1-dependent angiogenesis is augmented by H2S—findings reinforced by Longchamp et al., who demonstrate that H2S-dependent angiogenesis is triggered by amino acid deprivation.

The decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from non-vertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements. Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

Aging results in various deleterious changes in the human body that may lead to loss of function and the manifestation of chronic diseases. While diseases can generally be reliably diagnosed, the aging process itself requires more sophisticated approaches to evaluate its progression. Numerous attempts have been made to establish biomarkers to quantify human aging at the cellular, tissue, and organismal level. Here, an up-to-date overview of biomarkers related to human aging with an emphasis on biomarkers that take into account different mechanisms of aging between individuals is provided. Classical discrete molecular and non-molecular biomarkers handpicked by researches on the base of their strong correlation with age, as well as emerging omics-based biomarkers, are discussed and potential future directions and developments in the field of aging assessment are outlined.

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. Significance: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165–76. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 115

Translational control during cell division determines when cells start a new cell cycle, how fast they complete it, the number of successive divisions, and how cells coordinate proliferation with available nutrients. The translational efficiencies of mRNAs in cells progressing synchronously through the mitotic cell cycle, while preserving the coupling of cell division with cell growth, remain uninvestigated. We now report comprehensive ribosome profiling of a yeast cell size series from the time of cell birth, to identify mRNAs under periodic translational control. The data reveal coordinate translational activation of mRNAs encoding lipogenic enzymes late in the cell cycle including Acc1p, the rate‐limiting enzyme acetyl‐CoA carboxylase. An upstream open reading frame (uORF) confers the translational control of ACC1 and adjusts Acc1p protein levels in different nutrients. The ACC1 uORF is relevant for cell division because its ablation delays cell cycle progression, reduces cell size, and suppresses the replicative longevity of cells lacking the Sch9p protein kinase regulator of ribosome biogenesis. These findings establish an unexpected relationship between lipogenesis and protein synthesis in mitotic cell divisions.

Summary: Most ribosomal proteins (RP) are regarded as essential, static components that contribute only to ribosome biogenesis and protein synthesis. However, emerging evidence suggests that RNA-binding RP are dynamic and can influence cellular processes by performing “extraribosomal,” regulatory functions involving binding to select critical target mRNAs. We report here that the RP, Rpl22, and its highly homologous paralog Rpl22-Like1 (Rpl22l1 or Like1) play critical, extraribosomal roles in embryogenesis. Indeed, they antagonistically control morphogenesis through developmentally regulated localization to the nucleus, where they modulate splicing of the pre-mRNA encoding smad2, an essential transcriptional effector of Nodal/TGF-β signaling. During gastrulation, Rpl22 binds to intronic sequences of smad2 pre-mRNA and induces exon 9 skipping in cooperation with hnRNP-A1. This action is opposed by its paralog, Like1, which promotes exon 9 inclusion in the mature transcript. The nuclear roles of these RP in controlling morphogenesis represent a fundamentally different and paradigm-shifting mode of action for RP. : Zhang et al. reveal that ribosomal proteins can perform regulatory functions of fundamental importance while separated from the ribosome. They demonstrate that ribosomal proteins Rpl22 and Rpl22-Like1 (Like1) are retained in the nucleus during gastrulation, where they control morphogenesis by modulating the splicing of Smad2 pre-mRNA in cooperation with HNRNP-A1. Keywords: ribosomal protein, paralog, morphogenesis, gastrulation, extraribosomal function, Rpl22, Rpl22l1, pre-mRNA splicing, Smad2, hnRNP-A1

Once thought to be impossible, it is now clear that changing the activity of several conserved genetic pathways can lead to lifespan extension in experimental organisms. In humans, however, the goal is to extend healthspan, the functional and disease-free period of life. Are the current pathways to lifespan extension also improving healthspan?

SummaryObesity is a major risk factor driving the global type II diabetes pandemic. However, the molecular factors linking obesity to disease remain to be elucidated. Gender differences are apparent in humans and are also observed in murine models. Here, we link these differences to expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which, upon HFD feeding, becomes significantly reduced in the skeletal muscle and adipose tissue of male but not female mice. Strikingly, restoring 4E-BP1 expression in male mice protects them against HFD-induced obesity and insulin resistance. Male 4E-BP1 transgenic mice also exhibit reduced white adipose tissue accumulation accompanied by decreased circulating levels of leptin and triglycerides. Importantly, transgenic 4E-BP1 male mice are also protected from aging-induced obesity and metabolic decline on a normal diet. These results demonstrate that 4E-BP1 is a gender-specific suppressor of obesity that regulates insulin sensitivity and energy metabolism.

Summary In the coming decades, a massive shift in the aging segment of the population will have major social and economic consequences around the world. One way to offset this increase is to expedite the development of geroprotectors, substances that slow aging, repair age‐associated damage and extend healthy lifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and some are in human use for specific disease indications, the path toward determining whether they affect aging in humans remains obscure. Translation to the clinic is hampered by multiple issues including absence of a common set of criteria to define, select, and classify these substances, given the complexity of the aging process and their enormous diversity in mechanism of action. Translational research efforts would benefit from the formation of a scientific consensus on the following: the definition of ‘geroprotector’, the selection criteria for geroprotectors, a comprehensive classification system, and an analytical model. Here, we review current approaches to selection and put forth our own suggested selection criteria. Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, saving time and cost involved in translation to clinic.