Publications by authors named "Nir Barzilai"

203 Publications

Extending human healthspan and longevity: a symposium report.

Ann N Y Acad Sci 2021 Sep 8. Epub 2021 Sep 8.

The Buck Institute for Research on Aging, Novato, California.

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.
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http://dx.doi.org/10.1111/nyas.14681DOI Listing
September 2021

Einstein-Nathan Shock Center: translating the hallmarks of aging to extend human health span.

Geroscience 2021 Aug 31. Epub 2021 Aug 31.

Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.

The overarching mission of the Einstein-Nathan Shock Center (E-NSC) is to make scientific discoveries in geroscience, leveraging on the expertise in our center in 6 out of the 7 pillars of aging, and to translate their effects towards drug discovery. The relevance of this basic biology of aging discoveries to humans will be confirmed through the unique gero-human resource at E-NSC. This is achieved through services provided by E-NSC, connectivity among its members, attracting worldwide investigators, and providing them with the opportunities to become future leaders. The two central components of the E-NSC are (a) cutting-edge research programs and (b) unique E-NSC research support cores. E-NSC scientists lead NIH-supported cutting-edge research programs that integrate key hallmarks of aging including proteostasis/autophagy, metabolism/inflammaging, genetic/epigenetics, stem cells/regeneration, and translational aging/longevity. Since the inception of the E-NSC, the well-integrated, collaborative, and innovative nature of the multiple supporting state-of-the-art E-NSC research cores form the bedrock of research success at the E-NSC. The three state-of-the-art E-NSC research cores, (i) Proteostasis of Aging Core (PAC), (ii) the Health Span Core (HSC), and (iii) the Human Multi-Omics Core (HMOC), have allowed impressive expansion of translational biological research programs. Expansion was facilitated through the wealth of data coming from genomics/proteomics and metabolomic analysis on human longevity studies, due to access to a variety of biological samples from elderly subjects in clinical trials with aging-targeting drugs, and new drug design services via the PAC to target the hallmarks of aging.
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http://dx.doi.org/10.1007/s11357-021-00428-9DOI Listing
August 2021

The antagonistic pleiotropy of insulin-like growth factor 1.

Aging Cell 2021 Sep 7;20(9):e13443. Epub 2021 Aug 7.

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

While insulin-like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF-1 levels and clinical disease. We examined prospective associations of serum IGF-1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF-1 are protected from disease, while older individuals with high IGF-1 are at increased risk for incident disease or death. Second, the association between IGF-1 and risk is generally U-shaped, indicating that both high and low levels of IGF-1 may be detrimental. With the exception of a more uniformly positive relationship between IGF-1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age-associated diseases. These data suggest that IGF-1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.
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http://dx.doi.org/10.1111/acel.13443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441393PMC
September 2021

Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons.

Diabetes 2021 Jul 20. Epub 2021 Jul 20.

Departments of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461.

Similar to insulin, central administration of insulin-like Growth Factor-1 (IGF-1) can suppress hepatic glucose production (HGP), but it is unclear if this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we utilized pharmacologic and genetic approaches in combination with hyperinsulinemic-euglycemic clamps to decipher the role of these receptors in mediating central effects of IGF-1 and insulin on HGP. In rats, we observed that intracerebroventricular (ICV) administration of IGF-1 or insulin markedly increased the glucose infusion rate (GIR) by >50% and suppressed HGP (P<0.001). However, these effects were completely prevented by preemptive ICV infusion with an IGF-1R and InsR/IGF-1R Hybrid (HybridRs) blocking antibody. Likewise, ICV infusion of the InsR antagonist, S961, which also can bind HybridRs, interfered with the ability of central insulin, but not IGF-1 to increase the GIR. Furthermore, hyperinsulinemic clamps in mice lacking IGF-1Rs in AgRP neurons revealed ~30% reduction in the GIR in KO animals, which was explained by an impaired ability of peripheral insulin to completely suppress HGP (P<0.05). Signaling studies further revealed an impaired ability of peripheral insulin to trigger ribosomal S6 phosphorylation or PIP3 production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1Rs signaling in the MBH, and specifically in AgRP neurons, can phenocopy impaired regulation of HGP as previously demonstrated in mice lacking InsRs in these cells, suggesting a previously unappreciated role for IGF-1Rs and/or HybridRs in the regulation of central insulin/IGF-1 signaling on glucose metabolism.
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http://dx.doi.org/10.2337/db21-0028DOI Listing
July 2021

Trajectories of frailty in aging: Prospective cohort study.

PLoS One 2021 12;16(7):e0253976. Epub 2021 Jul 12.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Background: Emerging evidence suggests that there is significant variability in the progression of frailty in aging. We aimed to identify latent subpopulations of frailty trajectories, and examine their clinical and biological correlates.

Methods: We characterized frailty using a 41-item cumulative deficit score at baseline and annual visits up to 12 years in 681 older adults (55% women, mean age 74·6 years). Clinical risk profile and walking while talking performance as a clinical marker of trajectories were examined. Mortality risk associated with trajectories was evaluated using Cox regression adjusted for established survival predictors, and reported as hazard ratios (HR). Proteome-wide analysis was done.

Findings: Latent class modeling identified 4 distinct frailty trajectories: relatively stable (34·4%) as well as mild (36·1%), moderate (24·1%) and severely frail (5·4%). Four distinct classes of frailty trajectories were also shown in an independent sample of 515 older adults (60% women, 68% White, 26% Black). The stable group took a median of 31 months to accumulate one additional deficit compared to 20 months in the severely frail group. The worst trajectories were associated with modifiable risk factors such as low education, living alone, obesity, and physical inactivity as well as slower walking while talking speed. In the pooled sample, mild (HR 2·33, 95% CI 1·30-4·18), moderate (HR 2·49, 95% CI 1·33-4·66), and severely frail trajectories (HR 5·28, 95% CI 2·68-10·41) had higher mortality compared to the stable group. Proteomic analysis showed 11 proteins in lipid metabolism and growth factor pathways associated with frailty trajectories.

Conclusion: Frailty shows both stable and accelerated patterns in aging, which can be distinguished clinically and biologically.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274857PMC
July 2021

Genetic signature of human longevity in PKC and NF-κB signaling.

Aging Cell 2021 07 1;20(7):e13362. Epub 2021 Jul 1.

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3-stage study to identify functional longevity-associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity-associated genes in the nPKC and NF-κB signaling pathways by gene-based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non-coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF-κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-κB signaling pathways in exceptional longevity may include humans.
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http://dx.doi.org/10.1111/acel.13362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282271PMC
July 2021

A Compendium of Age-Related PheWAS and GWAS Traits for Human Genetic Association Studies, Their Networks and Genetic Correlations.

Front Genet 2021 1;12:680560. Epub 2021 Jun 1.

Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, United States.

The rich data from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) offer an unprecedented opportunity to identify the biological underpinnings of age-related disease (ARD) risk and multimorbidity. Surprisingly, however, a comprehensive list of ARDs remains unavailable due to the lack of a clear definition and selection criteria. We developed a method to identify ARDs and to provide a compendium of ARDs for genetic association studies. Querying 1,358 electronic medical record-derived traits, we first defined ARDs and age-related traits (ARTs) based on their prevalence profiles, requiring a unimodal distribution that shows an increasing prevalence after the age of 40 years, and which reaches a maximum peak at 60 years of age or later. As a result, we identified a list of 463 ARDs and ARTs in the GWAS and PheWAS catalogs. We next translated the ARDs and ARTs to their respective 276 Medical Subject Headings diseases and 45 anatomy terms. The most abundant disease categories are neoplasms (48 terms), cardiovascular diseases (44 terms), and nervous system diseases (27 terms). Employing data from a human symptoms-disease network, we found 6 symptom-shared disease groups, representing cancers, heart diseases, brain diseases, joint diseases, eye diseases, and mixed diseases. Lastly, by overlaying our ARD and ART list with genetic correlation data from the UK Biobank, we found 54 phenotypes in 2 clusters with high genetic correlations. Our compendium of ARD and ART is a highly useful resource, with broad applicability for studies of the genetics of aging, ARD, and multimorbidity.
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http://dx.doi.org/10.3389/fgene.2021.680560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204079PMC
June 2021

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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http://dx.doi.org/10.1038/s41467-021-23556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190084PMC
June 2021

Effect of longevity genetic variants on the molecular aging rate.

Geroscience 2021 06 4;43(3):1237-1251. Epub 2021 May 4.

Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA.

We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.
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http://dx.doi.org/10.1007/s11357-021-00376-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190315PMC
June 2021

Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia.

Neuron 2021 05 22;109(9):1465-1478.e4. Epub 2021 Mar 22.

Department of Computer Science, Columbia University, New York, NY 10027, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA. Electronic address:

The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 "case-only" genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia. We report a recurrent case mutation in PCDHA3 that results in the formation of cytoplasmic aggregates and failure to engage in homophilic interactions on the plasma membrane in cultured cells. Modeling purifying selection, we demonstrate that deleterious URVs are greatly overrepresented in the Ashkenazi population, yielding enhanced power for association studies. Identification of the cadherin/protocadherin family as risk genes helps specify the synaptic abnormalities central to schizophrenia.
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http://dx.doi.org/10.1016/j.neuron.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177045PMC
May 2021

ARDD 2020: from aging mechanisms to interventions.

Aging (Albany NY) 2020 12 30;12(24):24484-24503. Epub 2020 Dec 30.

Blavatnik Institute, Department of Genetics, Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Boston, MA 94107, USA.

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 7 Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1 to 4 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 8 ARDD meeting that is scheduled for the 31 of August to 3 of September, 2021, at Columbia University, USA.
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http://dx.doi.org/10.18632/aging.202454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803558PMC
December 2020

Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers.

Neurobiol Aging 2021 03 30;99:101.e1-101.e9. Epub 2020 Sep 30.

Litwin-Zucker Center for Alzheimer's Disease, The Feinstein Institutes for Medical Research, Manhasset, NY, USA; Division of Geriatric Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. Electronic address:

To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRS), we estimated PRS in superagers (age ≥ 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRS decile to the lowest decile (OR = 4.82, p = 2.5 × 10), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 × 10). Thus PRS is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRS modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRS in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 × 10) among APOE4 carriers. This disproportionally large PRS among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (β = -0.02, p = 4.8 × 10) as a predictor of PRS. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.014DOI Listing
March 2021

Plasma proteomic profile of age, health span, and all-cause mortality in older adults.

Aging Cell 2020 11 22;19(11):e13250. Epub 2020 Oct 22.

Institute for Aging Research, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.

Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; β[SE] = 0.0262 [0.0012]; p = 3.21 × 10 ), WNT1-inducible-signaling pathway protein 2 (WISP-2; β[SE] = 0.0189 [0.0009]; p = 4.60 × 10 ), chordin-like protein 1 (CRDL1; β[SE] = 0.0203[0.0010]; p = 1.45 × 10 ), transgelin (TAGL; β[SE] = 0.0215 [0.0011]; p = 9.70 × 10 ), and R-spondin-1(RSPO1; β[SE] = 0.0208 [0.0011]; p = 1.09 × 10 ), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E-16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity.
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http://dx.doi.org/10.1111/acel.13250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681045PMC
November 2020

Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults.

Aging (Albany NY) 2020 10 18;12(20):19852-19866. Epub 2020 Oct 18.

Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY 40504, USA.

Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin attenuated the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.
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http://dx.doi.org/10.18632/aging.104096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655218PMC
October 2020

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin.

Geroscience 2021 06 9;43(3):1093-1112. Epub 2020 Sep 9.

Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.
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http://dx.doi.org/10.1007/s11357-020-00261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479299PMC
June 2021

Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity.

Aging Cell 2020 10 29;19(10):e13216. Epub 2020 Aug 29.

Faculty of Natural Sciences, University of Haifa, Haifa, Israel.

Centenarians (exceptionally long-lived individuals-ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews. The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested. The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.
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http://dx.doi.org/10.1111/acel.13216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576295PMC
October 2020

Geroscience in the Age of COVID-19.

Aging Dis 2020 Jul 23;11(4):725-729. Epub 2020 Jul 23.

9National Institute on Aging, NIH, USA.

The data on COVID-19 is clear on at least one point: Older adults are most vulnerable to hospitalization, disability and death following infection with the novel coronavirus. Therefore, therapeutically addressing degenerative aging processes as the main risk factors appears promising for tackling the present crisis and is expected to be relevant when tackling future infections, epidemics and pandemics. Therefore, utilizing a geroscience approach, targeting aging processes to prevent multimorbidity, via initiating broad clinical trials of potential geroprotective therapies, is recommended.
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http://dx.doi.org/10.14336/AD.2020.0629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390533PMC
July 2020

Plasma proteomic profile of frailty.

Aging Cell 2020 09 6;19(9):e13193. Epub 2020 Aug 6.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid-binding proteins, including fatty acid-binding protein (FABP) (p = 1.96 × 10 ) and FABPA (p = 8.10 × 10 ), leptin (p = 1.43 × 10 ), and ANTR2 (p = 7.95 × 10 ). Pathway analysis with the top 143 frailty-associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell-to-cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 × 10 ). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 × 10 ) than observed frailty (r = 0.37, p = 1.2 × 10 ). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction.
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http://dx.doi.org/10.1111/acel.13193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511877PMC
September 2020

Genetics of extreme human longevity to guide drug discovery for healthy ageing.

Nat Metab 2020 08 27;2(8):663-672. Epub 2020 Jul 27.

Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA.

Ageing is the greatest risk factor for most common chronic human diseases, and it therefore is a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. Recent genetic analysis of long-lived individuals is revealing common and rare variants enriched in these same conserved pathways that significantly correlate with longevity. In this Perspective, we summarize recent insights into the genetics of extreme human longevity and propose the use of this rare phenotype to identify genetic variants as molecular targets for gaining insight into the physiology of healthy ageing and the development of new therapies to extend the human healthspan.
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http://dx.doi.org/10.1038/s42255-020-0247-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912776PMC
August 2020

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan.

Aging (Albany NY) 2020 06 23;12(12):11185-11199. Epub 2020 Jun 23.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in the overexpression of humanin is sufficient to increase lifespan, dependent on . Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer's disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.
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http://dx.doi.org/10.18632/aging.103534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343442PMC
June 2020

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults.

Cells 2020 06 1;9(6). Epub 2020 Jun 1.

Department of Medicine, Division of Endocrinology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults ( = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05-1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680-0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08-2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004-1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29-0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.
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http://dx.doi.org/10.3390/cells9061368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349399PMC
June 2020

Benefits of Metformin in Attenuating the Hallmarks of Aging.

Cell Metab 2020 07 24;32(1):15-30. Epub 2020 Apr 24.

Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY, USA; Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York, NY, USA. Electronic address:

Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (targeting aging by metformin). This review focuses on metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.
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http://dx.doi.org/10.1016/j.cmet.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426PMC
July 2020

Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A.

Redox Biol 2020 05 4;32:101448. Epub 2020 Feb 4.

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland. Electronic address:

Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms. Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference (RNAi) screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematodal lifespan in a ROS-dependent manner. We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.
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http://dx.doi.org/10.1016/j.redox.2020.101448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096751PMC
May 2020

Chronic inflammation in the etiology of disease across the life span.

Nat Med 2019 12 5;25(12):1822-1832. Epub 2019 Dec 5.

Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
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http://dx.doi.org/10.1038/s41591-019-0675-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147972PMC
December 2019

Undulating changes in human plasma proteome profiles across the lifespan.

Nat Med 2019 12 5;25(12):1843-1850. Epub 2019 Dec 5.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

Aging is a predominant risk factor for several chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.
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http://dx.doi.org/10.1038/s41591-019-0673-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062043PMC
December 2019

Latest advances in aging research and drug discovery.

Aging (Albany NY) 2019 11 21;11(22):9971-9981. Epub 2019 Nov 21.

Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6 annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7 annual ARDD exhibition will transpire 2-4 of September, 2020, in Basel.
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http://dx.doi.org/10.18632/aging.102487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914421PMC
November 2019

Screening Human Embryos for Polygenic Traits Has Limited Utility.

Cell 2019 11 21;179(6):1424-1435.e8. Epub 2019 Nov 21.

Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel. Electronic address:

The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.
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http://dx.doi.org/10.1016/j.cell.2019.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957074PMC
November 2019

Varying Effects of APOE Alleles on Extreme Longevity in European Ethnicities.

J Gerontol A Biol Sci Med Sci 2019 11;74(Suppl_1):S45-S51

Department of Biostatistics, Boston University School of Public Health, Massachusetts.

APOE is a well-studied gene with multiple effects on aging and longevity. The gene has three alleles: e2, e3, and e4, whose frequencies vary by ethnicity. While the e2 is associated with healthy cognitive aging, the e4 allele is associated with Alzheimer's disease and early mortality and therefore its prevalence among people with extreme longevity (EL) is low. Using the PopCluster algorithm, we identified several ethnically different clusters in which the effect of the e2 and e4 alleles on EL changed substantially. For example, PopCluster discovered a large group of 1,309 subjects enriched of Southern Italian genetic ancestry with weaker protective effect of e2 (odds ratio [OR] = 1.27, p = .14) and weaker damaging effect of e4 (OR = 0.82, p = .31) on the phenotype of EL compared to other European ethnicities. Further analysis of this cluster suggests that the odds for EL in carriers of the e4 allele with Southern Italian genetic ancestry differ depending on whether they live in the United States (OR = 0.29, p = .009) or Italy (OR = 1.21, p = .38). PopCluster also found clusters enriched of subjects with Danish ancestry with varying effect of e2 on EL. The country of residence (Denmark or United States) appears to change the odds for EL in the e2 carriers.
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http://dx.doi.org/10.1093/gerona/glz179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330482PMC
November 2019
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