Aging, Lifespan & Longevity

Targeting enzyme aging.

Science. 2021 01 29;371(6528):462-463

Authors: Becker F, Rudolph KL

PMID: 33510013 [PubMed - indexed for MEDLINE]

Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification.

Nat Commun. 2021 01 28;12(1):640

Authors: Hwang I, Uchida H, Dai Z, Li F, Sanchez T, Locasale JW, Cantley LC, Zheng H, Paik J

Abstract
Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear. Here we report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induce cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.

PMID: 33510167 [PubMed - indexed for MEDLINE]

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun. 2021 01 28;12(1):654

Authors: Jones G, Trajanoska K, Santanasto AJ, Stringa N, Kuo CL, Atkins JL, Lewis JR, Duong T, Hong S, Biggs ML, Luan J, Sarnowski C, Lunetta KL, Tanaka T, Wojczynski MK, Cvejkus R, Nethander M, Ghasemi S, Yang J, Zillikens MC, Walter S, Sicinski K, Kague E, Ackert-Bicknell CL, Arking DE, Windham BG, Boerwinkle E, Grove ML, Graff M, Spira D, Demuth I, van der Velde N, de Groot LCPGM, Psaty BM, Odden MC, Fohner AE, Langenberg C, Wareham NJ, Bandinelli S, van Schoor NM, Huisman M, Tan Q, Zmuda J, Mellström D, Karlsson M, Bennett DA, Buchman AS, De Jager PL, Uitterlinden AG, Völker U, Kocher T, Teumer A, Rodriguéz-Mañas L, García FJ, Carnicero JA, Herd P, Bertram L, Ohlsson C, Murabito JM, Melzer D, Kuchel GA, Ferrucci L, Karasik D, Rivadeneira F, Kiel DP, Pilling LC

Abstract
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

PMID: 33510174 [PubMed - indexed for MEDLINE]

Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing.

Nat Rev Mol Cell Biol. 2021 Jan 28;:

Authors: Alberti S, Hyman AA

Abstract
Biomolecular condensates are membraneless intracellular assemblies that often form via liquid-liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.

PMID: 33510441 [PubMed - as supplied by publisher]

Delineating the relationship between immune system aging and myogenesis in muscle repair.

Aging Cell. 2021 Jan 28;:e13312

Authors: Tobin SW, Alibhai FJ, Wlodarek L, Yeganeh A, Millar S, Wu J, Li SH, Weisel RD, Li RK

Abstract
Recruited immune cells play a critical role in muscle repair, in part by interacting with local stem cell populations to regulate muscle regeneration. How aging affects their communication during myogenesis is unclear. Here, we investigate how aging impacts the cellular function of these two cell types after muscle injury during normal aging or after immune rejuvenation using a young to old (Y-O) or old to old (O-O) bone marrow (BM) transplant model. We found that skeletal muscle from old mice (20 months) exhibited elevated basal inflammation and possessed fewer satellite cells compared with young mice (3 months). After cardiotoxin muscle injury (CTX), old mice exhibited a blunted inflammatory response compared with young mice and enhanced M2 macrophage recruitment and IL-10 expression. Temporal immune and cytokine responses of old mice were partially restored to a young phenotype following reconstitution with young cells (Y-O chimeras). Improved immune responses in Y-O chimeras were associated with greater satellite cell proliferation compared with O-O chimeras. To identify how immune cell aging affects myoblast function, conditioned media (CM) from activated young or old macrophages was applied to cultured C2C12 myoblasts. CM from young macrophages inhibited myogenesis while CM from old macrophages reduced proliferation. These functional differences coincided with age-related differences in macrophage cytokine expression. Together, this study examines the infiltration and proliferation of immune cells and satellite cells after injury in the context of aging and, using BM chimeras, demonstrates that young immune cells retain cell autonomy in an old host to increase satellite cell proliferation.

PMID: 33511781 [PubMed - as supplied by publisher]

Cytoplasmic chromatin fragments-from mechanisms to therapeutic potential.

Elife. 2021 Jan 29;10:

Authors: Miller KN, Dasgupta N, Liu T, Adams PD, Vizioli MG

Abstract
Senescent cells, damaged cells that permanently exit the cell cycle, play important roles in development, tissue homeostasis, and tumorigenesis. Although many of these roles are beneficial in acute responses to stress and damage, the persistent accumulation of senescent cells is associated with many chronic diseases through their proinflammatory senescence-associated secretory phenotype (SASP). SASP expression is linked to DNA damage; however, the mechanisms that control the SASP are incompletely understood. More recently, it has been shown that senescent cells shed fragments of nuclear chromatin into the cytoplasm, so called cytoplasmic chromatin fragments (CCF). Here, we provide an overview of the current evidence linking DNA damage to the SASP through the formation of CCF. We describe mechanisms of CCF generation and their functional role in senescent cells, with emphasis on therapeutic potential.

PMID: 33512316 [PubMed - in process]

DNA damage-how and why we age?

Elife. 2021 Jan 29;10:

Authors: Yousefzadeh M, Henpita C, Vyas R, Soto-Palma C, Robbins P, Niedernhofer L

Abstract
Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.

PMID: 33512317 [PubMed - in process]

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans.

Aging Cell. 2021 Jan 29;:e13290

Authors: Sebastiani P, Federico A, Morris M, Gurinovich A, Tanaka T, Chandler KB, Andersen SL, Denis G, Costello K, Ferrucci L, Jennings L, Glass DJ, Monti S, Perls TT

Abstract
Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.

PMID: 33512769 [PubMed - as supplied by publisher]

Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk.

Elife. 2021 Jan 29;10:

Authors: Vazquez JM, Lynch VJ

Abstract
The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.

PMID: 33513090 [PubMed - as supplied by publisher]

New insights into the interplay between miRNAs and autophagy in the aging of intervertebral discs.

Ageing Res Rev. 2021 01;65:101227

Authors: Lan T, Shiyu-Hu, Shen Z, Yan B, Chen J

Abstract
Intervertebral disc degeneration (IDD) has been widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in the ageing process of intervertebral disc. Autophagy is an evolutionarily conserved process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic organelles. Autophagy has been proposed as a "double-edged sword" and autophagy dysfunction of IVD cells is considered as a crucial reason of IDD. A rapidly growing number of recent studies demonstrate that both miRNAs and autophagy play important roles in the progression of IDD. Furthermore, accumulated research has indicated that miRNAs target autophagy-related genes and influence the onset and development of IDD. Hence, this review focuses mainly on the current findings regarding the correlations between miRNA, autophagy, and IDD and provides new insights into the role of miRNA-autophagy pathway involved in IDD pathophysiology.

PMID: 33238206 [PubMed - indexed for MEDLINE]

Thymus involution sets the clock of the aging T-cell landscape: Implications for declined immunity and tissue repair.

Ageing Res Rev. 2021 01;65:101231

Authors: Elyahu Y, Monsonego A

Abstract
Aging is generally characterized as a gradual increase in tissue damage, which is associated with senescence and chronic systemic inflammation and is evident in a variety of age-related diseases. The extent to which such tissue damage is a result of a gradual decline in immune regulation, which consequently compromises the capacity of the body to repair damages, has not been fully explored. Whereas CD4 T lymphocytes play a critical role in the orchestration of immunity, thymus involution initiates gradual changes in the CD4 T-cell landscape, which may significantly compromise tissue repair. In this review, we describe the lifespan accumulation of specific dysregulated CD4 T-cell subsets and their coevolution with systemic inflammation in the process of declined immunity and tissue repair capacity with age. Then, we discuss the process of thymus involution-which appears to be most pronounced around puberty-as a possible driver of the aging T-cell landscape. Finally, we identify individualized T cell-based early diagnostic biomarkers and therapeutic strategies for age-related diseases.

PMID: 33248315 [PubMed - indexed for MEDLINE]

Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition.

Nat Neurosci. 2021 Jan;24(1):61-73

Authors: Jin WN, Shi K, He W, Sun JH, Van Kaer L, Shi FD, Liu Q

Abstract
Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.

PMID: 33257875 [PubMed - in process]

CoolMPS for robust sequencing of single-nuclear RNAs captured by droplet-based method.

Nucleic Acids Res. 2021 01 25;49(2):e11

Authors: Hahn O, Fehlmann T, Zhang H, Munson CN, Vest RT, Borcherding A, Liu S, Villarosa C, Drmanac S, Drmanac R, Keller A, Wyss-Coray T

Abstract
Massively-parallel single-cell and single-nucleus RNA sequencing (scRNA-seq, snRNA-seq) requires extensive sequencing to achieve proper per-cell coverage, making sequencing resources and availability of sequencers critical factors for conducting deep transcriptional profiling. CoolMPS is a novel sequencing-by-synthesis approach that relies on nucleotide labeling by re-usable antibodies, but whether it is applicable to snRNA-seq has not been tested. Here, we use a low-cost and off-the-shelf protocol to chemically convert libraries generated with the widely-used Chromium 10X technology to be sequenceable with CoolMPS technology. To assess the quality and performance of converted libraries sequenced with CoolMPS, we generated a snRNA-seq dataset from the hippocampus of young and old mice. Native libraries were sequenced on an Illumina Novaseq and libraries that were converted to be compatible with CoolMPS were sequenced on a DNBSEQ-400RS. CoolMPS-derived data faithfully replicated key characteristics of the native library dataset, including correct estimation of ambient RNA-contamination, detection of captured cells, cell clustering results, spatial marker gene expression, inter- and intra-replicate differences and gene expression changes during aging. In conclusion, our results show that CoolMPS provides a viable alternative to standard sequencing of RNA from droplet-based libraries.

PMID: 33264392 [PubMed - indexed for MEDLINE]

Translation elongation rate varies among organs and decreases with age.

Nucleic Acids Res. 2021 01 25;49(2):e9

Authors: Gerashchenko MV, Peterfi Z, Yim SH, Gladyshev VN

Abstract
There has been a surge of interest towards targeting protein synthesis to treat diseases and extend lifespan. Despite the progress, few options are available to assess translation in live animals, as their complexity limits the repertoire of experimental tools to monitor and manipulate processes within organs and individual cells. It this study, we developed a labeling-free method for measuring organ- and cell-type-specific translation elongation rates in vivo. It is based on time-resolved delivery of translation initiation and elongation inhibitors in live animals followed by ribosome profiling. It also reports translation initiation sites in an organ-specific manner. Using this method, we found that the elongation rates differ more than 50% among mouse organs and determined them to be 6.8, 5.0 and 4.3 amino acids per second for liver, kidney, and skeletal muscle, respectively. We further found that the elongation rate is reduced by 20% between young adulthood and mid-life. Thus, translation, a major metabolic process in cells, is tightly regulated at the level of elongation of nascent polypeptide chains.

PMID: 33264395 [PubMed - indexed for MEDLINE]

Adjustment of the PIF7-HFR1 transcriptional module activity controls plant shade adaptation.

EMBO J. 2021 Jan 04;40(1):e104273

Authors: Paulišić S, Qin W, Arora Verasztó H, Then C, Alary B, Nogue F, Tsiantis M, Hothorn M, Martínez-García JF

Abstract
Shade caused by the proximity of neighboring vegetation triggers a set of acclimation responses to either avoid or tolerate shade. Comparative analyses between the shade-avoider Arabidopsis thaliana and the shade-tolerant Cardamine hirsuta revealed a role for the atypical basic-helix-loop-helix LONG HYPOCOTYL IN FR 1 (HFR1) in maintaining the shade tolerance in C. hirsuta, inhibiting hypocotyl elongation in shade and constraining expression profile of shade-induced genes. We showed that C. hirsuta HFR1 protein is more stable than its A. thaliana counterpart, likely due to its lower binding affinity to CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), contributing to enhance its biological activity. The enhanced HFR1 total activity is accompanied by an attenuated PHYTOCHROME INTERACTING FACTOR (PIF) activity in C. hirsuta. As a result, the PIF-HFR1 module is differently balanced, causing a reduced PIF activity and attenuating other PIF-mediated responses such as warm temperature-induced hypocotyl elongation (thermomorphogenesis) and dark-induced senescence. By this mechanism and that of the already-known of phytochrome A photoreceptor, plants might ensure to properly adapt and thrive in habitats with disparate light amounts.

PMID: 33264441 [PubMed - in process]

mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression.

Genes Dev. 2021 Jan 01;35(1-2):59-64

Authors: Kon N, Ou Y, Wang SJ, Li H, Rustgi AK, Gu W

Abstract
Here, we showed that the acetylation-defective p53-4KR mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of mdm2 was fully rescued in the background of p535KR/5KR , but not p534KR/4KR background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in p53-5KR cells. Notably, the early-onset tumor formation observed in p535KR/5KR and p53-null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.

PMID: 33303641 [PubMed - in process]

Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.

Aging Cell. 2021 Jan;20(1):e13281

Authors: Gatto N, Dos Santos Souza C, Shaw AC, Bell SM, Myszczynska MA, Powers S, Meyer K, Castelli LM, Karyka E, Mortiboys H, Azzouz M, Hautbergue GM, Márkus NM, Shaw PJ, Ferraiuolo L

Abstract
Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation to studying mechanisms and potential therapies aiming to preserve neuronal health. Here, we show that induced astrocytes from fibroblasts donors in their childhood or adulthood display age-related transcriptional differences and functionally diverge in a spectrum of age-associated features, such as altered nuclear compartmentalisation, nucleocytoplasmic shuttling properties, oxidative stress response and DNA damage response. Remarkably, we also show an age-related differential response of induced neural progenitor cells derived astrocytes (iNPC-As) in their ability to support neurons in co-culture upon pro-inflammatory stimuli. These results show that iNPC-As are a renewable, readily available resource of human glia that retain the age-related features of the donor fibroblasts, making them a unique and valuable model to interrogate human astrocyte function over time in human CNS health and disease.

PMID: 33314575 [PubMed - in process]

SPATA4 improves aging-induced metabolic dysfunction through promotion of preadipocyte differentiation and adipose tissue expansion.

Aging Cell. 2021 Jan;20(1):e13282

Authors: Li Z, Xu K, Zhao S, Guo Y, Chen H, Ni J, Liu Q, Wang Z

Abstract
Spermatogenesis-associated protein 4 (SPATA4) is conserved across multiple species. However, the function of this gene remains largely unknown. In this study, we generated Spata4 transgenic mice to explore tissue-specific function of SPATA4. Spata4 overexpression mice displayed increased subcutaneous fat tissue compared with wild-type littermates at an old age, while this difference was not observed in younger mice. Aging-induced ectopic fat distribution, inflammation, and insulin resistance were also significantly attenuated by SPATA4. In vitro, SPATA4 promoted preadipocyte differentiation through activation of the ERK1/2 and C/EBPβ pathway and increased the expression of adipokines. These data suggest SPATA4 can regulate lipid accumulation in a tissue-specific manner and improve aging-induced dysmetabolic syndromes. Clarifying the mechanism of SPATA4 functioning in lipid metabolism might provide novel therapeutic targets for disease interventions.

PMID: 33314576 [PubMed - in process]

Cellular senescence in ageing: from mechanisms to therapeutic opportunities.

Nat Rev Mol Cell Biol. 2021 02;22(2):75-95

Authors: Di Micco R, Krizhanovsky V, Baker D, d'Adda di Fagagna F

Abstract
Cellular senescence, first described in vitro in 1961, has become a focus for biotech companies that target it to ameliorate a variety of human conditions. Eminently characterized by a permanent proliferation arrest, cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. Cellular senescence can also be a controlled programme occurring in diverse biological processes, including embryonic development. Senescent cell extrinsic activities, broadly related to the activation of a senescence-associated secretory phenotype, amplify the impact of cell-intrinsic proliferative arrest and contribute to impaired tissue regeneration, chronic age-associated diseases and organismal ageing. This Review discusses the mechanisms and modulators of cellular senescence establishment and induction of a senescence-associated secretory phenotype, and provides an overview of cellular senescence as an emerging opportunity to intervene through senolytic and senomorphic therapies in ageing and ageing-associated diseases.

PMID: 33328614 [PubMed - indexed for MEDLINE]

Modeling the human aging transcriptome across tissues, health status, and sex.

Aging Cell. 2021 Jan;20(1):e13280

Authors: Shokhirev MN, Johnson AA

Abstract
Aging in humans is an incredibly complex biological process that leads to increased susceptibility to various diseases. Understanding which genes are associated with healthy aging can provide valuable insights into aging mechanisms and possible avenues for therapeutics to prolong healthy life. However, modeling this complex biological process requires an enormous collection of high-quality data along with cutting-edge computational methods. Here, we have compiled a large meta-analysis of gene expression data from RNA-Seq experiments available from the Sequence Read Archive. We began by reprocessing more than 6000 raw samples-including mapping, filtering, normalization, and batch correction-to generate 3060 high-quality samples spanning a large age range and multiple different tissues. We then used standard differential expression analyses and machine learning approaches to model and predict aging across the dataset, achieving an R2 value of 0.96 and a root-mean-square error of 3.22 years. These models allow us to explore aging across health status, sex, and tissue and provide novel insights into possible aging processes. We also explore how preprocessing parameters affect predictions and highlight the reproducibility limits of these machine learning models. Finally, we develop an online tool for predicting the ages of human transcriptomic samples given raw gene expression counts. Together, this study provides valuable resources and insights into the transcriptomics of human aging.

PMID: 33336875 [PubMed - in process]