2023 Articles

Moqri M, Herzog C, Poganik JR; Biomarkers of Aging Consortium; Justice J, Belsky DW, Higgins-Chen A, Moskalev A, Fuellen G, Cohen AA, Bautmans I, Widschwendter M, Ding J, Fleming A, Mannick J, Han JJ, Zhavoronkov A, Barzilai N, Kaeberlein M, Cummings S, Kennedy BK, Ferrucci L, Horvath S, Verdin E, Maier AB, Snyder MP, Sebastiano V, Gladyshev VN. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell.  doi: 10.1016/j.cell.2023.08.003.

AbstractWith the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice. More Information

Tyshkovskiy A, Ma S, Shindyapina AV, Tikhonov S, Lee SG, Bozaykut P, Castro JP, Seluanov A, Schork NJ, Gorbunova V, Dmitriev SE, Miller RA, Gladyshev VN. (2023). Distinct longevity mechanisms across and within species and their association with aging. Cell.   doi: 10.1016/j.cell.2023.05.002.

AbstractLifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions. More Information

Liu W, Zhu P, Li M, Li Z, Yu Y, Liu G, Du J, Wang X, Yang J, Tian R, Seim I, Kaya A, Li M, Li M, Gladyshev VN, Zhou X.(2023). Large-scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals EMBO J.   doi: 10.15252/embj.2022112740.

AbstractLifespan varies significantly among mammals, with more than 100-fold difference between the shortest and longest living species. This natural difference may uncover the evolutionary forces and molecular features that define longevity. To understand the relationship between gene expression variation and longevity, we conducted a comparative transcriptomics analysis of liver, kidney, and brain tissues of 103 mammalian species. We found that few genes exhibit common expression patterns with longevity in the three organs analyzed. However, pathways related to translation fidelity, such as nonsense-mediated decay and eukaryotic translation elongation, correlated with longevity across mammals. Analyses of selection pressure found that selection intensity related to the direction of longevity-correlated genes is inconsistent across organs. Furthermore, expression of methionine restriction-related genes correlated with longevity and was under strong selection in long-lived mammals, suggesting that a common strategy is utilized by natural selection and artificial intervention to control lifespan. Our results indicate that lifespan regulation via gene expression is driven through polygenic and indirect natural selection. More Information

Ogrodnik M, Gladyshev VN.(2023). The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations. Nat Aging.   doi: 10.1038/s43587-023-00447-5.

AbstractWith recent rapid progress in research on aging, there is increasing evidence that many features commonly considered to be mechanisms or drivers of aging in fact represent adaptations. Here, we examine several such features, including cellular senescence, epigenetic aging and stem cell alterations. We draw a distinction between the causes and consequences of aging and define short-term consequences as ‘responses’ and long-term ones as ‘adaptations’. We also discuss ‘damaging adaptations’, which despite having beneficial effects in the short term, lead to exacerbation of the initial insult and acceleration of aging. Features commonly recognized as ‘basic mechanisms of the aging process’ are critically examined for the possibility of their adaptation-driven emergence from processes such as cell competition and the wound-like features of the aging body. Finally, we speculate on the meaning of these interactions for the aging process and their relevance for the development of antiaging interventions. More Information

Yang JH, Petty CA, Dixon-McDougall T, Lopez MV, Tyshkovskiy A, Maybury-Lewis S, Tian X, Ibrahim N, Chen Z, Griffin PT, Arnold M, Li J, Martinez OA, Behn A, Rogers-Hammond R, Angeli S, Gladyshev VN, Sinclair DA. (2023). Chemically induced reprogramming to reverse cellular aging. Aging (Albany NY).   doi: 10.18632/aging.204896.

AbstractA hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means. More Information

Lu AT, Fei Z, Haghani A, Robeck TR, Zoller JA, Li CZ, Lowe R, Yan Q, Zhang J, Vu H, Ablaeva J, Acosta-Rodriguez VA, Adams DM, Almunia J, Aloysius A, Ardehali R, Arneson A, Baker CS, Banks G, Belov K, Bennett NC, Black P, Blumstein DT, Bors EK, Breeze CE, Brooke RT, Brown JL, Carter GG, Caulton A, Cavin JM, Chakrabarti L, Chatzistamou I, Chen H, Cheng K, Chiavellini P, Choi OW, Clarke SM, Cooper LN, Cossette ML, Day J, DeYoung J, DiRocco S, Dold C, Ehmke EE, Emmons CK, Emmrich S, Erbay E, Erlacher-Reid C, Faulkes CG, Ferguson SH, Finno CJ, Flower JE, Gaillard JM, Garde E, Gerber L, Gladyshev VN, Gorbunova V, Goya RG, Grant MJ, Green CB, Hales EN, Hanson MB, Hart DW, Haulena M, Herrick K, Hogan AN, Hogg CJ, Hore TA, Huang T, Izpisua Belmonte JC, Jasinska AJ, Jones G, Jourdain E, Kashpur O, Katcher H, Katsumata E, Kaza V, Kiaris H, Kobor MS, Kordowitzki P, Koski WR, Krützen M, Kwon SB, Larison B, Lee SG, Lehmann M, Lemaitre JF, Levine AJ, Li C, Li X, Lim AR, Lin DTS, Lindemann DM, Little TJ, Macoretta N, Maddox D, Matkin CO, Mattison JA, McClure M, Mergl J, Meudt JJ, Montano GA, Mozhui K, Munshi-South J, Naderi A, Nagy M, Narayan P, Nathanielsz PW, Nguyen NB, Niehrs C, O’Brien JK, O’Tierney Ginn P, Odom DT, Ophir AG, Osborn S, Ostrander EA, Parsons KM, Paul KC, Pellegrini M, Peters KJ, Pedersen AB, Petersen JL, Pietersen DW, Pinho GM, Plassais J, Poganik JR, Prado NA, Reddy P, Rey B, Ritz BR, Robbins J, Rodriguez M, Russell J, Rydkina E, Sailer LL, Salmon AB, Sanghavi A, Schachtschneider KM, Schmitt D, Schmitt T, Schomacher L, Schook LB, Sears KE, Seifert AW, Seluanov A, Shafer ABA, Shanmuganayagam D, Shindyapina AV, Simmons M, Singh K, Sinha I, Slone J, Snell RG, Soltanmaohammadi E, Spangler ML, Spriggs MC, Staggs L, Stedman N, Steinman KJ, Stewart DT, Sugrue VJ, Szladovits B, Takahashi JS, Takasugi M, Teeling EC, Thompson MJ, Van Bonn B, Vernes SC, Villar D, Vinters HV, Wallingford MC, Wang N, Wayne RK, Wilkinson GS, Williams CK, Williams RW, Yang XW, Yao M, Young BG, Zhang B, Zhang Z, Zhao P, Zhao Y, Zhou W, Zimmermann J, Ernst J, Raj K, Horvath S.(2023). Universal DNA methylation age across mammalian tissues. Nat Aging.   doi: 10.1038/s43587-023-00462-6.

AbstractAging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals. More Information

Tyshkovskiy A, Zhang S, Gladyshev VN. (2023). Accelerated transcriptional elongation during aging impairs longevity. Cell Res.   doi: 10.1038/s41422-023-00829-9.

AbstractIncreased transcriptional errors in aged organisms have been demonstrated for multiple species; however, mechanistic details remained elusive. In a recent issue of Nature, Debès et al. reveal a novel form of aging-associated molecular damage, demonstrating that Pol II transcriptional elongation rate increases with age, presumably due to reduced nucleosomal density, whereas targeted reduction of Pol II speed can partially ameliorate this deleterious phenotype and extend lifespan in animals, such as roundworms and fruit flies. More Information

Haghani A, Li CZ, Robeck TR, Zhang J, Lu AT, Ablaeva J, Acosta-Rodríguez VA, Adams DM, Alagaili AN, Almunia J, Aloysius A, Amor NMS, Ardehali R, Arneson A, Baker CS, Banks G, Belov K, Bennett NC, Black P, Blumstein DT, Bors EK, Breeze CE, Brooke RT, Brown JL, Carter G, Caulton A, Cavin JM, Chakrabarti L, Chatzistamou I, Chavez AS, Chen H, Cheng K, Chiavellini P, Choi OW, Clarke S, Cook JA, Cooper LN, Cossette ML, Day J, DeYoung J, Dirocco S, Dold C, Dunnum JL, Ehmke EE, Emmons CK, Emmrich S, Erbay E, Erlacher-Reid C, Faulkes CG, Fei Z, Ferguson SH, Finno CJ, Flower JE, Gaillard JM, Garde E, Gerber L, Gladyshev VN, Goya RG, Grant MJ, Green CB, Hanson MB, Hart DW, Haulena M, Herrick K, Hogan AN, Hogg CJ, Hore TA, Huang T, Izpisua Belmonte JC, Jasinska AJ, Jones G, Jourdain E, Kashpur O, Katcher H, Katsumata E, Kaza V, Kiaris H, Kobor MS, Kordowitzki P, Koski WR, Krützen M, Kwon SB, Larison B, Lee SG, Lehmann M, Lemaître JF, Levine AJ, Li X, Li C, Lim AR, Lin DTS, Lindemann DM, Liphardt SW, Little TJ, Macoretta N, Maddox D, Matkin CO, Mattison JA, McClure M, Mergl J, Meudt JJ, Montano GA, Mozhui K, Munshi-South J, Murphy WJ, Naderi A, Nagy M, Narayan P, Nathanielsz PW, Nguyen NB, Niehrs C, Nyamsuren B, O’Brien JK, Ginn PO, Odom DT, Ophir AG, Osborn S, Ostrander EA, Parsons KM, Paul KC, Pedersen AB, Pellegrini M, Peters KJ, Petersen JL, Pietersen DW, Pinho GM, Plassais J, Poganik JR, Prado NA, Reddy P, Rey B, Ritz BR, Robbins J, Rodriguez M, Russell J, Rydkina E, Sailer LL, Salmon AB, Sanghavi A, Schachtschneider KM, Schmitt D, Schmitt T, Schomacher L, Schook LB, Sears KE, Seifert AW, Shafer ABA, Shindyapina AV, Simmons M, Singh K, Sinha I, Slone J, Snell RG, Soltanmohammadi E, Spangler ML, Spriggs M, Staggs L, Stedman N, Steinman KJ, Stewart DT, Sugrue VJ, Szladovits B, Takahashi JS, Takasugi M, Teeling EC, Thompson MJ, Van Bonn B, Vernes SC, Villar D, Vinters HV, Vu H, Wallingford MC, Wang N, Wilkinson GS, Williams RW, Yan Q, Yao M, Young BG, Zhang B, Zhang Z, Zhao Y, Zhao P, Zhou W, Zoller JA, Ernst J, Seluanov A, Gorbunova V, Yang XW, Raj K, Horvath S.(2023). DNA methylation networks underlying mammalian traits. Science.   doi: 10.1126/science.abq5693.

AbstractUsing DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species. More Information

Vijg J, Schumacher B, Abakir A, Antonov M, Bradley C, Cagan A, Church G, Gladyshev VN, Gorbunova V, Maslov AY, Reik W, Sharifi S, Suh Y, Walsh K (2023). Mitigating age-related somatic mutation burden. Trends Mol Med   doi: 10.1016/j.molmed.2023.04.002.

AbstractGenomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo, random somatic mutations as a cause of aging. More Information

Mitchell W, Goeminne L, Tyshkovskiy A, Zhang S, Paulo J, Pierce K, Choy A, Clish C, Gygi S, Gladyshev VN (2023). Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation. bioRxiv   doi: https://doi.org/10.1101/2023.06.30.546730

AbstractPartial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems, and warrant further investigation into adapting these approaches for in vivo age reversal. More Information

Zhang B, Lee DE, Trapp A, Tyshkovskiy A, Lu AT, Bareja A, Kerepesi C, McKay LK, Shindyapina AV, Dmitriev SE, Baht GS, Horvath S, Gladyshev VN, White JP. (2023). Multi-omic rejuvenation and life span extension on exposure to youthful circulation. Nature Aging   doi: 10.1038/s43587-023-00451-9.

AbstractHeterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span. More Information

Poganik JR, Zhang B, Baht GS, Tyshkovskiy A, Deik A, Kerepesi C, Yim SH, Lu AT, Haghani A, Gong T, Hedman AM, Andolf E, Pershagen G, Almqvist C, Clish CB, Horvath S, White JP, Gladyshev VN. (2023). Biological age is increased by stress and restored upon recovery. Cell Metabolism.   doi: 10.1016/j.cmet.2023.03.015.

AbstractAging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions. More Information

Ying K, Tyshkovskiy A, Trapp A, Liu H, Moqri M, Kerepesi C, Gladyshev VN (2023). ClockBase: a comprehensive platform for biological age profiling in human and mouse. bioRxiv.   doi: 10.1101/2023.02.28.530532

AbstractAging represents the greatest risk factor for chronic diseases and mortality, but to understand it, we need the ability to measure biological age. In recent years, many machine learning algorithms based on omics data, termed aging clocks, have been developed that can accurately predict the age of biological samples. However, there is currently no resource for systematic profiling of biological age. Here, we describe ClockBase, a platform that features biological age estimates based on multiple aging clock models applied to more than 2,000 DNA methylation datasets and nearly 200,000 samples. We further provide an online interface for statistical analyses and visualization of the data. To show how this resource could facilitate the discovery of biological age-modifying factors, we describe a novel anti-aging drug candidate, zebularine, which reduces the biological age estimates based on all aging clock models tested. We also show that pulmonary fibrosis accelerates epigenetic age. Together, ClockBase provides a resource for the scientific community to quantify and explore biological ages of samples, thus facilitating discovery of new longevity interventions and age-accelerating conditions. More Information

Yang JH, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, Blanchette M, Munding EM, Bhakta M, Chew YC, Guo W, Yang X, Maybury-Lewis S, Tian X, Ross JM, Coppotelli G, Meer MV, Rogers-Hammond R, Sinclair DA (2023). Loss of epigenetic information as a cause of mammalian aging. Cell.   doi: 10.1016/j.cell.2022.12.027

AbstractAll living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called “ICE” (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging. More Information

Moldakozhayev A, & Gladyshev VN (2023). Metabolism, homeostasis, and aging. Trends Endocrinol Metab.   doi: 10.1016/j.tem.2023.01.003

AbstractWe propose a two-mode (pursuit/maintenance) model of metabolism defined by usable resource availability. Pursuit, consisting of anabolism and catabolism, dominates when usable resources are plentiful and leads to the generation of metabolic waste. In turn, maintenance of a system is activated by elevated metabolic waste during resource depletion. Interaction with the environment results in pendulum-like swings between these metabolic states in thriveless attempts to maintain the least deleterious organismal state – ephemeral homeostasis. Imperfectness of biological processes during these attempts supports the accumulation of the deleteriome, driving organismal aging. We discuss how metabolic adjustment by the environment and resource stabilization may modulate healthspan and lifespan. More Information

Bennett DF, Goyala A, Statzer C, Beckett CW, Tyshkovskiy A, Gladyshev VN, Ewald CY, & de Magalhães JP (2023). Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1-imidazoline receptor. Aging Cell.   doi: 10.1111/acel.13774

AbstractRepurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we searched for known compounds that elicit a similar gene expression signature to caloric restriction and identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target. Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to calorically restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,2,3/SKN-1. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound. More Information