Aging, Lifespan & Longevity

Up-regulation of cofilin-1 in cell senescence associates with morphological change and p27kip1 -mediated growth delay.

Aging Cell. 2021 Jan;20(1):e13288

Authors: Tsai CH, Chang CY, Lin BZ, Wu YL, Wu MH, Lin LT, Huang WC, Holz JD, Sheu TJ, Lee JS, Kitsis RN, Tai PH, Lee YJ

Abstract
Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remains to be addressed. Here, we demonstrated, after a survey of various actin-binding proteins, that the post-translational up-regulation of cofilin-1 was essential for the reduced rate of actin depolymerization morphological enlargement in senescent cells. Additionally, up-regulated cofilin-1 mainly existed in the serine-3 phosphorylated form, according to the 2D gel immunoblotting assay. The up-regulation of cofilin-1 was also detected in aged mammalian tissues. The over-expression of wild-type cofilin-1 and constitutively phosphorylated cofilin-1 promoted cell senescence with an increased cell size. Additionally, senescent phenotypes were also reduced by knockdown of total cofilin-1, which led to a decrease in phosphorylated cofilin-1. The senescence induced by the over-expression of cofilin-1 was dependent on p27Kip1 , but not on the p53 and p16INK4 expressions. The knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that the over-expression of cofilin-1 induced the expression of p27Kip1 through transcriptional suppression of the transcriptional enhancer factors domain 1 (TEAD1) transcription factor. The TEAD1 transcription factor played a transrepressive role in the p27Kip1  gene promoter, as determined by the promoter deletion reporter gene assay. Interestingly, the down-regulation of TEAD1 was accompanied by the up-regulation of cofilin-1 in senescence. The knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and senescent phenotypes, respectively. Taken together, the current data suggest that cofilin-1/TEAD1/p27Kip1 signaling is involved in senescence-related morphological change and growth arrest.

PMID: 33336885 [PubMed - in process]

A ubiquitin switch controls autocatalytic inactivation of the DNA-protein crosslink repair protease SPRTN.

Nucleic Acids Res. 2021 01 25;49(2):902-915

Authors: Zhao S, Kieser A, Li HY, Reinking HK, Weickert P, Euteneuer S, Yaneva D, Acampora AC, Götz MJ, Feederle R, Stingele J

Abstract
Repair of covalent DNA-protein crosslinks (DPCs) by the metalloprotease SPRTN prevents genome instability, premature aging and carcinogenesis. SPRTN is specifically activated by DNA structures containing single- and double-stranded features, but degrades the protein components of DPCs promiscuously and independent of amino acid sequence. This lack of specificity is useful to target diverse protein adducts, however, it requires tight control in return, in order to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover the components and principles of a ubiquitin switch, which negatively regulates SPRTN. We demonstrate that monoubiquitylation is induced in an E3 ligase-independent manner and, in contrast to previous assumptions, does not control chromatin access of the enzyme. Data obtained in cells and in vitro reveal that monoubiquitylation induces inactivation of the enzyme by triggering autocatalytic cleavage in trans while also priming SPRTN for proteasomal degradation in cis. Finally, we show that the deubiquitylating enzyme USP7 antagonizes this negative control of SPRTN in the presence of DPCs.

PMID: 33348378 [PubMed - indexed for MEDLINE]

NAD+ metabolism and its roles in cellular processes during ageing.

Nat Rev Mol Cell Biol. 2021 02;22(2):119-141

Authors: Covarrubias AJ, Perrone R, Grozio A, Verdin E

Abstract
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.

PMID: 33353981 [PubMed - indexed for MEDLINE]

Similarities and interplay between senescent cells and macrophages.

J Cell Biol. 2021 Feb 01;220(2):

Authors: Behmoaras J, Gil J

Abstract
Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage-senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

PMID: 33355620 [PubMed - in process]

Mitochondrial DNA in extracellular vesicles declines with age.

Aging Cell. 2021 Jan;20(1):e13283

Authors: Lazo S, Noren Hooten N, Green J, Eitan E, Mode NA, Liu QR, Zonderman AB, Ezike N, Mattson MP, Ghosh P, Evans MK

Abstract
The mitochondrial free radical theory of aging suggests that accumulating oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a central role in aging. Circulating cell-free mtDNA (ccf-mtDNA) isolated from blood may be a biomarker of disease. Extracellular vesicles (EVs) are small (30-400 nm), lipid-bound vesicles capable of shuttling proteins, nucleic acids, and lipids as part of intercellular communication systems. Here, we report that a portion of ccf-mtDNA in plasma is encapsulated in EVs. To address whether EV mtDNA levels change with human age, we analyzed mtDNA in EVs from individuals aged 30-64 years cross-sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner.

PMID: 33355987 [PubMed - in process]

Peripheral inflammation preceeding ischemia impairs neuronal survival through mechanisms involving miR-127 in aged animals.

Aging Cell. 2021 Jan;20(1):e13287

Authors: Loppi S, Korhonen P, Bouvy-Liivrand M, Caligola S, Turunen TA, Turunen MP, Hernandez de Sande A, Kołosowska N, Scoyni F, Rosell A, García-Berrocoso T, Lemarchant S, Dhungana H, Montaner J, Koistinaho J, Kanninen KM, Kaikkonen MU, Giugno R, Heinäniemi M, Malm T

Abstract
Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke-induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron-specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co-existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR-127, that is highly neuronal, to be associated with increased cell death in the aged, LPS-injected ischemic mice. Target prediction tools indicate that miR-127 interacts with several basally expressed neuronal genes, and of these we verify miR-127 binding to Psmd3. Finally, we report reduced expression of miR-127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.

PMID: 33369048 [PubMed - in process]

Effects of myocardial ischemia/reperfusion injury on plasma metabolomic profile during aging.

Aging Cell. 2021 Jan;20(1):e13284

Authors: de Lucia C, Piedepalumbo M, Wang L, Carnevale Neto F, Raftery D, Gao E, Praticò D, Promislow DEL, Koch WJ

Abstract
BACKGROUND: Heart disease is a frequent cause of hospitalization and mortality for elderly patients. A common feature of both heart disease and aging itself is the involvement of metabolic organ alterations ultimately leading to changes in circulating metabolite levels. However, the specific contribution of aging and ischemic injury to the metabolic dysregulation occurring in older adults with ischemic heart disease is still unknown.
AIM: To evaluate the effects of aging and ischemia/reperfusion (I/R) injury on plasma metabolomic profiling in mice.
METHODS: Young and aged mice were subjected to a minimally invasive model of I/R injury or sham operation. Complete evaluation of cardiac function and untargeted plasma metabolomics analysis were performed.
RESULTS: We confirmed that aged mice from the sham group had impaired cardiac function and augmented left ventricular (LV) dimensions compared to young sham-operated mice. Further, we found that ischemic injury did not drastically reduce LV systolic/diastolic function and dyssynchrony in aged compared to young mice. Using an untargeted metabolomics approach focused on aqueous metabolites, we found that ischemic injury does not affect the plasma metabolomic profile either in young or old mice. Our data also demonstrate that age significantly affects circulating metabolite levels (predominantly amino acids, phospholipids and organic acids) and perturbs several pathways involved in amino acid, glucid and nucleic acid metabolism as well as pyridoxal-5'-phosphate salvage pathway in both sham and ischemic mice.
CONCLUSIONS: Our approach increases our understanding of age-associated plasma metabolomic signatures in mice with and without heart disease excluding confounding factors related to metabolic comorbidities.

PMID: 33377274 [PubMed - in process]

Is exercise a senolytic medicine? A systematic review.

Aging Cell. 2021 Jan;20(1):e13294

Authors: Chen XK, Yi ZN, Wong GT, Hasan KMM, Kwan JS, Ma AC, Chang RC

Abstract
Cellular senescence, a state of irreversible growth arrest triggered by various stressors, engages in a category of pathological processes, whereby senescent cells accumulate in mitotic tissues. Senolytics as novel medicine against aging and various diseases through the elimination of senescent cells has emerged rapidly in recent years. Exercise is a potent anti-aging and anti-chronic disease medicine, which has shown the capacity to lower the markers of cellular senescence over the past decade. However, whether exercise is a senolytic medicine for aging and various diseases remains unclear. Here, we have conducted a systematic review of the published literature studying the senolytic effects of exercise or physical activity on senescent cells under various states in both human and animal models. Exercise can reduce the markers of senescent cells in healthy humans, while it lowered the markers of senescent cells in obese but not healthy animals. The discrepancy between human and animal studies may be due to the relatively small volume of research and the variations in markers of senescent cells, types of cells/tissues, and health conditions. These findings suggest that exercise has senolytic properties under certain conditions, which warrant further investigations.

PMID: 33378138 [PubMed - in process]

Diacetyl odor shortens longevity conferred by food deprivation in C. elegans via downregulation of DAF-16/FOXO.

Aging Cell. 2021 Jan;20(1):e13300

Authors: Park S, Artan M, Jeong DE, Park HH, Son HG, Kim SS, Jung Y, Choi Y, Lee JI, Kim K, Lee SV

Abstract
Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors.

PMID: 33382195 [PubMed - in process]

Adaptability of the ubiquitin-proteasome system to proteolytic and folding stressors.

J Cell Biol. 2021 Mar 01;220(3):

Authors: Work JJ, Brandman O

Abstract
Aging, disease, and environmental stressors are associated with failures in the ubiquitin-proteasome system (UPS), yet a quantitative understanding of how stressors affect the proteome and how the UPS responds is lacking. Here we assessed UPS performance and adaptability in yeast under stressors using quantitative measurements of misfolded substrate stability and stress-dependent UPS regulation by the transcription factor Rpn4. We found that impairing degradation rates (proteolytic stress) and generating misfolded proteins (folding stress) elicited distinct effects on the proteome and on UPS adaptation. Folding stressors stabilized proteins via aggregation rather than overburdening the proteasome, as occurred under proteolytic stress. Still, the UPS productively adapted to both stressors using separate mechanisms: proteolytic stressors caused Rpn4 stabilization while folding stressors increased RPN4 transcription. In some cases, adaptation completely prevented loss of UPS substrate degradation. Our work reveals the distinct effects of proteotoxic stressors and the versatility of cells in adapting the UPS.

PMID: 33382395 [PubMed - in process]

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ.

Aging Cell. 2021 Jan;20(1):e13295

Authors: Webb LMC, Fra-Bido S, Innocentin S, Matheson LS, Attaf N, Bignon A, Novarino J, Fazilleau N, Linterman MA

Abstract
Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre-Tfh) but no associated increase in germinal centre (GC)-Tfh cells in aged mice, suggesting age-driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch-associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age-associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age-induced changes in T-cell activation that affects the differentiation and ultimately the function of effector T cells.

PMID: 33387451 [PubMed - in process]

Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice.

Aging Cell. 2021 Jan;20(1):e13285

Authors: Squarzoni S, Schena E, Sabatelli P, Mattioli E, Capanni C, Cenni V, D'Apice MR, Andrenacci D, Sarli G, Pellegrino V, Festa A, Baruffaldi F, Storci G, Bonafè M, Barboni C, Sanapo M, Zaghini A, Lattanzi G

Abstract
Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G / G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders.

PMID: 33393189 [PubMed - in process]

Role of sirtuins in bone biology: Potential implications for novel therapeutic strategies for osteoporosis.

Aging Cell. 2021 Jan 04;:e13301

Authors: Li Q, Cheng JC, Jiang Q, Lee WY

Abstract
The decline in bone mass and bone strength and musculoskeletal problems associated with aging constitute a major challenge for affected individuals and the healthcare system globally. Sirtuins 1-7 (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide-dependent deacetylases with remarkable abilities to promote longevity and counteract age-related diseases. Sirtuin knockout and transgenic models have provided novel insights into the function and signaling of these proteins in bone homeostasis. Studies have revealed that sirtuins play a critical role in normal skeletal development and homeostasis through their direct action on bone cells and that their dysregulation might contribute to different bone diseases. Preclinical studies have demonstrated that mice treated with sirtuin agonists show protection against age-related, postmenopausal, and immobilization-induced osteoporosis. These findings suggest that sirtuins could be potential targets for the modulation of the imbalance in bone remodeling and treatment of osteoporosis and other bone disorders. The aim of this review was to provide a comprehensive updated review of the current knowledge on sirtuin biology, focusing specifically on their roles in bone homeostasis and osteoporosis, and potential pharmacological interventions targeting sirtuins for the treatment of osteoporosis.

PMID: 33393735 [PubMed - as supplied by publisher]

Childhood self-control forecasts the pace of midlife aging and preparedness for old age.

Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):

Authors: Richmond-Rakerd LS, Caspi A, Ambler A, d'Arbeloff T, de Bruine M, Elliott M, Harrington H, Hogan S, Houts RM, Ireland D, Keenan R, Knodt AR, Melzer TR, Park S, Poulton R, Ramrakha S, Rasmussen LJH, Sack E, Schmidt AT, Sison ML, Wertz J, Hariri AR, Moffitt TE

Abstract
The ability to control one's own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children's self-control across their first decade of life using a multi-occasion/multi-informant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children's self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals' self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.

PMID: 33397808 [PubMed - in process]

Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases.

Nat Commun. 2021 01 04;12(1):49

Authors: Pérez-Jiménez MM, Monje-Moreno JM, Brokate-Llanos AM, Venegas-Calerón M, Sánchez-García A, Sansigre P, Valladares A, Esteban-García S, Suárez-Pereira I, Vitorica J, Ríos JJ, Artal-Sanz M, Carrión ÁM, Muñoz MJ

Abstract
Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer's disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

PMID: 33397961 [PubMed - indexed for MEDLINE]

The aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2.

Nat Commun. 2021 01 04;12(1):4

Authors: Chow RD, Majety M, Chen S

Abstract
Age is a major risk factor for severe coronavirus disease-2019 (COVID-19). Here, we interrogate the transcriptional features and cellular landscape of the aging human lung. By intersecting these age-associated changes with experimental data on SARS-CoV-2, we identify several factors that may contribute to the heightened severity of COVID-19 in older populations. The aging lung is transcriptionally characterized by increased cell adhesion and stress responses, with reduced mitochondria and cellular replication. Deconvolution analysis reveals that the proportions of alveolar type 2 cells, proliferating basal cells, goblet cells, and proliferating natural killer/T cells decrease with age, whereas alveolar fibroblasts, pericytes, airway smooth muscle cells, endothelial cells and IGSF21+ dendritic cells increase with age. Several age-associated genes directly interact with the SARS-CoV-2 proteome. Age-associated genes are also dysregulated by SARS-CoV-2 infection in vitro and in patients with severe COVID-19. These analyses illuminate avenues for further studies on the relationship between age and COVID-19.

PMID: 33397975 [PubMed - indexed for MEDLINE]

Intestinal differentiation involves cleavage of histone H3 N-terminal tails by multiple proteases.

Nucleic Acids Res. 2021 01 25;49(2):791-804

Authors: Ferrari KJ, Amato S, Noberini R, Toscani C, Fernández-Pérez D, Rossi A, Conforti P, Zanotti M, Bonaldi T, Tamburri S, Pasini D

Abstract
The proteolytic cleavage of histone tails, also termed histone clipping, has been described as a mechanism for permanent removal of post-translational modifications (PTMs) from histone proteins. Such activity has been ascribed to ensure regulatory function in key cellular processes such as differentiation, senescence and transcriptional control, for which different histone-specific proteases have been described. However, all these studies were exclusively performed using cell lines cultured in vitro and no clear evidence that histone clipping is regulated in vivo has been reported. Here we show that histone H3 N-terminal tails undergo extensive cleavage in the differentiated cells of the villi in mouse intestinal epithelium. Combining biochemical methods, 3D organoid cultures and in vivo approaches, we demonstrate that intestinal H3 clipping is the result of multiple proteolytic activities. We identified Trypsins and Cathepsin L as specific H3 tail proteases active in small intestinal differentiated cells and showed that their proteolytic activity is differentially affected by the PTM pattern of histone H3 tails. Together, our findings provide in vivo evidence of H3 tail proteolysis in mammalian tissues, directly linking H3 clipping to cell differentiation.

PMID: 33398338 [PubMed - indexed for MEDLINE]

Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats.

Aging Cell. 2021 Jan 05;:e13292

Authors: Da Silva JT, Tricou C, Zhang Y, Tofighbakhsh A, Seminowicz DA, Ro JY

Abstract
Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre-OA) and during the early and late phases of monosodium iodoacetate-induced OA in rats. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients.

PMID: 33400367 [PubMed - as supplied by publisher]

Equivalent DNA methylation variation between monozygotic co-twins and unrelated individuals reveals universal epigenetic inter-individual dissimilarity.

Genome Biol. 2021 Jan 05;22(1):18

Authors: Planterose Jiménez B, Liu F, Caliebe A, Montiel González D, Bell JT, Kayser M, Vidaki A

Abstract
BACKGROUND: Although the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now.
RESULTS: We enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue.
CONCLUSIONS: We have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.

PMID: 33402197 [PubMed - in process]

N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.

Genome Biol. 2021 Jan 05;22(1):17

Authors: Shafik AM, Zhang F, Guo Z, Dai Q, Pajdzik K, Li Y, Kang Y, Yao B, Wu H, He C, Allen EG, Duan R, Jin P

Abstract
BACKGROUND: N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain.
RESULTS: We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer's disease, which is correlated with reduced protein levels.
CONCLUSIONS: Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer's disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

PMID: 33402207 [PubMed - in process]